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Sample records for maximal tolerated dose

  1. Consideration of the volume dependence of tolerance doses

    International Nuclear Information System (INIS)

    Gremmel, H.; Wendhausen, H.

    1977-01-01

    A general formula for consideration of the dependence of tolerance doses upon volume is obtained by mathematical evaluation of known skin tolerance doses. The validity for different organs is verified using available data of literature. It is recommended to introduce the volume dependence into the Ellis-formula for tolerance doses. (orig.) [de

  2. Tolerance of the human spinal cord to single dose radiosurgery

    International Nuclear Information System (INIS)

    Ryu, S.; Zhu, G.; Yin, F.-F.; Ajlouni, M.; Kim, J.H.

    2003-01-01

    Tolerance of the spinal cord to the single dose of radiation is not well defined. Although there are cases of human spinal cord tolerance from re-irradiation to the same cord level, the information about the tolerance of human spinal cord to single large dose of radiosurgery is not available. We carried out spinal radiosurgery to treat spinal metastasis and studied the single dose tolerance of the human spinal cord in an ongoing dose escalation paradigm. A total of 39 patients with 48 lesions of spinal metastasis were treated with single dose radiosurgery at Henry Ford Hospital. The radiosurgery dose was escalated from 8 Gy to 16 Gy at 2 Gy increment. The radiation dose was prescribed to periphery of the spinal tumor. The radiation dose to the spinal cord was estimated by computerized dosimetry. The median follow-up time was 10 months (range 6-18 months) from the radiosurgery. The endpoint of the study was to demonstrate the efficacy of the spinal radiosurgery and to determine the tolerance of human spinal cord to single dose radiosurgery. The dose to the spinal cord was generally less than 50 % of the prescribed radiation dose. The volume of the spinal cord that received higher than this dose was less than 20 % of the anterior portion of the spinal cord. Maximum single dose of 8 Gy was delivered to the anterior 20 % of the spinal cord in this dose escalation study. The dose volume histogram will be presented. There was no acute or subacute radiation toxicity detected clinically and radiologically during the maximum follow-up of 20 months. Further dose escalation is in progress. The single tolerance dose of the human spinal cord appears to be at least 8 Gy when it was given to the 20 % of the cord volume, although the duration of follow up is not long enough to detect severe late cord toxicity. This study offers a valuable radiobiological basis of the normal spinal cord tolerance, and opens spinal radiosurgery as a safe treatment for spinal metastasis

  3. The irradiation tolerance dose of the proximal vagina

    International Nuclear Information System (INIS)

    Au, Samuel P.; Grigsby, Perry W.

    2003-01-01

    Purpose: The purpose of this investigation was to determine the irradiation tolerance level and complication rates of the proximal vagina to combined external irradiation and low dose rate (LDR) brachytherapy. Also, the mucosal tolerance for fractionated high dose rate (HDR) brachytherapy is further projected based on the biological equivalent dose (BED) of LDR for an acceptable complication rate. Materials and methods: Two hundred seventy-four patients with stages I-IV cervical carcinoma treated with irradiation therapy alone from 1987 to 1997 were retrospectively reviewed for radiation-associated late sequelae of the proximal vagina. All patients received LDR brachytherapy and 95% also received external pelvic irradiation. Follow-up ranged from 15 to 126 months (median, 43 months). The proximal vagina mucosa dose from a single ovoid (single source) or from both ovoids plus the tandem (all sources), together with the external irradiation dose, were used to derive the probability of a complication using the maximum likelihood logistic regression technique. The BED based on the linear-quadratic model was used to compute the corresponding tolerance levels for LDR or HDR brachytherapy. Results: Grades 1 and 2 complications occurred in 10.6% of patients and Grade 3 complications occurred in 3.6%. There were no Grade 4 complications. Complications occurred from 3 to 71 months (median, 7 months) after completion of irradiation, with over 60% occurring in the first year. By logistic regression analysis, both the mucosal dose from a single ovoid or that from all sources, combined with the external irradiation dose, demonstrate a statistically significant fit to the dose response complication curves (both with P=0.016). The single source dose was highly correlated with the all source dose with a cross-correlation coefficient 0.93. The all source dose was approximately 1.4 times the single source dose. Over the LDR brachytherapy dose rate range, the complication rate was

  4. Radiation therapy tolerance doses for treatment planning

    International Nuclear Information System (INIS)

    Lyman, J.T.

    1987-01-01

    To adequately plan acceptable dose distributions for radiation therapy treatments it is necessary to ensure that normal structures do not receive unacceptable doses. Acceptable doses are generally those that are below a stated tolerance dose for development of some level of complication. To support the work sponsored by the National Cancer Institute, data for the tolerance of normal tissues or organs to low-LET radiation has been compiled from a number of sources. These tolerance dose data are ostensibly for uniform irradiation of all or part of an organ, and are for either 5% (TD 5 ) or 50% (TD 50 ) complication probability. The ''size'' of the irradiated organ is variously stated in terms of the absolute volume or the fraction of the organ volume irradiated, or the area or the length of the treatment field. The accuracy of these data is questionable. Much of the data represent doses that one or several experienced therapists have estimated could be safely given rather than quantitative analyses of clinical observations. Because these data have been obtained from multiple sources with possible different criteria for the definition of a complication, there are sometimes different values for what is apparently the same end point. 20 refs., 1 fig., 1 tab

  5. Objective method to report planner-independent skin/rib maximal dose in balloon-based high dose rate (HDR) brachytherapy for breast cancer

    International Nuclear Information System (INIS)

    Kim, Yongbok; Trombetta, Mark G.

    2011-01-01

    Purpose: An objective method was proposed and compared with a manual selection method to determine planner-independent skin and rib maximal dose in balloon-based high dose rate (HDR) brachytherapy planning. Methods: The maximal dose to skin and rib was objectively extracted from a dose volume histogram (DVH) of skin and rib volumes. A virtual skin volume was produced by expanding the skin surface in three dimensions (3D) external to the breast with a certain thickness in the planning computed tomography (CT) images. Therefore, the maximal dose to this volume occurs on the skin surface the same with a conventional manual selection method. The rib was also delineated in the planning CT images and its maximal dose was extracted from its DVH. The absolute (Abdiff=|D max Man -D max DVH |) and relative (Rediff[%]=100x(|D max Man -D max DVH |)/D max DVH ) maximal skin and rib dose differences between the manual selection method (D max Man ) and the objective method (D max DVH ) were measured for 50 balloon-based HDR (25 MammoSite and 25 Contura) patients. Results: The average±standard deviation of maximal dose difference was 1.67%±1.69% of the prescribed dose (PD). No statistical difference was observed between MammoSite and Contura patients for both Abdiff and Rediff[%] values. However, a statistically significant difference (p value max >90%) compared with lower dose range (D max <90%): 2.16%±1.93% vs 1.19%±1.25% with p value of 0.0049. However, the Rediff[%] analysis eliminated the inverse square factor and there was no statistically significant difference (p value=0.8931) between high and low dose ranges. Conclusions: The objective method using volumetric information of skin and rib can determine the planner-independent maximal dose compared with the manual selection method. However, the difference was <2% of PD, on average, if appropriate attention is paid to selecting a manual dose point in 3D planning CT images.

  6. SU-D-204-02: BED Consistent Extrapolation of Mean Dose Tolerances

    Energy Technology Data Exchange (ETDEWEB)

    Perko, Z; Bortfeld, T; Hong, T; Wolfgang, J; Unkelbach, J [Massachusetts General Hospital, Boston, MA (United States)

    2016-06-15

    Purpose: The safe use of radiotherapy requires the knowledge of tolerable organ doses. For experimental fractionation schemes (e.g. hypofractionation) these are typically extrapolated from traditional fractionation schedules using the Biologically Effective Dose (BED) model. This work demonstrates that using the mean dose in the standard BED equation may overestimate tolerances, potentially leading to unsafe treatments. Instead, extrapolation of mean dose tolerances should take the spatial dose distribution into account. Methods: A formula has been derived to extrapolate mean physical dose constraints such that they are mean BED equivalent. This formula constitutes a modified BED equation where the influence of the spatial dose distribution is summarized in a single parameter, the dose shape factor. To quantify effects we analyzed 14 liver cancer patients previously treated with proton therapy in 5 or 15 fractions, for whom also photon IMRT plans were available. Results: Our work has two main implications. First, in typical clinical plans the dose distribution can have significant effects. When mean dose tolerances are extrapolated from standard fractionation towards hypofractionation they can be overestimated by 10–15%. Second, the shape difference between photon and proton dose distributions can cause 30–40% differences in mean physical dose for plans having the same mean BED. The combined effect when extrapolating proton doses to mean BED equivalent photon doses in traditional 35 fraction regimens resulted in up to 7–8 Gy higher doses than when applying the standard BED formula. This can potentially lead to unsafe treatments (in 1 of the 14 analyzed plans the liver mean dose was above its 32 Gy tolerance). Conclusion: The shape effect should be accounted for to avoid unsafe overestimation of mean dose tolerances, particularly when estimating constraints for hypofractionated regimens. In addition, tolerances established for a given treatment modality cannot

  7. Efficacy and tolerability of high-dose phenobarbital in children with focal seizures.

    Science.gov (United States)

    Okumura, Akihisa; Nakahara, Eri; Ikeno, Mitsuru; Abe, Shinpei; Igarashi, Ayuko; Nakazawa, Mika; Takasu, Michihiko; Shimizu, Toshiaki

    2016-04-01

    We retrospectively reviewed the outcomes of children with focal epilepsy treated with oral high-dose phenobarbital. We reviewed data on children (agedphenobarbital (>5 mg/kg/day to maintain a target serum level >40 μg/mL) for at least 6 months. Seizure frequency was evaluated after phenobarbital titration, and 1 and 2 years after high-dose phenobarbital treatment commenced. Treatment was judged effective when seizure frequencies fell by ⩾75%. Seven boys and eight girls were treated. The median age at commencement of high-dose phenobarbital therapy was 30 months. The maximal serum phenobarbital level ranged from 36.5 to 62.9 μg/mL. High-dose PB was effective in seven. In two patients, treatment was transiently effective, but seizure frequency later returned to the baseline. High-dose PB was ineffective in six. No significant association between effectiveness and any clinical variable was evident. Drowsiness was recorded in nine patients, but no patient developed a behavioral problem or hypersensitivity. Oral high-dose phenobarbital was effective in 7 of 15 patients with focal epilepsy and well tolerated. High-dose PB may be useful when surgical treatment is difficult. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  8. The guinea pig maximization test--with a multiple dose design

    DEFF Research Database (Denmark)

    Andersen, Klaus Ejner; Vølund, A; Frankild, S

    1995-01-01

    The guinea pig maximization test (GPMT) is usually performed with one moderately irritant induction dose of the allergen and gives a qualitative assessment-hazard identification-of the allergenicity of the chemical. We refined the GPMT by applying a multiple dose design and used 30 guinea pigs in...

  9. The guinea pig maximization test--with a multiple dose design

    DEFF Research Database (Denmark)

    Andersen, Klaus Ejner; Vølund, A; Frankild, S

    1995-01-01

    The guinea pig maximization test (GPMT) is usually performed with one moderately irritant induction dose of the allergen and gives a qualitative assessment-hazard identification-of the allergenicity of the chemical. We refined the GPMT by applying a multiple dose design and used 30 guinea pigs...

  10. 45 Gy - tolerance dose spinal cord - dogma or the facts?

    International Nuclear Information System (INIS)

    Maciejewski, B.; Hliniak, A.; Danczak-Ginalska, Z.; Meder, M.; Skolyszewski, J.; Reinfuss, M.; Korzeniowski, S.; Peszynski, J.; Jassem, J.

    1993-01-01

    Dose of 45 Gy as a tolerance dose for spinal cord was questioned based on review of clinical data. Some data show that for conventional fractionation with the dose per fraction of less than 2.0 Gy spinal cord tolerance dose may arise up to 50-55 Gy. This was the base for round-table discussion and the importance of clinical and physical risk factors of postirradiation spinal cord injury was discussed and previous diseases of spinal cord, size of dose per fraction and length of irradiated spinal cord were pointed out as high risk factors. It was concluded that from clinical point of view there is no reason and on need to verify and to increase tolerance dose for spinal cord. (author)

  11. Some thoughts on tolerance, dose, and fractionation in boron neutron capture therapy

    International Nuclear Information System (INIS)

    Gahbauer, R.; Goodman, J.; Blue, T.

    1988-01-01

    Unique to boron neutron capture therapy, the tolerance very strongly depends on the boron concentration in normal brain, skin and blood. If one first considers the ideal situation of a 2 KeV beam and a compound clearing from normal tissues and blood, the tolerance dose to epithermal beams relates to the maximum tolerated capture gamma dose and capture high LET dose, H (n,gamma)D and N(n,p) 14 C. The authors can relate this gamma and high LET dose to known clinical experience. Assuming gamma and high LET dose ratios as given by Fairchild and Bond, one may first choose a clearly safe high LET whole brain dose and calculate the unavoidably resulting gamma dose. To a first approximation 500 cGy of high LET dose results in 3,000 cGy gamma dose. One can speculate that this approximates the tolerance of whole brain to the 2 KeV beam with no contributing boron dose if the radiation is fractionated. It would clearly be beyond tolerance in a single fraction where most therapists would be uncomfortable to deliver even one third of the above doses

  12. Tolerance doses for treatment planning

    International Nuclear Information System (INIS)

    Lyman, J.T.

    1985-10-01

    Data for the tolerance of normal tissues or organs to (low-LET) radiation has been compiled from a number of sources which are referenced at the end of this document. This tolerance dose data are ostensibly for uniform irradiation of all or part of an organ, and are for either 5% (TD 5 ) or 50% (TD 50 ) complication probability. The ''size'' of the irradiated organ is variously stated in terms of the absolute volume or the fraction of the organ volume irradiated, or the area or the length of the treatment field. The accuracy of these data is questionable. Much of the data represents doses that one or several experienced therapists have estimated could be safely given rather than quantitative analyses of clinical observations. Because these data have been obtained from multiple sources with possible different criteria for the definition of a complication, there are sometimes different values for what is apparently the same endpoint. The data from some sources shows a tendancy to be quantized in 5 Gy increments. This reflects the size of possible round off errors. It is believed that all these data have been accumulated without the benefit of 3-D dose distributions and therefore the estimates of the size of the volume and/or the uniformity of the irradiation may be less accurate than is now possible. 19 refs., 4 figs

  13. Maximum tolerable radiation doses recommended by the Israel Advisory Committee on nuclear safety

    International Nuclear Information System (INIS)

    Tadmor, J.; Litai, D.; Lubin, E.

    1978-01-01

    Maximum tolerable doses have been recommended by the Israel Advisory Committee on Nuclear Safety. The recommendations which are based on a comparison with risks tolerated in other human activities, are for doses to radiation workers, for individual members of the population at the fence of a nuclear installation, and for the population at large, for both normal operating and accident conditions. Tolerable whole-body doses and doses to different critical organs are listed

  14. Microbial Biofilms: Persisters, Tolerance and Dosing

    Science.gov (United States)

    Cogan, N. G.

    2005-03-01

    Almost all moist surfaces are colonized by microbial biofilms. Biofilms are implicated in cross-contamination of food products, biofouling, medical implants and various human infections such as dental cavities, ulcerative colitis and chronic respiratory infections. Much of current research is focused on the recalcitrance of biofilms to typical antibiotic and antimicrobial treatments. Although the polymer component of biofilms impedes the penetration of antimicrobials through reaction-diffusion limitation, this does not explain the observed tolerance, it merely delays the action of the agent. Heterogeneities in growth-rate also slow the eradication of the bacteria since most antimicrobials are far less effective for non-growing, or slowly growing bacteria. This also does not fully describe biofilm tolerance, since heterogeneities arr primairly a result of nutrient consumption. In this investigation, we describe the formation of `persister' cells which neither grow nor die in the presence of antibiotics. We propose that the cells are of a different phenotype than typical bacterial cells and the expression of the phenotype is regulated by the growth rate and the antibiotic concentration. We describe several experiments which describe the dynamics of persister cells and which motivate a dosing protocol that calls for periodic dosing of the population. We then introduce a mathematical model, which describes the effect of such a dosing regiment and indicates that the relative dose/withdrawal times are important in determining the effectiveness of such a treatment. A reduced model is introduced and the similar behavior is demonstrated analytically.

  15. Comparative polygenic analysis of maximal ethanol accumulation capacity and tolerance to high ethanol levels of cell proliferation in yeast.

    Directory of Open Access Journals (Sweden)

    Thiago M Pais

    2013-06-01

    Full Text Available The yeast Saccharomyces cerevisiae is able to accumulate ≥17% ethanol (v/v by fermentation in the absence of cell proliferation. The genetic basis of this unique capacity is unknown. Up to now, all research has focused on tolerance of yeast cell proliferation to high ethanol levels. Comparison of maximal ethanol accumulation capacity and ethanol tolerance of cell proliferation in 68 yeast strains showed a poor correlation, but higher ethanol tolerance of cell proliferation clearly increased the likelihood of superior maximal ethanol accumulation capacity. We have applied pooled-segregant whole-genome sequence analysis to identify the polygenic basis of these two complex traits using segregants from a cross of a haploid derivative of the sake strain CBS1585 and the lab strain BY. From a total of 301 segregants, 22 superior segregants accumulating ≥17% ethanol in small-scale fermentations and 32 superior segregants growing in the presence of 18% ethanol, were separately pooled and sequenced. Plotting SNP variant frequency against chromosomal position revealed eleven and eight Quantitative Trait Loci (QTLs for the two traits, respectively, and showed that the genetic basis of the two traits is partially different. Fine-mapping and Reciprocal Hemizygosity Analysis identified ADE1, URA3, and KIN3, encoding a protein kinase involved in DNA damage repair, as specific causative genes for maximal ethanol accumulation capacity. These genes, as well as the previously identified MKT1 gene, were not linked in this genetic background to tolerance of cell proliferation to high ethanol levels. The superior KIN3 allele contained two SNPs, which are absent in all yeast strains sequenced up to now. This work provides the first insight in the genetic basis of maximal ethanol accumulation capacity in yeast and reveals for the first time the importance of DNA damage repair in yeast ethanol tolerance.

  16. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy.

    Directory of Open Access Journals (Sweden)

    Mary P McGowan

    Full Text Available Mipomersen, an antisense oligonucleotide targeting apolipoprotein B synthesis, significantly reduces LDL-C and other atherogenic lipoproteins in familial hypercholesterolemia when added to ongoing maximally tolerated lipid-lowering therapy. Safety and efficacy of mipomersen in patients with severe hypercholesterolemia was evaluated.Randomized, double-blind, placebo-controlled, multicenter trial. Patients (n  = 58 were ≥18 years with LDL-C ≥7.8 mmol/L or LDL-C ≥5.1 mmol/L plus CHD disease, on maximally tolerated lipid-lowering therapy that excluded apheresis. Weekly subcutaneous injections of mipomersen 200 mg (n  = 39 or placebo (n  = 19 were added to lipid-lowering therapy for 26 weeks.percent reduction in LDL-C from baseline to 2 weeks after the last dose of treatment. Mipomersen (n = 27 reduced LDL-C by 36%, from a baseline of 7.2 mmol/L, for a mean absolute reduction of 2.6 mmol/L. Conversely, mean LDL-C increased 13% in placebo (n = 18 from a baseline of 6.5 mmol/L (mipomersen vs placebo p<0.001. Mipomersen produced statistically significant (p<0.001 reductions in apolipoprotein B and lipoprotein(a, with no change in high-density lipoprotein cholesterol. Mild-to-moderate injection site reactions were the most frequently reported adverse events with mipomersen. Mild-to-moderate flu-like symptoms were reported more often with mipomersen. Alanine transaminase increase, aspartate transaminase increase, and hepatic steatosis occurred in 21%, 13% and 13% of mipomersen treated patients, respectively. Adverse events by category for the placebo and mipomersen groups respectively were: total adverse events, 16(84.2%, 39(100%; serious adverse events, 0(0%, 6(15.4%; discontinuations due to adverse events, 1(5.3%, 8(20.5% and cardiac adverse events, 1(5.3%, 5(12.8%.Mipomersen significantly reduced LDL-C, apolipoprotein B, total cholesterol and non-HDL-cholesterol, and lipoprotein(a. Mounting evidence suggests it may be a

  17. Application of organ tolerance dose-constraints in clinical studies in radiation oncology

    International Nuclear Information System (INIS)

    Doerr, Wolfgang; Herrmann, Thomas; Baumann, Michael

    2014-01-01

    In modern radiation oncology, tolerance dose-constraints for organs at risk (OAR) must be considered for treatment planning, but particularly in order to design clinical studies. Tolerance dose tables, however, only address one aspect of the therapeutic ratio of any clinical study, i.e., the limitation of adverse events, but not the desired potential improvement in the tumor effect of a novel treatment strategy. A sensible application of ''tolerance doses'' in a clinical situation requires consideration of various critical aspects addressed here: definition of tolerance dose, specification of an endpoint/symptom, consideration of radiation quality and irradiation protocol, exposed volume and dose distribution, and patient-related factors of radiosensitivity. The currently most comprehensive estimates of OAR radiation tolerance are in the QUANTEC compilations (2010). However, these tolerance dose values must only be regarded as a rough orientation and cannot answer the relevant question for the patients, i.e., if the study can achieve a therapeutic advantage; this can obviously be answered only by the final scientific analysis of the study results. Despite all limitations, the design of clinical studies should currently refer to the QUANTEC values for appreciation of the risk of complications, if needed supplemented by one's own data or further information from the literature. The implementation of a consensus on the safety interests of the patients and on an application and approval process committed to progress in medicine, with transparent quality-assuring requirements with regard to the structural safeguarding of the study activities, plays a central role in clinical research in radiation oncology. (orig.) [de

  18. Optimization of the dose level for a given treatment plan to maximize the complication-free tumor cure

    International Nuclear Information System (INIS)

    Lind, B.K.; Mavroidis, P.; Hyoedynmaa, S.; Kappas, C.

    1999-01-01

    During the past decade, tumor and normal tissue reactions after radiotherapy have been increasingly quantified in radiobiological terms. For this purpose, response models describing the dependence of tumor and normal tissue reactions on the irradiated volume, heterogeneity of the delivered dose distribution and cell sensitivity variations can be taken into account. The probability of achieving a good treatment outcome can be increased by using an objective function such as P + , the probability of complication-free tumor control. A new procedure is presented, which quantifies P + from the dose delivery on 2D surfaces and 3D volumes and helps the user of any treatment planning system (TPS) to select the best beam orientations, the best beam modalities and the most suitable beam energies. The final step of selecting the prescribed dose level is made by a renormalization of the entire dose plan until the value of P + is maximized. The index P + makes use of clinically established dose-response parameters, for tumors and normal tissues of interest, in order to improve its clinical relevance. The results, using P + , are compared against the assessments of experienced medical physicists and radiation oncologists for two clinical cases. It is observed that when the absorbed dose level for a given treatment plan is increased, the treatment outcome first improves rapidly. As the dose approaches the tolerance of normal tissues the complication-free curve begins to drop. The optimal dose level is often just below this point and it depends on the geometry of each patient and target volume. Furthermore, a more conformal dose delivery to the target results in a higher control rate for the same complication level. This effect can be quantified by the increased value of the P + parameter. (orig.)

  19. Individualized Dose Prescription for Hypofractionation in Advanced Non-Small-Cell Lung Cancer Radiotherapy: An in silico Trial

    Energy Technology Data Exchange (ETDEWEB)

    Hoffmann, Aswin L.; Troost, Esther G.C.; Huizenga, Henk; Kaanders, Johannes H.A.M. [Radboud University Nijmegen Medical Centre, Department of Radiation Oncology, Nijmegen (Netherlands); Bussink, Johan, E-mail: j.bussink@rther.umcn.nl [Radboud University Nijmegen Medical Centre, Department of Radiation Oncology, Nijmegen (Netherlands)

    2012-08-01

    Purpose: Local tumor control and outcome remain poor in patients with advanced non-small-cell lung cancer (NSCLC) treated by external beam radiotherapy. We investigated the therapeutic gain of individualized dose prescription with dose escalation based on normal tissue dose constraints for various hypofractionation schemes delivered with intensity-modulated radiation therapy. Methods and Materials: For 38 Stage III NSCLC patients, the dose level of an existing curative treatment plan with standard fractionation (66 Gy) was rescaled based on dose constraints for the lung, spinal cord, esophagus, brachial plexus, and heart. The effect on tumor total dose (TTD) and biologic tumor effective dose in 2-Gy fractions (TED) corrected for overall treatment time (OTT) was compared for isotoxic and maximally tolerable schemes given in 15, 20, and 33 fractions. Rescaling was accomplished by altering the dose per fraction and/or the number of fractions while keeping the relative dose distribution of the original treatment plan. Results: For 30 of the 38 patients, dose escalation by individualized hypofractionation yielded therapeutic gain. For the maximally tolerable dose scheme in 33 fractions (MTD{sub 33}), individualized dose escalation resulted in a 2.5-21% gain in TTD. In the isotoxic schemes, the number of fractions could be reduced with a marginal increase in TED. For the maximally tolerable dose schemes, the TED could be escalated up to 36.6%, and for all patients beyond the level of the isotoxic and the MTD{sub 33} schemes (range, 3.3-36.6%). Reduction of the OTT contributed to the therapeutic gain of the shortened schemes. For the maximally tolerable schemes, the maximum esophageal dose was the dominant dose-limiting constraint in most patients. Conclusions: This modeling study showed that individualized dose prescription for hypofractionation in NSCLC radiotherapy, based on scaling of existing treatment plans up to normal tissue dose constraints, enables dose

  20. Implications of the quadratic cell survival curve and human skin radiation ''tolerance doses'' on fractionation and superfractionation dose selection

    International Nuclear Information System (INIS)

    Douglas, B.G.

    1982-01-01

    An analysis of early published multifraction orthovoltage human acute skin irradiation tolerance isoeffect doses is presented. It indicates that human acute skin radiation reactions may result from the repetition, with each dose fraction, of a cell survival curve of the form: S = e/sup -(αD + βD 2 )/). The analysis also shows no need for an independent proliferation related time factor for skin, for daily treatments of six weeks or less in duration. The value obtained for the constant β/α for orthovoltage irradiation from these data is 2.9 x 10 -3 rad -1 for the cell line determining acute skin tolerance. A radiation isoeffect relationship, based on the quadratic cell survival curve, is introduced for human skin. This relationship has some advantages over the nominal standard dose (NSD). First, its use is not restricted to tolerance level reactions. Second, a modification of the relationship, which is also introduced, may be employed in the selection of doses per treatment when irradiation dose fractions are administered at short intervals where repair of sublethal injury is incomplete

  1. SODIUM BICARBONATE FACILITATES LOW-DOSE ORAL TOLERANCE TO PEANUT IN MICE

    Science.gov (United States)

    Rationale: Oral tolerance specifically inhibits production of allergic IgE antibody and is therefore a potential method for suppressing food allergy. We have previously demonstrated that a single oral dose of one mg is sufficient to induce oral tolerance to egg white but not pean...

  2. Maximal safe dose of I-131 after failure of standard fixed dose therapy in patients with differentiated thyroid carcinoma

    International Nuclear Information System (INIS)

    Lee, Jong-Jin; Chung, June-Key; Kim, Sung-Eun; Kang, Won-Jun; Park, Do-Joon; Lee, Dong-Soo; Cho, Bo-Youn; Lee, Myung-Chul

    2008-01-01

    The maximal safe dose (MSD) on the basis of bone marrow irradiation levels allows the delivery of a large amount of I-131 to thyroid cancer tissue. The efficacy of MSD therapy in differentiated metastatic thyroid cancers that persisted after conventional fixed dose therapy is investigated. Forty-seven differentiated thyroid carcinoma patients with non-responsive residual disease despite repetitive fixed dose I-131 therapy were enrolled in this study. Their postoperative pathologies were 43 papillary carcinomas and 4 follicular carcinomas. The MSD was calculated with the Memorial Sloan-Kettering Cancer Center protocol using serial blood samples. The MSDs were administered at intervals of 6 months. Treatment responses were evaluated using I-131 whole-body scans and serum thyroglobulin measurements. The mean calculated MSD was 12.5±2.1 GBq (339.6±57.5 mCi). Of the 46 patients, 7 (14.9%) showed complete remission, 15 (31.9%) partial remission, 19 (40.4%) stable disease, and 6 (12.8%) disease progression. Of the patients who showed complete or partial remission, 15 (65%) showed response after the first MSD session and 6 (26%) showed response after the second session. Twenty-nine patients (62%) experienced transient cytopenia after therapy, but three did not recover to the baseline level. The maximal safe dose provides an effective means of treatment in patients who failed to respond adequately to conventional fixed dose therapy. I-131 MSD therapy can be considered in patients who fail fixed dose therapy. (author)

  3. WE-AB-207B-01: Dose Tolerance for SBRT/SABR

    Energy Technology Data Exchange (ETDEWEB)

    Grimm, J [Johns Hopkins University, Baltimore, MD (United States)

    2016-06-15

    Purpose: Stereotactic body radiation therapy (SBRT) / stereotactic ablative body radiotherapy (SABR) is gaining popularity, but quantitative dose tolerance has still been lacking. To improve this, the April 2016 issue of Seminars in Radiation Oncology will have normal tissue complication probability (NTCP) models for 10 critical structures: optic pathway, cochlea, oral mucosa, esophagus, chestwall, aorta, bronchi, duodenum, small bowel, and spinal cord. Methods: The project included more than 1500 treatments in 1–5 fractions using CyberKnife, Gamma Knife, or LINAC, with 60 authors from 15 institutions. NTCP models were constructed from the 97 grade 2–3 complications, predominantly scored using the common terminology criteria for adverse events (CTCAEv4). Dose volume histogram (DVH) data from each institutional dataset was loaded into the DVH Evaluator software (DiversiLabs, LLC, Huntingdon Valley, Pa) for modeling. The current state of the literature for the critical structures was depicted using DVH Risk Maps: comparative graphs of dose tolerance limits that can include estimated risk levels, reported complications, DVH data for study patients, as well as high- and low-risk dose tolerance limits. Results: For relatively acceptable toxicity like grade 1–3 rib fractures and chestwall pain, the high-risk limits have 50% risk and the low-risk limits have 5% risk. Emami et al (IJROBP 1991 May 15;21(1):109–22) used 50% and 5% risk levels for all structures, whereas this effort used clinically acceptable ranges for each: in structures like aorta or spinal cord where complications must be avoided, the high- and low-risk limits have about 3% and 1% risk, respectively, in this issue of Seminars. These statistically based guidelines can help ensure plan quality for each patient. Conclusion: NTCP for SBRT is now becoming available. Hypofractionated dose tolerance can be dramatically different than extrapolations of conventional fractionation so NTCP analysis of the

  4. WE-AB-207B-01: Dose Tolerance for SBRT/SABR

    International Nuclear Information System (INIS)

    Grimm, J

    2016-01-01

    Purpose: Stereotactic body radiation therapy (SBRT) / stereotactic ablative body radiotherapy (SABR) is gaining popularity, but quantitative dose tolerance has still been lacking. To improve this, the April 2016 issue of Seminars in Radiation Oncology will have normal tissue complication probability (NTCP) models for 10 critical structures: optic pathway, cochlea, oral mucosa, esophagus, chestwall, aorta, bronchi, duodenum, small bowel, and spinal cord. Methods: The project included more than 1500 treatments in 1–5 fractions using CyberKnife, Gamma Knife, or LINAC, with 60 authors from 15 institutions. NTCP models were constructed from the 97 grade 2–3 complications, predominantly scored using the common terminology criteria for adverse events (CTCAEv4). Dose volume histogram (DVH) data from each institutional dataset was loaded into the DVH Evaluator software (DiversiLabs, LLC, Huntingdon Valley, Pa) for modeling. The current state of the literature for the critical structures was depicted using DVH Risk Maps: comparative graphs of dose tolerance limits that can include estimated risk levels, reported complications, DVH data for study patients, as well as high- and low-risk dose tolerance limits. Results: For relatively acceptable toxicity like grade 1–3 rib fractures and chestwall pain, the high-risk limits have 50% risk and the low-risk limits have 5% risk. Emami et al (IJROBP 1991 May 15;21(1):109–22) used 50% and 5% risk levels for all structures, whereas this effort used clinically acceptable ranges for each: in structures like aorta or spinal cord where complications must be avoided, the high- and low-risk limits have about 3% and 1% risk, respectively, in this issue of Seminars. These statistically based guidelines can help ensure plan quality for each patient. Conclusion: NTCP for SBRT is now becoming available. Hypofractionated dose tolerance can be dramatically different than extrapolations of conventional fractionation so NTCP analysis of the

  5. Induction of oral tolerance with micro-doses of ovomucoid depends on the length of the feeding period

    DEFF Research Database (Denmark)

    Kjær, Tanja; Frøkiær, Hanne

    2002-01-01

    Oral administration of antigen induces antigen-specific immunologic tolerance, which is known to be dose-dependent. We studied the influence of continuous oral administration of nanogram and microgram doses of antigen on oral tolerance induction. Mice were continuously exposed to varying doses (1...

  6. Tolerance of the Brachial Plexus to High-Dose Reirradiation

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Allen M., E-mail: achen5@kumc.edu; Yoshizaki, Taeko; Velez, Maria A.; Mikaeilian, Argin G.; Hsu, Sophia; Cao, Minsong

    2017-05-01

    Purpose: To study the tolerance of the brachial plexus to high doses of radiation exceeding historically accepted limits by analyzing human subjects treated with reirradiation for recurrent tumors of the head and neck. Methods and Materials: Data from 43 patients who were confirmed to have received overlapping dose to the brachial plexus after review of radiation treatment plans from the initial and reirradiation courses were used to model the tolerance of this normal tissue structure. A standardized instrument for symptoms of neuropathy believed to be related to brachial plexus injury was utilized to screen for toxicity. Cumulative dose was calculated by fusing the initial dose distributions onto the reirradiation plan, thereby creating a composite plan via deformable image registration. The median elapsed time from the initial course of radiation therapy to reirradiation was 24 months (range, 3-144 months). Results: The dominant complaints among patients with symptoms were ipsilateral pain (54%), numbness/tingling (31%), and motor weakness and/or difficulty with manual dexterity (15%). The cumulative maximum dose (Dmax) received by the brachial plexus ranged from 60.5 Gy to 150.1 Gy (median, 95.0 Gy). The cumulative mean (Dmean) dose ranged from 20.2 Gy to 111.5 Gy (median, 63.8 Gy). The 1-year freedom from brachial plexus–related neuropathy was 67% and 86% for subjects with a cumulative Dmax greater than and less than 95.0 Gy, respectively (P=.05). The 1-year complication-free rate was 66% and 87%, for those reirradiated within and after 2 years from the initial course, respectively (P=.06). Conclusion: The development of brachial plexus–related symptoms was less than expected owing to repair kinetics and to the relatively short survival of the subject population. Time-dose factors were demonstrated to be predictive of complications.

  7. In vivo assessment of catheter positioning accuracy and prolonged irradiation time on liver tolerance dose after single-fraction 192Ir high-dose-rate brachytherapy

    Directory of Open Access Journals (Sweden)

    Kropf Siegfried

    2011-09-01

    Full Text Available Abstract Background To assess brachytherapy catheter positioning accuracy and to evaluate the effects of prolonged irradiation time on the tolerance dose of normal liver parenchyma following single-fraction irradiation with 192 Ir. Materials and methods Fifty patients with 76 malignant liver tumors treated by computed tomography (CT-guided high-dose-rate brachytherapy (HDR-BT were included in the study. The prescribed radiation dose was delivered by 1 - 11 catheters with exposure times in the range of 844 - 4432 seconds. Magnetic resonance imaging (MRI datasets for assessing irradiation effects on normal liver tissue, edema, and hepatocyte dysfunction, obtained 6 and 12 weeks after HDR-BT, were merged with 3D dosimetry data. The isodose of the treatment plan covering the same volume as the irradiation effect was taken as a surrogate for the liver tissue tolerance dose. Catheter positioning accuracy was assessed by calculating the shift between the 3D center coordinates of the irradiation effect volume and the tolerance dose volume for 38 irradiation effects in 30 patients induced by catheters implanted in nearly parallel arrangement. Effects of prolonged irradiation were assessed in areas where the irradiation effect volume and tolerance dose volume did not overlap (mismatch areas by using a catheter contribution index. This index was calculated for 48 irradiation effects induced by at least two catheters in 44 patients. Results Positioning accuracy of the brachytherapy catheters was 5-6 mm. The orthogonal and axial shifts between the center coordinates of the irradiation effect volume and the tolerance dose volume in relation to the direction vector of catheter implantation were highly correlated and in first approximation identically in the T1-w and T2-w MRI sequences (p = 0.003 and p p = 0.001 and p = 0.004, respectively. There was a significant shift of the irradiation effect towards the catheter entry site compared with the planned dose

  8. A spatially encoded dose difference maximal intensity projection map for patient dose evaluation: A new first line patient quality assurance tool

    Energy Technology Data Exchange (ETDEWEB)

    Hu Weigang; Graff, Pierre; Boettger, Thomas; Pouliot, Jean [Department of Radiation Oncology, University of California, San Francisco, San Francisco, California 94143 (United States); and others

    2011-04-15

    Purpose: To develop a spatially encoded dose difference maximal intensity projection (DD-MIP) as an online patient dose evaluation tool for visualizing the dose differences between the planning dose and dose on the treatment day. Methods: Megavoltage cone-beam CT (MVCBCT) images acquired on the treatment day are used for generating the dose difference index. Each index is represented by different colors for underdose, acceptable, and overdose regions. A maximal intensity projection (MIP) algorithm is developed to compress all the information of an arbitrary 3D dose difference index into a 2D DD-MIP image. In such an algorithm, a distance transformation is generated based on the planning CT. Then, two new volumes representing the overdose and underdose regions of the dose difference index are encoded with the distance transformation map. The distance-encoded indices of each volume are normalized using the skin distance obtained on the planning CT. After that, two MIPs are generated based on the underdose and overdose volumes with green-to-blue and green-to-red lookup tables, respectively. Finally, the two MIPs are merged with an appropriate transparency level and rendered in planning CT images. Results: The spatially encoded DD-MIP was implemented in a dose-guided radiotherapy prototype and tested on 33 MVCBCT images from six patients. The user can easily establish the threshold for the overdose and underdose. A 3% difference between the treatment and planning dose was used as the threshold in the study; hence, the DD-MIP shows red or blue color for the dose difference >3% or {<=}3%, respectively. With such a method, the overdose and underdose regions can be visualized and distinguished without being overshadowed by superficial dose differences. Conclusions: A DD-MIP algorithm was developed that compresses information from 3D into a single or two orthogonal projections while hinting the user whether the dose difference is on the skin surface or deeper.

  9. A spatially encoded dose difference maximal intensity projection map for patient dose evaluation: a new first line patient quality assurance tool.

    Science.gov (United States)

    Hu, Weigang; Graff, Pierre; Boettger, Thomas; Pouliot, Jean

    2011-04-01

    To develop a spatially encoded dose difference maximal intensity projection (DD-MIP) as an online patient dose evaluation tool for visualizing the dose differences between the planning dose and dose on the treatment day. Megavoltage cone-beam CT (MVCBCT) images acquired on the treatment day are used for generating the dose difference index. Each index is represented by different colors for underdose, acceptable, and overdose regions. A maximal intensity projection (MIP) algorithm is developed to compress all the information of an arbitrary 3D dose difference index into a 2D DD-MIP image. In such an algorithm, a distance transformation is generated based on the planning CT. Then, two new volumes representing the overdose and underdose regions of the dose difference index are encoded with the distance transformation map. The distance-encoded indices of each volume are normalized using the skin distance obtained on the planning CT. After that, two MIPs are generated based on the underdose and overdose volumes with green-to-blue and green-to-red lookup tables, respectively. Finally, the two MIPs are merged with an appropriate transparency level and rendered in planning CT images. The spatially encoded DD-MIP was implemented in a dose-guided radiotherapy prototype and tested on 33 MVCBCT images from six patients. The user can easily establish the threshold for the overdose and underdose. A 3% difference between the treatment and planning dose was used as the threshold in the study; hence, the DD-MIP shows red or blue color for the dose difference > 3% or < or = 3%, respectively. With such a method, the overdose and underdose regions can be visualized and distinguished without being overshadowed by superficial dose differences. A DD-MIP algorithm was developed that compresses information from 3D into a single or two orthogonal projections while hinting the user whether the dose difference is on the skin surface or deeper.

  10. Biosphere Dose Conversion Factors for Reasonably Maximally Exposed Individual and Average Member of Critical Group

    International Nuclear Information System (INIS)

    K. Montague

    2000-01-01

    The purpose of this calculation is to develop additional Biosphere Dose Conversion Factors (BDCFs) for a reasonably maximally exposed individual (RMEI) for the periods 10,000 years and 1,000,000 years after the repository closure. In addition, Biosphere Dose Conversion Factors for the average member of a critical group are calculated for those additional radionuclides postulated to reach the environment during the period after 10,000 years and up to 1,000,000 years. After the permanent closure of the repository, the engineered systems within the repository will eventually lose their abilities to contain radionuclide inventory, and the radionuclides will migrate through the geosphere and eventually enter the local water table moving toward inhabited areas. The primary release scenario is a groundwater well used for drinking water supply and irrigation, and this calculation takes these postulated releases and follows them through various pathways until they result in a dose to either a member of critical group or a reasonably maximally exposed individual. The pathways considered in this calculation include inhalation, ingestion, and direct exposure

  11. Biphasic Effect of Curcumin on Morphine Tolerance: A Preliminary Evidence from Cytokine/Chemokine Protein Array Analysis

    Directory of Open Access Journals (Sweden)

    Jui-An Lin

    2011-01-01

    Full Text Available The aim of this study was to evaluate the effect of curcumin on morphine tolerance and the corresponding cytokine/chemokine changes. Male ICR mice were made tolerant to morphine by daily subcutaneous injection for 7 days. Intraperitoneal injections of vehicle, low-dose or high-dose curcumin were administered 15 min after morphine injection, either acutely or chronically for 7 days to test the effect of curcumin on morphine-induced antinociception and development of morphine tolerance. On day 8, cumulative dose-response curves were generated and the 50% of maximal analgesic dose values were calculated and compared among groups. Corresponding set of mice were used for analyzing the cytokine responses by antibody-based cytokine protein array. Acute, high-dose curcumin enhanced morphine-induced antinociception. While morphine tolerance was attenuated by administration of low-dose curcumin following morphine injections for 7 days, it was aggravated by chronic high-dose curcumin following morphine injection, suggesting a biphasic effect of curcumin on morphine-induced tolerance. Of the 96 cytokine/chemokines analyzed by mouse cytokine protein array, 14 cytokines exhibited significant changes after the different 7-day treatments. Mechanisms for the modulatory effects of low-dose and high-dose curcumin on morphine tolerance were discussed. Even though curcumin itself is a neuroprotectant and low doses of the compound serve to attenuate morphine tolerance, high-doses of curcumin might cause neurotoxicity and aggravate morphine tolerance by inhibiting the expression of antiapoptotic cytokines and neuroprotective factors. Our results indicate that the effect of curcumin on morphine tolerance may be biphasic, and therefore curcumin should be used cautiously.

  12. An estimate of the maximal doses incurred by persons accompanying patients in the waiting area of a nuclear medicine department

    International Nuclear Information System (INIS)

    Dzik-Jurasz, A.S.K.; Farwell, J.

    1997-01-01

    The aim of the study was to make an estimate of the maximal doses that might be incurred by persons accompanying active patients in a nuclear medicine department waiting area. This was in order to determine whether the dose to such individuals approached current legislative or recently recommended limits. Thermoluminescent dosemeters were taped to the walls of the waiting area at waist level to the sitting individual, such that their record would reflect as closely as possible the dose incurred by an individual sitting next to an active patient. Dividing the recorded dose with the total occupancy time of that seat derived an average dose rate. Maximal doses were estimated by the product of the latter and maximal occupancy times. It was assumed that an accompanying individual would have been sitting next to the active patient for their whole duration of stay. The maximum estimates were 278 μSv and 103.2 μSv. These values are likely to be overestimates by the virtue of the TLD integrating the whole dose of its surrounds, especially adjacent active individuals. By current legislation and recent recommendations the values are reassuringly low, but idiosyncrasies in local practice might need to be considered in individual departments. (author)

  13. Lack of evidence for increased tolerance of rat spinal cord with decreasing fraction doses below 2 Gy

    International Nuclear Information System (INIS)

    Ang, K.K.; van der Kogel, A.J.; van der Schueren, E.

    1985-01-01

    The radiation tolerance of the spinal cord, both in man and in rats, has been shown to depend strongly on the size of the dose per fraction. With fraction doses down to about 2 Gy, the spinal cord tolerance can be predicted by a modified Ellis formula. More recently alternative isoeffect formulas were based on the linear-quadratic (LQ) model of cell survival where the effect of dose fractionation is characterized by the ratio α/β which varies from tissue to tissue. For the spinal cord, as well as for other late responding tissues, the ratio α/β is small, in contrast to most acutely responding tissues. Both the Ellis-type formula, and to a lesser extent the LQ-model, predict a continuously increasing tolerance dose with decreasing fraction size. From previous experiments on the rat cervical spinal cord with doses per fraction down to about 2 Gy, the ratio α/β was determined to be 1.7 Gy, and the LQ-model would predict a rise in tolerance with a reduction in fraction size to far below 2 Gy. Based on these predictions clinical studies have been initiated assuming a significantly increased tolerance by reduction of fraction size to about 1 Gy. However, in the present experiments no evidence was found for such an increase in tolerance with fraction sizes below 2 Gy

  14. Dose-dependent response of Trichoderma harzianum in improving drought tolerance in rice genotypes.

    Science.gov (United States)

    Pandey, Veena; Ansari, Mohammad W; Tula, Suresh; Yadav, Sandep; Sahoo, Ranjan K; Shukla, Nandini; Bains, Gurdeep; Badal, Shail; Chandra, Subhash; Gaur, A K; Kumar, Atul; Shukla, Alok; Kumar, J; Tuteja, Narendra

    2016-05-01

    This study demonstrates a dose-dependent response of Trichoderma harzianum Th-56 in improving drought tolerance in rice by modulating proline, SOD, lipid peroxidation product and DHN / AQU transcript level, and the growth attributes. In the present study, the effect of colonization of different doses of T. harzianum Th-56 strain in rice genotypes were evaluated under drought stress. The rice genotypes treated with increasing dose of T. harzianum strain Th-56 showed better drought tolerance as compared with untreated control plant. There was significant change in malondialdehyde, proline, higher superoxide dismutase level, plant height, total dry matter, relative chlorophyll content, leaf rolling, leaf tip burn, and the number of scorched/senesced leaves in T. harzianum Th-56 treated rice genotypes under drought stress. This was corroborated with altered expression of aquaporin and dehydrin genes in T. harzianum Th-56 treated rice genotypes. The present findings suggest that a dose of 30 g/L was the most effective in improving drought tolerance in rice, and its potential exploitation will contribute to the advancement of rice genotypes to sustain crop productivity under drought stress. Interaction studies of T. harzianum with three aromatic rice genotypes suggested that PSD-17 was highly benefitted from T. harzianum colonization under drought stress.

  15. Intensity-Modulated Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer: A Dose-Escalation Planning Study

    International Nuclear Information System (INIS)

    Lievens, Yolande; Nulens, An; Gaber, Mousa Amr; Defraene, Gilles; De Wever, Walter; Stroobants, Sigrid; Van den Heuvel, Frank

    2011-01-01

    Purpose: To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). Methods and Materials: For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). Results: IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. Conclusion: In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT.

  16. Quantitative in vivo assessment of radiation injury of the liver using Gd-EOB-DTPA enhanced MRI: tolerance dose of small liver volumes

    Directory of Open Access Journals (Sweden)

    Pech Maciej

    2011-04-01

    Full Text Available Abstract Backround Hepatic radiation toxicity restricts irradiation of liver malignancies. Better knowledge of hepatic tolerance dose is favourable to gain higher safety and to optimize radiation regimes in radiotherapy of the liver. In this study we sought to determine the hepatic tolerance dose to small volume single fraction high dose rate irradiation. Materials and methods 23 liver metastases were treated by CT-guided interstitial brachytherapy. MRI was performed 3 days, 6, 12 and 24 weeks after therapy. MR-sequences were conducted with T1-w GRE enhanced by hepatocyte-targeted Gd-EOB-DTPA. All MRI data sets were merged with 3D-dosimetry data. The reviewer indicated the border of hypointensity on T1-w images (loss of hepatocyte function or hyperintensity on T2-w images (edema. Based on the volume data, a dose-volume-histogram was calculated. We estimated the threshold dose for edema or function loss as the D90, i.e. the dose achieved in at least 90% of the pseudolesion volume. Results At six weeks post brachytherapy, the hepatocyte function loss reached its maximum extending to the former 9.4Gy isosurface in median (i.e., ≥9.4Gy dose exposure led to hepatocyte dysfunction. After 12 and 24 weeks, the dysfunctional volume had decreased significantly to a median of 11.4Gy and 14Gy isosurface, respectively, as a result of repair mechanisms. Development of edema was maximal at six weeks post brachytherapy (9.2Gy isosurface in median, and regeneration led to a decrease of the isosurface to a median of 11.3Gy between 6 and 12 weeks. The dose exposure leading to hepatocyte dysfunction was not significantly different from the dose provoking edema. Conclusion Hepatic injury peaked 6 weeks after small volume irradiation. Ongoing repair was observed up to 6 months. Individual dose sensitivity may differ as demonstrated by a relatively high standard deviation of threshold values in our own as well as all other published data.

  17. Tolerability in the elderly population of high-dose alpha lipoic acid: a potential antioxidant therapy for the eye

    Directory of Open Access Journals (Sweden)

    Sarezky D

    2016-09-01

    Full Text Available Daniel Sarezky, Aaishah R Raquib, Joshua L Dunaief, Benjamin J Kim Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Purpose: Alpha lipoic acid (ALA is an antioxidant and iron-chelating supplement that has potential benefits for geographic atrophy in dry age-related macular degeneration as well as other eye diseases. The purpose of this study was to determine the tolerability of ALA in the elderly population. Patients and methods: Fifteen subjects, age ≥65 years, took sequential ALA doses of 600, 800, and 1,200 mg. Each dose was taken once daily with a meal for 5 days. After each dose was taken by the subjects for 5 days, the subjects were contacted by phone, a review of systems was performed, and they were asked if they thought they could tolerate taking that dose of ALA for an extended period of time. Results: The 600 mg dose was well tolerated. At the 800 mg dose, one subject had an intolerable flushing sensation. At the 1,200 mg dose, two subjects had intolerable upper gastrointestinal side effects and one subject had an intolerable flushing sensation. Subjects taking gastrointestinal prophylaxis medications had no upper gastrointestinal side effects. Conclusion: High-dose ALA is not completely tolerated by the elderly. These preliminary data suggest that gastrointestinal prophylaxis may improve tolerability. (ClinicalTrials.gov, NCT02613572. Keywords: age-related macular degeneration, geographic atrophy, antioxidant, gastrointestinal, dietary supplements, lipoic acid

  18. Application of organ tolerance dose-constraints in clinical studies in radiation oncology

    Energy Technology Data Exchange (ETDEWEB)

    Doerr, Wolfgang [Medical University/AKH Vienna, Dept. of Radiation Oncology/Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Comprehensive Cancer Center, Vienna (Austria); Technical University Dresden, Department of Radiotherapy and Radiation Oncology, OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden (Germany); Task Group ' ' Tolerance Doses' ' of the German Society for Radiation Oncology (DEGRO), Berlin (Germany); Herrmann, Thomas [Task Group ' ' Tolerance Doses' ' of the German Society for Radiation Oncology (DEGRO), Berlin (Germany); Baumann, Michael [Technical University Dresden, Department of Radiotherapy and Radiation Oncology, OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden (Germany); Task Group ' ' Tolerance Doses' ' of the German Society for Radiation Oncology (DEGRO), Berlin (Germany)

    2014-07-15

    In modern radiation oncology, tolerance dose-constraints for organs at risk (OAR) must be considered for treatment planning, but particularly in order to design clinical studies. Tolerance dose tables, however, only address one aspect of the therapeutic ratio of any clinical study, i.e., the limitation of adverse events, but not the desired potential improvement in the tumor effect of a novel treatment strategy. A sensible application of ''tolerance doses'' in a clinical situation requires consideration of various critical aspects addressed here: definition of tolerance dose, specification of an endpoint/symptom, consideration of radiation quality and irradiation protocol, exposed volume and dose distribution, and patient-related factors of radiosensitivity. The currently most comprehensive estimates of OAR radiation tolerance are in the QUANTEC compilations (2010). However, these tolerance dose values must only be regarded as a rough orientation and cannot answer the relevant question for the patients, i.e., if the study can achieve a therapeutic advantage; this can obviously be answered only by the final scientific analysis of the study results. Despite all limitations, the design of clinical studies should currently refer to the QUANTEC values for appreciation of the risk of complications, if needed supplemented by one's own data or further information from the literature. The implementation of a consensus on the safety interests of the patients and on an application and approval process committed to progress in medicine, with transparent quality-assuring requirements with regard to the structural safeguarding of the study activities, plays a central role in clinical research in radiation oncology. (orig.) [German] In der modernen Radioonkologie muessen Toleranzdosisgrenzen fuer die Risikoorgane (''organs at risk'', OAR) zur Behandlungsplanung, besonders aber zur Gestaltung klinischer Studien, herangezogen werden

  19. Efficacy and Tolerability of High-Dose Escitalopram in Posttraumatic Stress Disorder.

    Science.gov (United States)

    Qi, Wei; Gevonden, Martin; Shalev, Arieh

    2017-02-01

    Open-label trials suggest that escitalopram (up to 20 mg/d) is an effective treatment for some, but not all posttraumatic stress disorder (PTSD) patients. Higher doses of escitalopram effectively reduced major depression symptoms in patients who had not responded to regular doses. The current study examines the efficacy, tolerability, and adherence to high-dose escitalopram in PTSD. Forty-five PTSD patients received 12 weeks of gradually increasing doses of escitalopram reaching 40 mg daily at 4 weeks. Among those, 12 participants received regular doses of antidepressants at study onset including escitalopram (n = 7). The Clinician-Administered PTSD Scale (CAPS) evaluated PTSD symptoms severity before treatment, at 3 months (upon treatment termination), and at 6 months (maintenance effect). A 20% reduction in CAPS scores was deemed clinically significant. Adverse events and medication adherence were monitored at each clinical session. Linear mixed-models analysis showed a significant reduction of mean CAPS scores (11.5 ± 18.1 points) at 3 months and maintenance of gains by 6 months (F2,34.56 = 8.15, P = 0.001). Eleven participants (34.3%) showed clinically significant improvement at 3 months. Only 9 participants (20%) left the study. There were no serious adverse events and few mild ones with only 2 adverse events (diarrhea, 11.1%; drowsiness, 11.1%) reported by more than 10% of participants. High doses of escitalopram are tolerable and well adhered to in PTSD. Their beneficial effect at a group level is due to a particularly good response in a subset of patients.Variability in prior pharmacological treatment precludes a definite attribution of the results to high doses of escitalopram.

  20. Effect of dose rate on intestinal tolerance in mice. Implications in radiotherapy

    International Nuclear Information System (INIS)

    Wambersie, A.; Stienon-Smoes, M.R.; Octave-Prignot, M.

    1978-01-01

    Effect of dose rate on intestinal tolerance after 60 Co irradiation was studied in BALB/c mice. Intestinal tolerance was assessed from LD50, after selective abdominal irradiation and after total body irradiation. Three dose rates were compared, corresponding to irradiation times of about 15-20 minutes ('acute irradiation' taken as reference), 5-6 hours and 10-15 hours. Irradiations were performed simultaneously, with three telecobaltherapy units, the dose rates being adjusted with lead shields and by increasing the distances. Comparison of the experimental data already published indicates that, for some biological systems and effects, additional dose necessary to reach a given effect when passing from 'acute' to 'continuous low dose rate' irradiation is comparable to that expected when considering only repair of sublethal lesions. For other biological systems and effects, it is necessary to consider, besides repair of sublethal lesions, other mechanisms such as cell distribution and, for tumours, the oxygen effect. A differential effect then appears to be possible. However, as far as the clinical applications are concerned, a general agreement is not yet reached on the exact shape of the iso-effect curves as a function of irradiation time for the effects relevant to radiation therapy [fr

  1. Tolerance doses of cutaneous and mucosal tissues in ring-necked parakeets (Psittacula krameri) for external beam megavoltage radiation.

    Science.gov (United States)

    Barron, Heather W; Roberts, Royce E; Latimer, Kenneth S; Hernandez-Divers, Stephen; Northrup, Nicole C

    2009-03-01

    Currently used dosages for external-beam megavoltage radiation therapy in birds have been extrapolated from mammalian patients and often appear to provide inadequate doses of radiation for effective tumor control. To determine the tolerance doses of cutaneous and mucosal tissues of normal birds in order to provide more effective radiation treatment for tumors that have been shown to be radiation responsive in other species, ingluvial mucosa and the skin over the ingluvies of 9 ring-necked parakeets (Psittacula krameri) were irradiated in 4-Gy fractions to a total dose of either 48, 60, or 72 Gy using an isocentric cobalt-60 teletherapy unit. Minimal radiation-induced epidermal changes were present in the high-dose group histologically. Neither dose-related acute nor chronic radiation effects could be detected in any group grossly in cutaneous or mucosal tissue over a 9-month period. Radiation doses of 72 Gy in 4-Gy fractions were well tolerated in the small number of ring-necked parakeets in this initial tolerance dose study.

  2. A study to evaluate safety and tolerability of repeated doses of tirasemtiv in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Shefner, Jeremy M; Watson, Mary Lou; Meng, Lisa; Wolff, Andrew A

    2013-12-01

    Abstract Tirasemtiv is a fast skeletal muscle activator that increases the sensitivity of the sarcomere to calcium, increasing the efficiency of muscle contraction when the muscle is stimulated at submaximal contraction frequencies. A previous study showed single doses of tirasemtiv to be well tolerated and associated with potentially important improvements in a variety of functional outcomes. This study determined safety of tirasemtiv when given at doses up to 500 mg daily for three weeks. Tirasemtiv was given as a single daily dose up to 375 mg for two weeks, with and without concomitant riluzole. In a separate cohort, an ascending dose protocol evaluated a total dose of 500 mg daily given in two divided doses. Safety and tolerability were assessed, as well as measures of function, muscle strength and endurance. Results showed that tirasemtiv was well tolerated, with dizziness the most common adverse event. Tirasemtiv approximately doubled the serum concentration of riluzole. Trends were noted for improvement in ALSFRS-R, Maximum Minute Ventilation, and Nasal Inspiratory Pressure. In conclusion, tirasemtiv is well tolerated and can be given safely with a reduced dose of riluzole. Positive trends in multiple exploratory outcome measures support the further study of this agent in ALS.

  3. Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels

    Science.gov (United States)

    Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipo...

  4. Buprenorphine dose induction in non-opioid-tolerant pre-release prisoners.

    Science.gov (United States)

    Vocci, Frank J; Schwartz, Robert P; Wilson, Monique E; Gordon, Michael S; Kinlock, Timothy W; Fitzgerald, Terrence T; O'Grady, Kevin E; Jaffe, Jerome H

    2015-11-01

    In a previously reported randomized controlled trial, formerly opioid-dependent prisoners were more likely to enter community drug abuse treatment when they were inducted in prison onto buprenorphine/naloxone (hereafter called buprenorphine) than when they received counseling without buprenorphine in prison (47.5% vs. 33.7%, p=0.012) (Gordon et al., 2014). In this communication we report on the results of the induction schedule and the adverse event profile seen in pre-release prisoners inducted onto buprenorphine. This paper examines the dose induction procedure, a comparison of the proposed versus actual doses given per week, and side effects reported for 104 adult participants who were randomized to buprenorphine treatment in prison. Self-reported side effects were analyzed using generalized estimated equations to determine changes over time in side effects. Study participants were inducted onto buprenorphine at a rate faster than the induction schedule. Of the 104 (72 males, 32 females) buprenorphine recipients, 64 (37 males, 27 females) remained on medication at release from prison. Nine participants (8.6%) discontinued buprenorphine because of unpleasant opioid side effects. There were no serious adverse events reported during the in-prison phase of the study. Constipation was the most frequent symptom reported (69 percent). Our findings suggest that buprenorphine administered to non-opioid-tolerant adults should be started at a lower, individualized dose than customarily used for adults actively using opioids, and that non-opioid-tolerant pre-release prisoners can be successfully inducted onto therapeutic doses prior to release. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Dose-volume considerations in stereotaxic brain radiation therapy

    International Nuclear Information System (INIS)

    Houdek, P.V.; Schwade, J.G.; Pisciotta, V.J.; Medina, A.J.; Lewin, A.A.; Abitbol, A.A.; Serago, C.F.

    1988-01-01

    Although brain radiation therapy experience suggests that a gain in the therapeutic ratio may be achieved by optimizing the dose-volume relationship, no practical system for quantitative assessment of dose-volume data has been developed. This presentation describes the rationale for using the integral dose function for this purpose and demonstrates that with the use of a conventional treatment planning computer and a series of computed tomographic scans, first-order optimization of the dose-volume function can be accomplished in two steps: first, high-dose volume is minimized by selecting an appropriate treatment technique and tumor margin, and then dosage is maximized by calculating the brain tolerance dose as a function of the irradiated volume

  6. Optimizing fluorescently tethered Hsp90 inhibitor dose for maximal specific uptake by breast tumors

    Science.gov (United States)

    Crouch, Brian T.; Duer, Joy; Wang, Roujia; Gallagher, Jennifer; Hall, Allison; Soo, Mary Scott; Hughes, Philip; Haystead, Timothy A. J.; Ramanujam, Nirmala

    2018-03-01

    Despite improvements in surgical resection, 20-40% of patients undergoing breast conserving surgery require at least one additional re-excision. Leveraging the unique surface expression of heat shock protein 90 (Hsp90), a chaperone protein involved in several key hallmarks of cancer, in breast cancer provides an exciting opportunity to identify residual disease during surgery. We developed a completely non-destructive strategy using HS-27, a fluorescently-tethered Hsp90 inhibitor, to assay surface Hsp90 expression on intact tissue specimens using a fluorescence microendoscope with a field of view of 750 μm and subcellular resolution of 4 μm. HS-27 consists of an FDA approved Hsp90 inhibitor tethered to fluorescein isothiocyanate (EX 488nm, EM 525nm). Here, we optimized ex vivo HS-27 administration in pre-clinical breast cancer models and validated our approach on 21 patients undergoing standard of care ultrasound guided core needle biopsy. HS-27 administration time was fixed at 1- minute to minimize imaging impact on clinical workflow. HS-27 and HS-217 (non-specific control) doses were modulated from 1 μM up to 100 μM to identify the dose maximizing the ratio of specific uptake (HS-27 fluorescence) to non-specific uptake (HS-217 fluorescence). The specificity ratio was maximized at 100 μM and was significantly greater than all other doses (pcancer makes this technology attractive for assessing tumor margins, as one agent can be used for all subtypes.

  7. Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection.

    Science.gov (United States)

    Nations, Kari R; Bursi, Roberta; Dogterom, Peter; Ereshefsky, Larry; Gertsik, Lev; Mant, Tim; Schipper, Jacques

    2012-09-01

    A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100-400 mg bid; MDD range 100-600 mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study

  8. Power maximization of variable-speed variable-pitch wind turbines using passive adaptive neural fault tolerant control

    Science.gov (United States)

    Habibi, Hamed; Rahimi Nohooji, Hamed; Howard, Ian

    2017-09-01

    Power maximization has always been a practical consideration in wind turbines. The question of how to address optimal power capture, especially when the system dynamics are nonlinear and the actuators are subject to unknown faults, is significant. This paper studies the control methodology for variable-speed variable-pitch wind turbines including the effects of uncertain nonlinear dynamics, system fault uncertainties, and unknown external disturbances. The nonlinear model of the wind turbine is presented, and the problem of maximizing extracted energy is formulated by designing the optimal desired states. With the known system, a model-based nonlinear controller is designed; then, to handle uncertainties, the unknown nonlinearities of the wind turbine are estimated by utilizing radial basis function neural networks. The adaptive neural fault tolerant control is designed passively to be robust on model uncertainties, disturbances including wind speed and model noises, and completely unknown actuator faults including generator torque and pitch actuator torque. The Lyapunov direct method is employed to prove that the closed-loop system is uniformly bounded. Simulation studies are performed to verify the effectiveness of the proposed method.

  9. Evaluation of dose components for healthy tissue tolerance studies on dogs at the HFR Petten

    International Nuclear Information System (INIS)

    Watkins, P.; Moss, R.L.; Siefert, A.; Huiskamp, R.; Gavin, P.; Konijnenberg, M.

    1993-01-01

    Before the start of clinical trails of BNCT on glioma patients at the Petten reactor, certain preconditions must be determined. In particular the tolerance of healthy brain tissue exposed to the epithermal neutron beam requires investigation. In these studies, beagle dogs have been subjected to different levels of irradiation and 10 B, the latter in the form of BSH. To support this work a treatment planning tool is being developed to predict the various dose components within the treatment volume. A Monte Carlo code, MCNP, has been used to simulate the particle transport and to predict the different dose rate distributions. The doses rates generated by MCNP are manipulated with a processing code, TREAT, to give irradiation times, peak dose positions and to display the required data in a graphical format. This paper explains the basic methodology used in the system and a practical case is presented for one of the healthy tissue tolerance dogs. Doses, both physical and RBE weighted, have been produced for pre-treatment planning studies

  10. Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

    Science.gov (United States)

    Malow, Beth; Adkins, Karen W.; McGrew, Susan G.; Wang, Lily; Goldman, Suzanne E.; Fawkes, Diane; Burnette, Courtney

    2012-01-01

    Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures…

  11. Normal tissue tolerance to external beam radiation therapy: The stomach; Dose de tolerance a l'irradiation des tissus sains: l'estomac

    Energy Technology Data Exchange (ETDEWEB)

    Oberdiac, P. [Service de radiotherapie, hopital de Bellevue, CHU de Saint-Etienne, 42 - Saint-Etienne (France); Mineur, L. [Unite d' oncologie digestive et radiotherapie, institut Sainte-Catherine, 84 - Avignon (France)

    2010-07-15

    In the following article, we will discuss general issues relating to acute and late gastric's radiation toxicities. The tolerance of the stomach to complete or partial organ irradiation is more un-appreciated than for most other organs. We consulted the Medline database via PubMed and used the key words gastric - radiotherapy - toxicity. Currently, 60 Gy or less is prescribed in gastric radiation therapy. Acute clinical toxicity symptoms are predominantly nausea and vomiting. Although there is a general agreement that the whole stomach tolerance is for doses of 40 to 45 Gy without unacceptable complication, it is well established that a stomach dose of 35 Gy increases the risk of ulcer complications. (authors)

  12. Safety and tolerability of high doses of glucocorticoides

    Directory of Open Access Journals (Sweden)

    Rakić Branislava D.

    2016-01-01

    Full Text Available Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone, which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L, in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

  13. Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I single-dose escalation trial.

    Science.gov (United States)

    Gulec, Seza A; Cohen, Steven J; Pennington, Kenneth L; Zuckier, Lionel S; Hauke, Ralph J; Horne, Heather; Wegener, William A; Teoh, Nick; Gold, David V; Sharkey, Robert M; Goldenberg, David M

    2011-06-15

    Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of (90)Y-clivatuzumab tetraxetan ((90)Y-labeled hPAM4) in patients with advanced pancreatic cancer. Twenty-one patients (4 stage III; 17 stage IV) received (111)In-hPAM4 for imaging and serum sampling before (90)Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). (111)In-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before (90)Y-hPAM4; otherwise, 20 patients received (90)Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m(2) (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v.3) grade 3 to 4 neutropenia and thrombocytopenia increasing with (90)Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m(2) encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m(2) as the maximal tolerated (90)Y dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32%-52% tumor diameter shrinkage). (90)Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated (90)Y dose, and is a potential new therapeutic for advanced pancreatic cancer. ©2011 AACR.

  14. The Tolerance and Accumulation of Miscanthus Sacchariflorus (maxim.) Benth., an Energy Plant Species, to Cadmium.

    Science.gov (United States)

    Zhang, Jie; Yang, Shiyong; Huang, Yongjie; Zhou, Shoubiao

    2015-01-01

    Miscanthus sacchariflorus (Maxim.) Benth. is a metallophyte suitable for the phytoremediation of mine wastes. The tolerance and accumulation of M. sacchariflorus to cadmium was studied by pot experiments. The results showed that O2·- generation rate, plasma membrane permeability and MDA content of M. sacchariflorus leaves increased with increasing Cd concentrations in soil, but significant effect was only observed when Cd concentrations were ≥50 mg·kg(-1). SOD and POD activities increased initially but decreased later on, whereas CAT activity only increased significantly at higher Cd concentrations, 50-100 mg·kg(-1). The content of photosynthetic pigment and growth of M. sacchariflorus were both not significantly affected when Cd concentration was ≤25 mg·kg(-1). In contrast, both parameters were significantly affected when Cd concentration was ≥50 mg·kg(-1). M. sacchariflorus could accumulate much Cd, but most of the Cd assimilated was retained in the belowground part, suggesting that M. sacchariflorus has poor ability to translocate Cd to the aboveground part. Our results suggested that although M. sacchariflorus was not a hyper-accumulator, it has a strong capacity to tolerate and stabilize the Cd. Therefore, M. sacchariflorus has a certain potential in the phytostabilization of Cd-contaminated soils.

  15. Determination of tolerance dose uncertainties and optimal design of dose response experiments with small animal numbers

    International Nuclear Information System (INIS)

    Karger, C.P.; Hartmann, G.H.

    2001-01-01

    Background: Dose response experiments aim to determine the complication probability as a function of dose. Adjusting the parameters of the frequently used dose response model P(D)=1/[1+(D 50 /D) k ] to the experimental data, 2 intuitive quantities are obtained: The tolerance dose D 50 and the slope parameter k. For mathematical reasons, however, standard statistic software uses a different set of parameters. Therefore, the resulting fit parameters of the statistic software as well as their standard errors have to be transformed to obtain D 50 and k as well as their standard errors. Material and Methods: The influence of the number of dose levels on the uncertainty of the fit parameters is studied by a simulation for a fixed number of animals. For experiments with small animal numbers, statistical artifacts may prevent the determination of the standard errors of the fit parameters. Consequences on the design of dose response experiments are investigated. Results: Explicit formulas are presented, which allow to calculate the parameters D 50 and k as well as their standard errors from the output of standard statistic software. The simulation shows, that the standard errors of the resulting parameters are independent of the number of dose levels, as long as the total number of animals involved in the experiment, remains constant. Conclusion: Statistical artifacts in experiments containing small animal numbers may be prevented by an adequate design of the experiment. For this, it is suggested to select a higher number of dose levels, rather than using a higher number of animals per dose level. (orig.) [de

  16. Effect of x-ray low doses on tolerance to salinity in Latuca Sativa plantules

    International Nuclear Information System (INIS)

    Ramirez Fernandez, R.; Gonzalez Nunez, L.M.; Perez Talavera, S.

    1998-01-01

    The work presents the effect of different radiation doses (ranging from 50 to 200 Gy) applied on irradiated lettuce seeds in a ray source for surface therapy, with a working regime of 30 k and 10 m and a dose rate of 12,9 Gy/mins on the germination and growth of plantules in the presence or absence of salinity. The results indicated meaningful differences in the magnitude of the stimulation effect and the doses that caused it for normal conditions, as well as substantial increments in plantules tolerance from irradiated seeds

  17. Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects.

    Science.gov (United States)

    Liu, Dongyang; Jiang, Ji; Zhang, Li; Tan, Fenlai; Wang, Yingxiang; Zhang, Don; Hu, Pei

    2014-04-01

    Icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, has proved effectiveness in xenografted nude mice. Purpose of the present studies was to investigate tolerability and pharmacokinetics of Icotinib in healthy subjects for the first time, including dose proportionality, food effect, and tolerability. Two studies were conducted in total of 22 healthy subjects: a randomized, two-Latin-square crossover, dose proportional study (n = 12) and a randomized two-way crossover food-effect study (n = 10). Plasma concentration of Icotinib reached peak at a median Tmax of 0.75-3.5 h after single dose and then declined with a mean t1/2β of 6.02-7.83 h. Over the dose range of 100-600 mg, AUC values were proportional to dose and Cmax showed a slight saturation when dose increases. Only 0.2 % of the dose was excreted through kidney in unchanged Icotinib. After dosing 400 mg of Icotinib with high-fat and high-calorie meal, mean Cmax and AUC were significantly increased by 59 and 79 %, respectively. Three subjects experienced four adverse events (rash, increase in AST and ALT, and external injury). Rash and increased levels of AST and ALT were considered as drug-related. No serious adverse events were reported. The current work demonstrated that Icotinib was well tolerated in healthy male subjects (n = 22) over the dose range of 100-600 mg with or without food. Icotinib exposure, expressed in AUC, was proportionally increased with dose over the above dose range. Food intake significantly increased the absorption and exposure of Icotinib in healthy subjects.

  18. The effect of small radiation doses on the rat spinal cord: the concept of partial tolerance

    International Nuclear Information System (INIS)

    Ang, K.K.; Van Der Kogel, A.J.; Van Der Schueren, E.

    1983-01-01

    To evaluate the tolerance of the rat spinal cord to small radiation doses per fraction, an increasing number of fractions is required for induction of paralysis. The assessment of doses of 1-2 Gy, as used in the clinic, would require that over 100 fractions be given. The validity of replacing part of a fractionated irradiation of the spinal cord by a single large dose has been tested. Fractionated irradiation doses with 18 MeV X rays were followed by a ''top-up'' dose of 15 Gy as a single treatment. This is the fraction size of a treatment with two irradiation doses leading to paralysis in 50% of the animals (ED 50). Fractionated treatments were carried out with 2, 5, 10 and 20 fractions followed by the top-up dose of 15 Gy. the isoeffect curve, as a function of the number of fractions, has the same slope as experiments performed without top-up dose. The results show that the quality and quantity of cellular repair is not modified when part of a multifractionated exposure is replaced by a larger top-dose. An important consequence of this finding is, that in treatments with unequal fraction sizes, the partial tolerances can simply be added. Since a top-up dose can replace a sizable number of irradiation treatments, its application will allow investigations of the extent of sublethal damage repair for fraction sizes as low as 1 Gy

  19. Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a κ-Opioid Agonist in THC-Treated Mice.

    Science.gov (United States)

    Chopda, Girish R; Parge, Viraj; Thakur, Ganesh A; Gatley, S John; Makriyannis, Alexandros; Paronis, Carol A

    2016-08-01

    Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of Δ(9)-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the κ-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% of maximal possible effect. Treatment with THC produced 9- and 7-fold rightward shifts of the diuresis and antinociception dose-response curves for THC and, respectively, 7- and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to >35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the Bmax value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis dose-effect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  20. RBE/absorbed dose relationship of d(50)-Be neutrons determined for early intestinal tolerance in mice

    International Nuclear Information System (INIS)

    Gueulette, J.; Wambersie, A.

    1978-01-01

    RBE/absorbed dose relationship of d(50)-Be neutrons (ref.: 60 Co) was determined using intestinal tolerance in mice (LD50) after single and fractionated irradiation. RBE is 1.8 for a single fraction (about 1000 rad 60 Co dose); it increases when decreasing dose and reaches the plateau value of 2.8 for a 60 Co dose of about 200 rad. This RBE value is used for the clinical applications with the cyclotron 'Cyclone' at Louvain-la-Neuve [fr

  1. Results of the Phase I Dose-Escalating Study of Motexafin Gadolinium With Standard Radiotherapy in Patients With Glioblastoma Multiforme

    International Nuclear Information System (INIS)

    Ford, Judith M.; Seiferheld, Wendy; Alger, Jeffrey R.; Wu, Genevieve; Endicott, Thyra J.; Mehta, Minesh; Curran, Walter; Phan, See-Chun

    2007-01-01

    Purpose: Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. This Phase I trial studied the safety and tolerability of a 2-6-week course (10-22 doses) of MGd with radiotherapy for glioblastoma multiforme. Methods and Materials: A total of 33 glioblastoma multiforme patients received one of seven MGd regimens starting at 10 doses of 4 mg/kg/d MGd and escalating to 22 doses of 5.3 mg/kg/d MGd (5 or 10 daily doses then three times per week). The National Cancer Institute Cancer Therapy Evaluation Program toxicity and stopping rules were applied. Results: The maximal tolerated dose was 5.0 mg/kg/d MGd (5 d/wk for 2 weeks, then three times per week) for 22 doses. The dose-limiting toxicity was reversible transaminase elevation. Adverse reactions included rash/pruritus (45%), chills/fever (30%), and self-limiting vesiculobullous rash of the thumb and fingers (42%). The median survival of 17.6 months prompted a case-matched analysis. In the case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31) compared with the matched Radiation Therapy Oncology Group database patients with a median survival of 11.8 months (hazard ratio, 0.43; 95% confidence interval, 0.20-0.94). Conclusion: The maximal tolerated dose of MGd with radiotherapy for glioblastoma multiforme in this study was 5 mg/kg/d for 22 doses (daily for 2 weeks, then three times weekly). The baseline survival calculations suggest progression to Phase II trials is appropriate, with the addition of MGd to radiotherapy with concurrent and adjuvant temozolomide

  2. An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

    Science.gov (United States)

    Chaker, A M; Al-Kadah, B; Luther, U; Neumann, U; Wagenmann, M

    2015-01-01

    The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. In an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians. Treatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as "good" or "very good" by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as "good" or "very good". The dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

  3. Maximum tolerated dose in a phase I trial on adaptive dose painting by numbers for head and neck cancer

    International Nuclear Information System (INIS)

    Madani, Indira; Duprez, Fréderic; Boterberg, Tom; Van de Wiele, Christophe; Bonte, Katrien; Deron, Philippe; De Gersem, Werner; Coghe, Marc; De Neve, Wilfried

    2011-01-01

    Purpose: To determine the maximum tolerated dose (MTD) in a phase I trial on adaptive dose-painting-by-numbers (DPBN) for non-metastatic head and neck cancer. Materials and methods: Adaptive intensity-modulated radiotherapy was based on voxel intensity of pre-treatment and per-treatment [ 18 F]fluoro-2-deoxy-D-glucose positron emission tomography ( 18 F-FDG-PET) scans. Dose was escalated to a median total dose of 80.9 Gy in the high-dose clinical target volume (dose level I) and 85.9 Gy in the gross tumor volume (dose level II). The MTD would be reached, if ⩾33% of patients developed any grade ⩾4 toxicity (DLT) up to 3 months follow-up. Results: Between February 2007 and August 2009, seven patients at dose level I and 14 at dose level II were treated. All patients completed treatment without interruption. At a median follow-up for surviving patients of 38 (dose level I) and 22 months (dose level II) there was no grade ⩾4 toxicity during treatment and follow-up but six cases of mucosal ulcers at latency of 4–10 months, of which five (36%) were observed at dose level II. Mucosal ulcers healed spontaneously in four patients. Conclusions: Considering late mucosal ulcers as DLT, the MTD of a median dose of 80.9 Gy has been reached in our trial.

  4. Maximal safe dose therapy of I-131 after failure of standard fixed dose therapy in patients with differentiated thyroid carcinoma

    International Nuclear Information System (INIS)

    Lee, Jong Jin; Seok, Ju Won; Uh, Jae Sun

    2005-01-01

    In patients with recurrent or metastatic differentiated thyroid carcinoma, residual disease despite repetitive fixed dose I-131 therapy presents an awkward situation in terms of treatment decision making. Maximal safe dose (MSD) administration base on bone marrow radiation allows the delivery of a large amount I-131 to thyroid cancer tissue within the safety margin. We investigated the efficacy of MSD in differentiated thyroid cancers, which had persisted after conventional fixed dose therapy. Forty-six patients with differentiated thyroid carcinoma who had non-responsible residual disease despite repetitive fixed dose I-131 therapy were enrolled in this study. The postoperative pathology consisted of 43 papillary carcinomas and 3 follicular carcinomas. MSD was calculated according the Memorial Sloan Kettering Cancer Center protocol using blood samples. MSDs were administered at intervals of at least 6 months. Treatment responses were evaluated using I-131 whole body scan (WBS) and serum thyroglobulin measurements. Mean calculated MSD was 12.5±2.1 GBq. Of the 46 patients, 6 (13.0%) showed complete remission, 15 (32.6%) partial response, 19 (41.3%) stable disease, and 6 (13.0%) disease progression. Thus, about a half of the patients showed complete or partial remission, and of these patients, 14 (67%) showed response after a single MSD administration and 6 (29%) showed response after the second dose of MSD administrations. Twenty-nine patients (63%) experienced transient cytopenia after therapy, and recovered spontaneously with the exception of one. MSD administration is an effective method even in the patients who failed to be treated by conventional fixed dose therapy. MSD therapy of I-131 can be considered in the patients who failed by fixed dose therapy

  5. Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis.

    Science.gov (United States)

    Srivastava, Shashikant; Magombedze, Gesham; Koeuth, Thearith; Sherman, Carleton; Pasipanodya, Jotam G; Raj, Prithvi; Wakeland, Edward; Deshpande, Devyani; Gumbo, Tawanda

    2017-08-01

    Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC 0-24 ) to MIC. Optimal microbial kill was achieved at an AUC 0-24 /MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87% and >99% of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300-mg/day dose did not achieve AUC 0-24 s associated with linezolid toxicity, while 600 mg/day achieved those AUC 0-24 s in linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials. Copyright © 2017 Srivastava et al.

  6. Efficacy, safety and tolerability of escitalopram in doses up to 50 mg in Major Depressive Disorder (MDD: an open-label, pilot study

    Directory of Open Access Journals (Sweden)

    Crawford Gordon M

    2011-03-01

    Full Text Available Abstract Background Escitalopram is licensed for use at doses up to 20 mg but is used clinically at higher doses. There is limited published data at higher doses and none in the treatment of Major Depressive Disorder (MDD. Methods This open-label, pilot study was designed to investigate the efficacy, safety and tolerability of escitalopram in doses up to 50 mg in MDD. It was conducted in 60 primary care patients with MDD who had not responded to adequate treatment with citalopram. Patients were treated with escalating doses of escitalopram up to 50 mg for up to 32 weeks until they achieved remission (Montgomery-Asberg Depression Rating Scale [MADRS] ≤8 or failed to tolerate the dose. Results Forty-two patients (70% completed the study. Twenty-one patients (35% achieved remission with 8 of the 21 patients (38% needing the 50 mg dose to achieve remission. Median time to remission was 24 weeks and median dose in remission was 30 mg. No significant safety issues were identified although tolerability appeared to decline above a dose of 40 mg with 26% of patients unable to tolerate 50 mg. Twelve (20% patients had adverse events leading to discontinuation. The most common adverse events were headache (35%, nausea, diarrhoea and nasopharyngitis (all 25%. Minor mean weight gain was found during the study, which did not appear to be dose-related. Half of the patients who completed the study chose to continue treatment with escitalopram rather than taper down the dose at 32 weeks. Conclusions Dose escalation with escitalopram above 20 mg may have a useful role in the management of patients with MDD, although further studies are needed to confirm this finding. Trial Registration ClinicalTrials.gov: NCT00785434

  7. Efficacy and Tolerability of Fixed-Dose Combination of Dexketoprofen and Dicyclomine Injection in Acute Renal Colic

    Directory of Open Access Journals (Sweden)

    A. Porwal

    2012-01-01

    Full Text Available Objective. To evaluate the efficacy and tolerability of a fixed-dose combination of dexketoprofen and dicyclomine (DXD injection in patients with acute renal colic. Patients and Methods. Two hundred and seventeen patients were randomized to receive either DXD (n=109 or fixed-dose combination of diclofenac and dicyclomine injection (DLD; n=108, intramuscularly. Pain intensity (PI was self-evaluated by patients on visual analogue scale (VAS at baseline and at 1, 2, 4, 6, and 8 hours. Efficacy parameters were proportion of responders, difference in PI (PID at 8 hours, and sum of analogue of pain intensity differences (SAPID. Tolerability was assessed by patients and physicians. Results. DXD showed superior efficacy in terms of proportion of responders (98.17% versus 81.48; P<0.0001, PID at 8 hours (P=0.002, and SAPID0–8 hours (P=0.004. The clinical global impression for change in pain was significantly better for DXD than DLD. The incidence of adverse events was comparable in both groups. However, global assessment of tolerability was rated significantly better for DXD. Conclusion. DXD showed superior efficacy and tolerability than DLD in patients clinically diagnosed to be suffering from acute renal colic.

  8. Efficacy and Tolerability of Fixed-Dose Combination of Dexketoprofen and Dicyclomine Injection in Acute Renal Colic

    Science.gov (United States)

    Porwal, A.; Mahajan, A. D.; Oswal, D. S.; Erram, S. S.; Sheth, D. N.; Balamurugan, S.; Kamat, V.; Enadle, R. P.; Badadare, A.; Bhatnagar, S. K.; Walvekar, R. S.; Dhorepatil, S.; Naik, R. C.; Basu, I.; Kshirsagar, S. N.; Keny, J. V.; Sengupta, S.

    2012-01-01

    Objective. To evaluate the efficacy and tolerability of a fixed-dose combination of dexketoprofen and dicyclomine (DXD) injection in patients with acute renal colic. Patients and Methods. Two hundred and seventeen patients were randomized to receive either DXD (n = 109) or fixed-dose combination of diclofenac and dicyclomine injection (DLD; n = 108), intramuscularly. Pain intensity (PI) was self-evaluated by patients on visual analogue scale (VAS) at baseline and at 1, 2, 4, 6, and 8 hours. Efficacy parameters were proportion of responders, difference in PI (PID) at 8 hours, and sum of analogue of pain intensity differences (SAPID). Tolerability was assessed by patients and physicians. Results. DXD showed superior efficacy in terms of proportion of responders (98.17% versus 81.48; P < 0.0001), PID at 8 hours (P = 0.002), and SAPID0–8 hours (P = 0.004). The clinical global impression for change in pain was significantly better for DXD than DLD. The incidence of adverse events was comparable in both groups. However, global assessment of tolerability was rated significantly better for DXD. Conclusion. DXD showed superior efficacy and tolerability than DLD in patients clinically diagnosed to be suffering from acute renal colic. PMID:22577544

  9. Nonlinear Impairment Compensation Using Expectation Maximization for PDM 16-QAM Systems

    DEFF Research Database (Denmark)

    Zibar, Darko; Winther, Ole; Franceschi, Niccolo

    2012-01-01

    We show experimentally that by using non-linear signal processing based algorithm, expectation maximization, nonlinear system tolerance can be increased by 2 dB. Expectation maximization is also effective in combating I/Q modulator nonlinearities and laser linewidth....

  10. Radiobiological restrictions and tolerance doses of repeated single-fraction hdr-irradiation of intersecting small liver volumes for recurrent hepatic metastases

    Directory of Open Access Journals (Sweden)

    Wust Peter

    2010-05-01

    Full Text Available Abstract Background To assess radiobiological restrictions and tolerance doses as well as other toxic effects derived from repeated applications of single-fraction high dose rate irradiation of small liver volumes in clinical practice. Methods Twenty patients with liver metastases were treated repeatedly (2 - 4 times at identical or intersecting locations by CT-guided interstitial brachytherapy with varying time intervals. Magnetic resonance imaging using the hepatocyte selective contrast media Gd-BOPTA was performed before and after treatment to determine the volume of hepatocyte function loss (called pseudolesion, and the last acquired MRI data set was merged with the dose distributions of all administered brachytherapies. We calculated the BED (biologically equivalent dose for a single dose d = 2 Gy for different α/β values (2, 3, 10, 20, 100 based on the linear-quadratic model and estimated the tolerance dose for liver parenchyma D90 as the BED exposing 90% of the pseudolesion in MRI. Results The tolerance doses D90 after repeated brachytherapy sessions were found between 22 - 24 Gy and proved only slightly dependent on α/β in the clinically relevant range of α/β = 2 - 10 Gy. Variance analysis showed a significant dependency of D90 with respect to the intervals between the first irradiation and the MRI control (p 90 and the pseudolesion's volume. No symptoms of liver dysfunction or other toxic effects such as abscess formation occurred during the follow-up time, neither acute nor on the long-term. Conclusions Inactivation of liver parenchyma occurs at a BED of approx. 22 - 24 Gy corresponding to a single dose of ~10 Gy (α/β ~ 5 Gy. This tolerance dose is consistent with the large potential to treat oligotopic and/or recurrent liver metastases by CT-guided HDR brachytherapy without radiation-induced liver disease (RILD. Repeated small volume irradiation may be applied safely within the limits of this study.

  11. Intravenous infusion of docosahexaenoic acid increases serum concentrations in a dose-dependent manner and increases seizure latency in the maximal PTZ model.

    Science.gov (United States)

    Trépanier, Marc-Olivier; Kwong, Kei-Man; Domenichiello, Anthony F; Chen, Chuck T; Bazinet, Richard P; Burnham, W M

    2015-09-01

    Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (n-3 PUFA) that has been shown to raise seizure thresholds in the maximal pentylenetetrazole model following acute subcutaneous (s.c.) administration in rats. Following s.c. administration, however, the dose-response relationship for DHA has shown an inverted U-pattern. The purposes of the present experiment were as follows: (1) to determine the pattern of serum unesterified concentrations resulting from the intravenous (i.v.) infusions of various doses of DHA, (2) to determine the time course of these concentrations following the discontinuation of the infusions, and (3) to determine whether seizure protection in the maximal PTZ model would correlate with serum unesterified DHA levels. Animals received 5-minute i.v. infusions of saline or 25, 50, 100, or 200mg/kg of DHA via a cannula inserted into one of the tail veins. Blood was collected during and after the infusions by means of a second cannula inserted into the other tail vein (Experiment 1). A separate group of animals received saline or 12.5-, 25-, 50-, 100-, or 200 mg/kg DHA i.v. via a cannula inserted into one of the tail veins and were then seizure-tested in the maximal PTZ model either during infusion or after the discontinuation of the infusions. Slow infusions of DHA increased serum unesterified DHA concentrations in a dose-dependent manner, with the 200-mg/kg dose increasing the concentration approximately 260-fold compared with saline-infused animals. Following discontinuation of the infusions, serum concentrations rapidly dropped toward baseline, with half-lives of approximately 40 and 11s for the 25-mg/kg dose and 100-mg/kg dose, respectively. In the seizure-tested animals, DHA significantly increased latency to seizure onset in a dose-dependent manner. Following the discontinuation of infusion, seizure latency rapidly decreased toward baseline. Overall, our study suggests that i.v. infusion of unesterified DHA results in

  12. Phase I safety, tolerability and pharmacokinetic study of recombinant human mannan-binding lectin

    DEFF Research Database (Denmark)

    Petersen, K.A.; Matthiesen, F.; Agger, T.

    2006-01-01

    (rhMBL) is in development as a novel therapeutic approach. To assess the safety, tolerability, and pharmacokinetics of rhMBL, a placebo-controlled double-blinded study was performed in MBL-deficient healthy male subjects. rhMBL was administered as both single intravenous (i.v.) infusions (0.01, 0...... mild and no serious adverse events were recorded. There were no clinically significant changes in laboratory evaluations, ECG or vital signs, and no anti-MBL antibodies were detected following rhMBL administration. After single i.v. doses of rhMBL the maximal plasma levels increased in a dose...... of the complement system without non-specific activation of the complement cascade.In conclusion, no safety or tolerability concern was raised following rhMBL administration no signs of immunogenicity detected, and an rhMBL plasma level judged sufficient to achieve therapeutic benefit (>1000 ng/mL) can be achieved....

  13. Maximal frustration as an immunological principle.

    Science.gov (United States)

    de Abreu, F Vistulo; Mostardinha, P

    2009-03-06

    A fundamental problem in immunology is that of understanding how the immune system selects promptly which cells to kill without harming the body. This problem poses an apparent paradox. Strong reactivity against pathogens seems incompatible with perfect tolerance towards self. We propose a different view on cellular reactivity to overcome this paradox: effector functions should be seen as the outcome of cellular decisions which can be in conflict with other cells' decisions. We argue that if cellular systems are frustrated, then extensive cross-reactivity among the elements in the system can decrease the reactivity of the system as a whole and induce perfect tolerance. Using numerical and mathematical analyses, we discuss two simple models that perform optimal pathogenic detection with no autoimmunity if cells are maximally frustrated. This study strongly suggests that a principle of maximal frustration could be used to build artificial immune systems. It would be interesting to test this principle in the real adaptive immune system.

  14. Limits of dose escalation in lung cancer: a dose-volume histogram analysis comparing coplanar and non-coplanar techniques

    Energy Technology Data Exchange (ETDEWEB)

    Derycke, S; Van Duyse, B; Schelfhout, J; De Neve, W

    1995-12-01

    To evaluate the feasibility of dose escalation in radiotherapy of inoperable lung cancer, a dose-volume histogram analysis was performed comparing standard coplanar (2D) with non-coplanar (3D) beam arrangements on a non-selected group of 20 patients planned by Sherouse`s GRATISTM 3D-planning system. Serial CT-scanning was performed and 2 Target Volumes (Tvs) were defined. Gross Tumor Volume (GTV) defined a high-dose Target Volume (TV-1). GTV plus location of node stations with > 10% probability of invasion (Minet et al.) defined an intermediate-dose Target Volume (TV-2). However, nodal regions which are incompatible with cure were excluded from TV-2. These are ATS-regions 1, 8, 9 and 14 all left and right as well as heterolateral regions. For 3D-planning, Beam`s Eye View selected (by an experienced planner) beam arrangements were optimised using Superdot, a method of target dose-gradient annihilation developed by Sherouse. A second 3D-planning was performed using 4 beam incidences with maximal angular separation. The linac`s isocenter for the optimal arrangement was located at the geometrical center of gravity of a tetraheder, the tetraheder`s comers being the consecutive positions of the virtual source. This ideal beam arrangement was approximated as close as possible, taking into account technical limitations (patient-couch-gantry collisions). Criteria for tolerance were met if no points inside the spinal cord exceeded 50 Gy and if at least 50% of the lung volume received less than 20Gy. If dose regions below 50 Gy were judged acceptable at TV-2, 2D- as well as 3D-plans allow safe escalation to 80 Gy at TV-1. When TV-2 needed to be encompassed by isodose surfaces exceeding 50Gy, 3D-plans were necessary to limit dose at the spinal cord below tolerance. For large TVs dose is limited by lung tolerance for 3D-plans. An analysis (including NTCP-TCP as cost functions) of rival 3D-plans is being performed.

  15. An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Takahashi, Michihiro; Takita, Yasushi; Goto, Taro; Ichikawa, Hironobu; Saito, Kazuhiko; Matsumoto, Hideo; Tanaka, Yasuo

    2011-02-01

    The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen. This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores. Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time-dependent manner; the mean change from baseline to endpoint was -15.0 (Patomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients. © 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.

  16. The H3 antagonist ABT-288 is tolerated at significantly higher exposures in subjects with schizophrenia than in healthy volunteers.

    Science.gov (United States)

    Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Gertsik, Lev; Dutta, Sandeep

    2014-06-01

    ABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia. This was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively. Of the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations. ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake. © 2013 The British Pharmacological Society.

  17. Reirradiation tolerance of the rat heart

    International Nuclear Information System (INIS)

    Wondergem, Jan; Ravels, Frank J.M. van; Reijnart, Ivonne W.C.; Strootman, Erwin G.

    1996-01-01

    Purpose: To investigate the influence of reirradiation on the tolerance of the heart after a previous irradiation treatment. Methods and Materials: Female Wistar rats were locally irradiated to the thorax. Development of cardiac function loss was studied with the ex vivo working rat heart preparation. To compare the retreatment experiments, initial, and reirradiation doses were expressed as the percentage of the extrapolated tolerance dose (ETD). Results: Local heart irradiation with a single dose led to a dose-dependent and progressive decrease in cardiac function. The progressive nature of irradiation-induced heart disease is shown to affect the outcome of the retreatment, depending on both the time interval between subsequent doses and the size of the initial dose. The present data demonstrate that hearts are capable of repairing a large part of the initial dose of 10 Gy within the first 24 h. However, once biological damage as a result of the first treatment is fixed, the heart does not show any long-term recovery. At intervals up to 6 months between an initial treatment with 10 Gy and subsequent reirradiation, the reirradiation tolerance dose slightly decreased from 74% of the ETD ref (at 24-h interval) to 68% of the ETD ref (at 6-month interval). Between 6 and 9 months, reirradiation tolerance dose dropped more even to 43% of the ETD ref . Treatment of the heart with an initial dose of 17.5 Gy, instead of 10 Gy, 6 months prior to reirradiation, also led to a further decrease of the reirradiation tolerance dose ( ref ). Conclusions: The outcome of the present study shows a decreased tolerance of the heart to reirradiation at long time intervals (interval > 6 months). This has clinical implications for the estimation of reirradiation tolerance in patients whose mediastinum has to be reirradiated a long time after a first irradiation course

  18. Multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole)

    International Nuclear Information System (INIS)

    Bleehen, N.M.; Newman, H.F.; Maughan, T.S.; Workman, P.

    1989-01-01

    The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone

  19. Normal tissue tolerance to external beam radiation therapy: Cardiac structures; Dose de tolerance des tissus sains: le coeur

    Energy Technology Data Exchange (ETDEWEB)

    Doyen, J. [Service d' oncologie-radiotherapie, centre Antoine-Lacassagne, 06 - Nice (France); Giraud, P. [Universite Rene-Descartes Paris 5, 75 - Paris (France); Service d' oncologie-radiotherapie, hopital europeen Georges-Pompidou, 75 - Paris (France); Belkacemi, Y. [Faculte de medecine de Creteil, universite Paris 12, 94 - Creteil (France); Service d' oncologie-radiotherapie, CHU Henri-Mondor, 94 - Creteil (France)

    2010-07-15

    Radiation thoracic tumors may be associated with cardiac toxicity because of the central position of the heart in the thorax. The present review aims to describe the cardiotoxicity during radiotherapy of different tumor sites most associated with this complication and the risk factors of cardiotoxicity during radiation therapy. Medline literature searches were performed using the following cardiac - heart - radiotherapy - toxicity - cardiotoxicity - breast cancer - lymphoma. Cardiac toxicity after breast cancer and mediastinal lymphoma is the most reported radiation-induced complication. The most frequent clinical complications are pericarditis, congestive heart failure, and heart infarction. These events are mostly asymptomatic. Thus clinicians have to give particular attention to these complications. Anthracycline treatment is a major risk factor for additional cardiotoxicity during radiotherapy with a synergistic effect. Correction of cardiovascular risk is an important point of the prevention of heart complications. Total dose delivered to the planned target volume (PTV), the dose per fraction and the irradiated volume were correlated to the risk of cardiotoxicity. Volume of heart receiving 35 Gy must be inferior to 30% and dose per fraction should not exceed 2 Gy when dose of prescription exceeds 30 Gy. Maximum heart distance (maximal thickness of heart irradiated) must be less than 1 cm during irradiation of breast cancer. Modern irradiation techniques seem to be associated with a limited risk of heart complication. The use of anthracycline, other cardio-toxic chemotherapies and targeted therapies should incite for great caution by performing a careful treatment planning and optimisation. (authors)

  20. The Physician Tendency in Stereotactic Radiosurgery Dose Prescription in Benign Intracranial Tumor at dr. Cipto Mangunkusumo National Hospital, Jakarta

    Directory of Open Access Journals (Sweden)

    Henry Kodrat

    2016-09-01

    Full Text Available Stereotactic radiosurgery (SRS is one of the treatment modalities for benign intra-cranial tumor, especiallyfor the tumor located next to the critical neural structure. The prescribed dose for radiosurgery depends onthe maximal tumor diameter and surrounding normal tissue tolerance dose. This cross sectional study wasconducted to evaluate the physician’s tendency in radiosurgery dose prescription. We observed treatmentplanning data of 32 patients with benign intra-cranial tumor, which had been treated with SRS at Dr. CiptoMangunkusumo National Hospital in 2009-2010. The peripheral dose, organ at risk (OAR dose limitiationand maximum tumor diameter were recorded. We compared our SRS dose with dose limitation, whichallowed safer dosing based on maximal tumor diameter perspective and the nearest OAR dose constraint.From maximal tumor diameter perspective, we prescribed mean±SD radiosurgery doses, which were11.63±2.21Gy, 10.21±1.29Gy and 9.88±1.07Gy for the tumor size ≤2cm, 2.01-3cm and 3,01-4cm respectively.Our radiosurgery dose was the lowest than dose limitation based on the nearest OAR perspective, followedby maximal tumor diameter perspective. It was concluded that radiosurgery dose had the tendency to beinfluenced by surrounding healthy tissue tolerance rather than maximal tumor diameter. Keywords: stereotactic, radiosurgery, benign tumor, dose.   Kecenderungan Dokter dalam Menentukan Dosis StereotacticRadiosurgery untuk Tumor Jinak Intrakranial diRSUP Nasional dr. Cipto Mangunkusumo, Jakarta Abstrak Stereotactic radiosurgery (SRS merupakan salah satu modalitas pengobatan tumor jinak intra-kranialterutama untuk tumor yang berdekatan dengan struktur saraf penting. Penentuan dosis pada radiosurgerytergantung pada diameter tumor maksimal dan dosis toleransi jaringan sehat sekitarnya. Penelitian inidilakukan untuk mengevaluasi kecenderungan dokter dalam menentukan dosis radiosurgery. Penelitian crosssectional ini mengevaluasi data

  1. Early Mucosal Reactions During and After Head-and-Neck Radiotherapy: Dependence of Treatment Tolerance on Radiation Dose and Schedule Duration

    International Nuclear Information System (INIS)

    Fenwick, John D.; Lawrence, Geoff P.; Malik, Zafar; Nahum, Alan E.; Mayles, W. Philip M.

    2008-01-01

    Purpose: To more precisely localize the dose-time boundary between head-and-neck radiotherapy schedules inducing tolerable and intolerable early mucosal reactions. Methods and Materials: Total cell-kill biologically effective doses (BED CK ) have been calculated for 84 schedules, including incomplete repair effects, but making no other corrections for the effect of schedule duration T. [BED CK ,T] scatterplots are graphed, overlying BED CKboundary (T) curves on the plots and using discriminant analysis to optimize BED CKboundary (T) to best represent the boundary between the tolerable and intolerable schedules. Results: More overlap than expected is seen between the tolerable and intolerable treatments in the 84-schedule [BED CK ,T] scatterplot, but this was largely eliminated by removing gap and tolerated accelerating schedules from the plot. For the remaining 57 predominantly regular schedules, the BED CKboundary (T) boundary increases with increasing T (p = 0.0001), curving upwards significantly nonlinearly (p = 0.00007) and continuing to curve beyond 15 days (p = 0.035). The regular schedule BED CKboundary (T) boundary does not describe tolerability well for accelerating schedules (p = 0.002), with several tolerated accelerating schedules lying above the boundary where regular schedules would be intolerable. Gap schedule tolerability also is not adequately described by the regular schedule boundary (p = 0.04), although no systematic offset exists between the regular boundary and the overall gap schedule tolerability pattern. Conclusions: All schedules analyzed (regular, gap, and accelerating) with BED CK values below BED CKboundary (T)=69.5x(T/32.2)/sin((T/32.2) (radians) )-3.5Gy 10 (forT≤50 days) are tolerable, and many lying above the boundary are intolerable. The accelerating schedules analyzed were tolerated better overall than are the regular schedules with similar [BED CK ,T] values.

  2. Short-term digestive tolerance of different doses of NUTRIOSE®FB, a food dextrin, in adult men

    NARCIS (Netherlands)

    Heuvel, E.G.H.M. van den; Wils, D.; Pasman, W.J.; Bakker, M.; Saniez, M.-H.; Kardinaal, A.F.M.

    2004-01-01

    Objective: To determine the tolerance of increasing dosages of an incompletely hydrolysed and/or incompletely absorbed food dextrin coming from wheat starch, NUTRIOSE®FB, at daily levels of 10 and 15 g up to 60 and 80 g, respectively. Design: A randomized, double-blind, multiple dose,

  3. Similar efficacy and tolerability of double-dose chloroquine and artemether-lumefantrine for treatment of Plasmodium falciparum infection in Guinea-Bissau: a randomized trial

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia

    2011-01-01

    In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele,......, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine.......In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele...

  4. Pegylated Long-Acting Human Growth Hormone Possesses a Promising Once-Weekly Treatment Profile, and Multiple Dosing Is Well Tolerated in Adult Patients with Growth Hormone Deficiency

    DEFF Research Database (Denmark)

    Søndergaard, Esben; Klose, Marianne Christina; Hansen, Mette

    2011-01-01

    Background: Recombinant human GH (rhGH) replacement therapy in children and adults currently requires daily sc injections for several years or lifelong, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed for once-weekly administration. Objectives......: Our objective was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of NNC126-0083 in adult patients with GH deficiency (GHD). Subjects and Methods: Thirty-three adult patients with GHD, age 20-65 yr, body mass index 18.5-35.0 kg/m(2), and glycated...... to 240 h after the third dosing. Physical examination, antibodies, and local tolerability were assessed. Results: NNC126-0083 was well tolerated with no difference in local tolerability compared with placebo and with no signs of lipoatrophy. A more than dose-proportional exposure was observed...

  5. In vivo assessment of the gastric mucosal tolerance dose after single fraction, small volume irradiation of liver malignancies by computed tomography-guided, high-dose-rate brachytherapy

    International Nuclear Information System (INIS)

    Streitparth, Florian; Pech, Maciej; Boehmig, Michael; Ruehl, Ricarda; Peters, Nils; Wieners, Gero; Steinberg, Johannes; Lopez-Haenninen, Enrique; Felix, Roland; Wust, Peter; Ricke, Jens

    2006-01-01

    Purpose: The aim of this study was to assess the tolerance dose of gastric mucosa for single-fraction computed tomography (CT)-guided, high-dose-rate (HDR) brachytherapy of liver malignancies. Methods and Materials: A total of 33 patients treated by CT-guided HDR brachytherapy of liver malignancies in segments II and/or III were included. Dose planning was performed upon a three-dimensional CT data set acquired after percutaneous applicator positioning. All patients received gastric protection post-treatment. For further analysis, the contours of the gastric wall were defined in every CT slice using Brachyvision Software. Dose-volume histograms were calculated for each treatment and correlated with clinical data derived from questionnaires assessing Common Toxicity Criteria (CTC). All patients presenting symptoms of upper GI toxicity were examined endoscopically. Results: Summarizing all patients the minimum dose applied to 1 ml of the gastric wall (D 1ml ) ranged from 6.3 to 34.2 Gy; median, 14.3 Gy. Toxicity was present in 18 patients (55%). We found nausea in 16 (69%), emesis in 9 (27%), cramping in 13 (39%), weight loss in 12 (36%), gastritis in 4 (12%), and ulceration in 5 patients (15%). We found a threshold dose D 1ml of 11 Gy for general gastric toxicity and 15.5 Gy for gastric ulceration verified by an univariate analysis (p = 0.01). Conclusions: For a single fraction, small volume irradiation we found in the upper abdomen a threshold dose D 1ml of 15.5 Gy for the clinical endpoint ulceration of the gastric mucosa. This in vivo assessment is in accordance with previously published tolerance data

  6. Effect of low dose of X rays about the tolerance to the salinity and the agricultural yield in cultivations of economic importance for Cuba

    International Nuclear Information System (INIS)

    Ramirez Fernandez, Ramiro; Gonzalez Nunnez, Luis Manuel; Garcia Rodriguez, Blanca; Licea Castro, Luis; Porras Leon, Elia

    1999-01-01

    The effect of low dose of X rays on rice and lettuce plant salt tolerance and on the agricultural yield in plants of cucumber and tomato was studied. The results showed a meaningful increase in the tolerance of the plants to salt stress in both crops for some of the applied dose and were determined the better doses for the increment of the crop yield of the studied varieties. Also was carried out an analysis of regression that showed a high correlation between the variables of the growth and the agricultural yield and on this base it is discussed the possibility of selecting the stimulant dose range during the early plants growth stages

  7. Effects of first-dose volume and exercise on the efficacy and tolerability of bowel preparations for colonoscopy in Chinese people

    Directory of Open Access Journals (Sweden)

    Qin Y

    2016-04-01

    Full Text Available Ying Qin, Wei Liu, Songbai Lin, Xiangfeng Li International Medical Services, Peking Union Medical College Hospital, Beijing, People’s Republic of China Aim: This study was designed to compare the efficacy and tolerability of bowel preparations with and without the higher first-dose volume of polyethylene glycol (PEG solution or exercise after drinking PEG solution in Chinese people. Methods: A total of 330 participants who had a colonoscopy done in Peking Union Medical College Hospital were randomly and evenly assigned to three groups. Participants in Group A ingested 1 L PEG solution and then ingested 2 L PEG solution at a rate of 250 mL every 15 minutes. Participants in Group B ingested 3 L PEG solution at a rate of 250 mL every 15 minutes and then exercised more than 10 minutes after ingesting each liter of PEG solution. Participants in Group C ingested 3 L PEG solution at a rate of 250 mL every 15 minutes. Experienced gastrointestinal endoscopists rated the efficacy of bowel preparations based on the Boston Bowel Preparation Scale score. A questionnaire regarding participants’ symptoms associated with bowel preparations was administered to evaluate participants’ tolerability. Results: The three groups had insignificant difference in the percentages of participants’ symptoms including dizziness, nausea, stomach ache, bloating, and asthenia. However, the percentages of participants having hunger sensation, sleep disturbance, and anal discomfort were significantly higher in groups with the higher first-dose volume of PEG solution or exercise after drinking PEG solution than without them. The three groups had insignificant difference in the Boston Bowel Preparation Scale score. Conclusion: Whether to add the higher first-dose volume of PEG solution and exercise after drinking PEG solution or not, all participants achieved a similar quality of bowel preparations. Bowel preparations without the additional first-dose volume of PEG

  8. Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

    Science.gov (United States)

    Han, Yi; Ayalasomayajula, Surya; Pan, Wei; Yang, Fan; Yuan, Yaozong; Langenickel, Thomas; Hinder, Markus; Kalluri, Sampath; Pal, Parasar; Sunkara, Gangadhar

    2017-02-01

    Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max ) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2 ) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC 0-last ), and maximum plasma concentration (C max ) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

  9. Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects.

    Science.gov (United States)

    Sarashina, Akiko; Koiwai, Kazuki; Seman, Leo J; Yamamura, Norio; Taniguchi, Atsushi; Negishi, Takahiro; Sesoko, Shogo; Woerle, Hans J; Dugi, Klaus A

    2013-01-01

    This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.

  10. Normal tissue tolerance to external beam radiation therapy: Peripheral nerves; Dose de tolerance a l'irradiation des tissus sains: les nerfs peripheriques

    Energy Technology Data Exchange (ETDEWEB)

    Henriques de Figueiredo, B.; Dejean, C.; Sargos, P.; Kantor, G. [Departement de radiotherapie, institut Bergonie, centre regional de lutte contre le cancer, 33 - Bordeaux (France); Huchet, A.; Mamou, N. [Service d' oncologie medicale et de radiotherapie, CHU Saint-Andre, 33 - Bordeaux (France); Loiseau, H. [Service de neurochirurgie, CHU Pellegrin, 33 - Bordeaux (France)

    2010-07-15

    Plexopathies and peripheral neuropathies appear progressively and with several years delay after radiotherapy. These lesions are observed principally after three clinical situations: supraclavicular and axillar irradiations for breast cancer, pelvic irradiations for various pathologies and limb irradiations for soft tissue sarcomas. Peripheral nerves and plexus (brachial and lumbosacral) are described as serial structures and are supposed to receive less than a given maximum dose linked to the occurrence of late injury. Literature data, mostly ancient, define the maximum tolerable dose to a threshold of 60 Gy and highlight also a great influence of fractionation and high fraction doses. For peripheral nerves, most frequent late effects are pain with significant differences of occurrence between 50 and 60 Gy. At last, associated pathologies (diabetes, vascular pathology, neuropathy) and associated treatments have probably to be taken into account as additional factors, which may increase the risk of these late radiation complications. (authors)

  11. Radiation tolerance of the spinal cord previously-damaged by tumor operation: long term neurological improvement and time-dose-volume relationships after irradiation of intraspinal gliomas

    International Nuclear Information System (INIS)

    Kopelson, G.

    1982-01-01

    Of 26 patients with intramedullary spinal cord gliomas (9 astrocytomas, 5 glioblastomas, 12 ependymomas) seen at the Massachusetts General Hospital from 1962-1980, 24 were irradiated (21 initially and 3 after post-surgical recurrence). Those 19 patients who survived at least 1 year after completion of irradiation were evaluated for post-irradiation neurological changes.No patient developed radiation myelopathy. Return to a permanently and completely normal neurological status occured for 33/51 (65%) of pre-irradiation neurological deficits. The major cause of post-irradiation neurological deterioration was tumor recurrence. Although 18/19 patients had their thoracic or lumbar spinal cords irradiated, each with field sizes greater than 10 cm, spinal cord doses approaching, equalling, or occasionally exceeding various definitions of spinal cord tolerance were tolerated well without evidence of radiation myelopathy. Spinal cords of patients with intramedullary gliomas, often with major neurological deficits prior to irradiation, may be treated safely to doses approaching or equalling spinal cord tolerance levels. These doses are expected to locally control most ependymomas and astrocytomas without an increased radiation myelopathy. Caution should be observed if doses higher than this are contemplated in an attempt to cure glioblastoma, because the 5% tolerance level of the damaged spinal remains to be defined

  12. Pharmacokinetic properties and tolerability of low-dose SoluMatrix diclofenac.

    Science.gov (United States)

    Desjardins, Paul J; Olugemo, Kemi; Solorio, Daniel; Young, Clarence L

    2015-02-01

    This study compared the pharmacokinetic properties and safety profile of low-dose (18- and 35-mg) diclofenac capsules manufactured using SoluMatrix Fine Particle Technology (Trademark of iCeutica Inc. (Philadelphia, Pennsylvania), and the technology is licensed to Iroko Pharmaceuticals, LLC (Philadelphia, Pennsylvania) for exclusive use in NSAIDs), which produces submicron-sized drug particles with enhanced dissolution properties, to those of diclofenac potassium immediate-release (IR) 50-mg tablets. This Phase 1, single-center, randomized, open-label, single-dose crossover study was conducted in 40 healthy volunteers. Subjects received, in randomized order, SoluMatrix diclofenac 18- or 35-mg capsules in the fasting condition, SoluMatrix diclofenac 35-mg capsules under fed conditions, and diclofenac potassium IR 50-mg tablets under fasting and fed conditions. Pharmacokinetic parameters (T(max), C(max), AUC(0-t), AUC(0-∞)) were calculated from the concentrations of diclofenac in the plasma. Absorption, food effect, and dose proportionality were determined using a mixed-model ANOVA for C(max), AUC(0-t), AUC(0-∞). Tolerability was assessed by recording adverse events, physical examination findings, vital sign measurements: clinical laboratory test results. Overall, 35 healthy volunteers aged 18 to 52 years completed the study. The mean age of the subjects was 33.4 years, and approximately half were men (47.5%). Median T(max) values were similar between the low-dose SoluMatrix diclofenac 35-mg capsules and the diclofenac potassium IR 50-mg tablets (both, ~1.0 hour). The mean maximum plasma concentration (C(max)) after the administration of low-dose SoluMatrix diclofenac 35-mg capsules was 26% lower than that with diclofenac potassium IR 50-mg tablets under fasting conditions (868.72 vs 1194.21 ng/mL). The administration of low-dose SoluMatrix diclofenac 35-mg capsules was associated with a 23% lower overall systemic exposure compared with that of diclofenac

  13. Tolerance of Glyphosate-Resistant Maize to Glyphosate Plus MCPA Amine Is Influenced by Dose and Timing

    Directory of Open Access Journals (Sweden)

    Nader Soltani

    2015-01-01

    Full Text Available There is little information on tolerance of glyphosate-resistant maize to glyphosate plus MCPA amine as influenced by dose and timing under Ontario environmental conditions. A total of seven field trials were conducted at various locations in Ontario, Canada, in 2011–2013 to evaluate tolerance of field maize to tank mixes of glyphosate (900 g a.e./ha plus MCPA amine (79, 158, 315, 630, 1260, 2520, or 5040 g a.e./ha at either the 4- or 8-leaf stage. The predicted dose of MCPA amine that caused 5, 10, and 20% injury was 339, 751, and 1914 g a.e./ha when applied to 4-leaf maize but only 64, 140, and 344 g a.e./ha when applied to 8-leaf maize, respectively. The predicted dose of MCPA amine that caused 5, 10, and 20% reduction in shoot dry weight of maize was 488, 844, and 1971 g a.e./ha when applied to 4-leaf maize and only 14, 136, and 616 g a.e./ha when applied to 8-leaf maize, respectively. The predicted dose of MCPA amine that caused 5, 10, and 20% yield reduction was 2557, 4247, and >5040 g a.e./ha when applied to 4-leaf maize and 184, 441, and 1245 g a.e./ha when applied to 8-leaf maize, respectively. Based on these results, glyphosate plus MCPA amine applied at the manufacturer’s recommended dose of 630 g a.e./ha applied to 4-leaf maize has potential to cause injury but the injury is transient with no significant reduction in yield. However, when glyphosate plus MCPA amine is applied to 8-leaf maize it has the potential to cause significant injury and yield loss in maize.

  14. A Detailed Dosimetric Analysis of Spinal Cord Tolerance in High-Dose Spine Radiosurgery.

    Science.gov (United States)

    Katsoulakis, Evangelia; Jackson, Andrew; Cox, Brett; Lovelock, Michael; Yamada, Yoshiya

    2017-11-01

    Dose-volume tolerance of the spinal cord (SC) in spinal stereotactic radiosurgery (SRS) is difficult to define because radiation myelitis rates are low, and published reports document cases of myelopathy but do not account for the total number of patients treated at given dose-volume combinations who do not have myelitis. This study reports SC toxicity from single-fraction spinal SRS and presents a comprehensive atlas of the incidence of adverse events to examine dose-volume predictors. A prospective database of all patients undergoing single-fraction spinal SRS at our institution between 2004 and 2011 was reviewed. SC toxicity was defined by clinical myelitis with accompanying magnetic resonance imaging (MRI) signal changes that were not attributable to tumor progression. Dose-volume histogram (DVH) atlases were created for these endpoints. Rates of adverse events with 95% confidence limits and probabilities that rates of adverse events were 13.33 Gy, and minimum doses to the hottest 0.1, 0.2, 0.5, and 1 cc were >10.66, 10.9, and 8 Gy, respectively; however, both myelitis cases occurred below the 34th percentile for Dmax and there were 194 DVHs in total with Dmax >13.33 Gy. A median SC Dmax of 13.85 Gy is safe and supports that a Dmax limit of 14 Gy carries a low <1% rate of myelopathy. No dose-volume thresholds or relationships between SC dose and myelitis were apparent. This is the largest study examining dosimetric data and radiation-induced myelitis in de novo spine SRS. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Benefits of the maximum tolerated dose (MTD) and maximum tolerated concentration (MTC) concept in aquatic toxicology

    International Nuclear Information System (INIS)

    Hutchinson, Thomas H.; Boegi, Christian; Winter, Matthew J.; Owens, J. Willie

    2009-01-01

    There is increasing recognition of the need to identify specific sublethal effects of chemicals, such as reproductive toxicity, and specific modes of actions of the chemicals, such as interference with the endocrine system. To achieve these aims requires criteria which provide a basis to interpret study findings so as to separate these specific toxicities and modes of action from not only acute lethality per se but also from severe inanition and malaise that non-specifically compromise reproductive capacity and the response of endocrine endpoints. Mammalian toxicologists have recognized that very high dose levels are sometimes required to elicit both specific adverse effects and present the potential of non-specific 'systemic toxicity'. Mammalian toxicologists have developed the concept of a maximum tolerated dose (MTD) beyond which a specific toxicity or action cannot be attributed to a test substance due to the compromised state of the organism. Ecotoxicologists are now confronted by a similar challenge and must develop an analogous concept of a MTD and the respective criteria. As examples of this conundrum, we note recent developments in efforts to validate protocols for fish reproductive toxicity and endocrine screens (e.g. some chemicals originally selected as 'negatives' elicited decreases in fecundity or changes in endpoints intended to be biomarkers for endocrine modes of action). Unless analogous criteria can be developed, the potentially confounding effects of systemic toxicity may then undermine the reliable assessment of specific reproductive effects or biomarkers such as vitellogenin or spiggin. The same issue confronts other areas of aquatic toxicology (e.g., genotoxicity) and the use of aquatic animals for preclinical assessments of drugs (e.g., use of zebrafish for drug safety assessment). We propose that there are benefits to adopting the concept of an MTD for toxicology and pharmacology studies using fish and other aquatic organisms and the

  16. Temporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV

    Energy Technology Data Exchange (ETDEWEB)

    Gillmann, Clarissa, E-mail: clarissa.gillmann@med.uni-heidelberg.de [Department of Radiation Oncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg (Germany); Jäkel, Oliver [Department of Radiation Oncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg (Germany); Heidelberg Ion Beam Therapy Center (HIT), Heidelberg (Germany); Department of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg (Germany); Schlampp, Ingmar [Department of Radiation Oncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg (Germany); Karger, Christian P. [Department of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg (Germany)

    2014-04-01

    Purpose: To compare the relative biological effectiveness (RBE)–weighted tolerance doses for temporal lobe reactions after carbon ion radiation therapy using 2 different versions of the local effect model (LEM I vs LEM IV) for the same patient collective under identical conditions. Methods and Materials: In a previous study, 59 patients were investigated, of whom 10 experienced temporal lobe reactions (TLR) after carbon ion radiation therapy for low-grade skull-base chordoma and chondrosarcoma at Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany in 2002 and 2003. TLR were detected as visible contrast enhancements on T1-weighted MRI images within a median follow-up time of 2.5 years. Although the derived RBE-weighted temporal lobe doses were based on the clinically applied LEM I, we have now recalculated the RBE-weighted dose distributions using LEM IV and derived dose-response curves with Dmax,V-1 cm³ (the RBE-weighted maximum dose in the remaining temporal lobe volume, excluding the volume of 1 cm³ with the highest dose) as an independent dosimetric variable. The resulting RBE-weighted tolerance doses were compared with those of the previous study to assess the clinical impact of LEM IV relative to LEM I. Results: The dose-response curve of LEM IV is shifted toward higher values compared to that of LEM I. The RBE-weighted tolerance dose for a 5% complication probability (TD{sub 5}) increases from 68.8 ± 3.3 to 78.3 ± 4.3 Gy (RBE) for LEM IV as compared to LEM I. Conclusions: LEM IV predicts a clinically significant increase of the RBE-weighted tolerance doses for the temporal lobe as compared to the currently applied LEM I. The limited available photon data do not allow a final conclusion as to whether RBE predictions of LEM I or LEM IV better fit better clinical experience in photon therapy. The decision about a future clinical application of LEM IV therefore requires additional analysis of temporal lobe reactions in a

  17. Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Ronald W Irwin

    Full Text Available To develop allopregnanolone as a therapeutic for Alzheimer's disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal, intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL and maximally tolerated doses (MTD in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg

  18. The individual tolerance concept is not the sole explanation for the probit dose-effect model

    Energy Technology Data Exchange (ETDEWEB)

    Newman, M.C.; McCloskey, J.T.

    2000-02-01

    Predominant methods for analyzing dose- or concentration-effect data (i.e., probit analysis) are based on the concept of individual tolerance or individual effective dose (IED, the smallest characteristic dose needed to kill an individual). An alternative explanation (stochasticity hypothesis) is that individuals do not have unique tolerances: death results from stochastic processes occurring similarly in all individuals. These opposing hypotheses were tested with two types of experiments. First, time to stupefaction (TTS) was measured for zebra fish (Brachydanio rerio) exposed to benzocaine. The same 40 fish were exposed during five trials to test if the same order for TTS was maintained among trials. The IED hypothesis was supported with a minor stochastic component being present. Second, eastern mosquitofish (Gambusia holbrooki) were exposed to sublethal or lethal NaCl concentrations until a large portion of the lethally exposed fish died. After sufficient time for recovery, fish sublethally exposed and fish surviving lethal exposure were exposed simultaneously to lethal NaCl concentrations. No statistically significant effect was found of previous exposure on survival time but a large stochastic component to the survival dynamics was obvious. Repetition of this second type of test with pentachlorophenol also provided no support for the IED hypothesis. The authors conclude that neither hypothesis alone was the sole or dominant explanation for the lognormal (probit) model. Determination of the correct explanation (IED or stochastic) or the relative contributions of each is crucial to predicting consequences to populations after repeated or chronic exposures to any particular toxicant.

  19. Induction of drought tolerant mutants of rice

    International Nuclear Information System (INIS)

    El-Hissewy, A.A.; Abd Allah, A.

    2001-01-01

    The ultimate goal of crop breeding is to develop varieties with a high yield potential and desirable agronomic characteristics. In Egypt, the most important qualities sought by breeders have been high yield potential, resistance to major diseases and insects, and improved grain and eating quality. However, breeding efforts should concentrate on varieties with the potential to minimize yield losses under unfavorable conditions such as drought, and to maximize yields when conditions are favorable. Rice (Oryza sativa L.) in Egypt is completely irrigated and a significant portion of the rice cultivated area is subject to water deficit resulting from an inadequate or insufficient irrigation supply. Drought tolerance is a complex trait in that it results from the interaction of histological and physiological characters of plant with environmental factors, both above-ground and under-ground. Accordingly, root characters are closely related to drought tolerance. Little attention has been paid in Egyptian breeding programs to root characters and their relation to shoot characters. Furthermore, induced mutations are considered as one of the most important methods to induce useful mutants, especially with improved root characters, to overcome the drought problem. The present investigation aimed to study the effect of different doses of gamma rays on several characters of three Egyptian rice varieties, i.e. 'Giza 171', 'Giza 175' and 'Giza 176' and to induce one or more mutants possessing drought tolerance

  20. Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner.

    Science.gov (United States)

    Tai, S; Hyatt, W S; Gu, C; Franks, L N; Vasiljevik, T; Brents, L K; Prather, P L; Fantegrossi, W E

    2015-12-01

    These studies probed the relationship between intrinsic efficacy and tolerance/cross-tolerance between ∆(9)-THC and synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects and cellular changes concomitant with their repeated administration in mice. Dose-effect relationships for hypothermic effects were determined in order to confirm that SCBs JWH-018 and JWH-073 are higher efficacy agonists than ∆(9)-THC in mice. Separate groups of mice were treated with saline, sub-maximal hypothermic doses of JWH-018 or JWH-073 (3.0mg/kg or 10.0mg/kg, respectively) or a maximally hypothermic dose of 30.0mg/kg ∆(9)-THC once per day for 5 consecutive days while core temperature and locomotor activity were monitored via biotelemetry. Repeated administration of all drugs resulted in tolerance to hypothermic effects, but not locomotor effects, and this tolerance was still evident 14 days after the last drug administration. Further studies treated mice with 30.0mg/kg ∆(9)-THC once per day for 4 days, then tested with SCBs on day 5. Mice with a ∆(9)-THC history were cross-tolerant to both SCBs, and this cross-tolerance also persisted 14 days after testing. Select brain regions from chronically treated mice were examined for changes in CB1 receptor expression and function. Expression and function of hypothalamic CB1Rs were reduced in mice receiving chronic drugs, but cortical CB1R expression and function were not altered. Collectively, these data demonstrate that repeated ∆(9)-THC, JWH-018 and JWH-073 can induce long-lasting tolerance to some in vivo effects, which is likely mediated by region-specific downregulation and desensitization of CB1Rs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat

    Science.gov (United States)

    Bobeck, Erin N.; Haseman, Rachel A.; Hong, Dana; Ingram, Susan L.; Morgan, Michael M.

    2012-01-01

    Systemic administration of morphine typically produces greater tolerance than higher efficacy mu-opioid receptor (MOPr) agonists, such as fentanyl. The objective of the present study was to test this relationship by measuring antinociceptive efficacy and tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray (vlPAG). MOPr agonist efficacy was evaluated by microinjecting the irreversible opioid receptor antagonist β-funaltrexamine hydrochloride (β-FNA) into the vlPAG prior to a dose-response analysis of morphine and fentanyl antinociception. In contrast to systemic administration of morphine and fentanyl, microinjection of these drugs into the vlPAG had similar efficacy as measured by similar reductions in maximal antinociception following β-FNA administration. Analysis of tolerance revealed a rightward shift in the dose-response curve to a single pretreatment with morphine, but not fentanyl. Moreover, the magnitude of tolerance to morphine was comparable following one, four, or eight pretreatments. Tolerance to fentanyl also was evident following four or eight microinjections. These data are surprising in that antinociceptive efficacy appears to vary depending on the site of administration. Moreover, the similar efficacy following microinjection of morphine and fentanyl into the vlPAG was associated with comparable tolerance, with the one exception of no tolerance to acute administration of fentanyl. Perspective These data reveal that antinociceptive tolerance following vlPAG administration of opioids develops rapidly, is evident with both morphine and fentanyl, and the magnitude is relatively consistent regardless of the number of pretreatments. PMID:22766006

  2. Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose (MTD) in Future Studies.

    Science.gov (United States)

    Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

    2015-07-01

    High doses in Tg.rasH2 carcinogenicity studies are usually set at the maximum tolerated dose (MTD), although this dose selection strategy has not been critically evaluated. We analyzed the body weight gains (BWGs), mortality, and tumor response in control and treated groups of 29 Tg.rasH2 studies conducted at BioReliance. Based on our analysis, it is evident that the MTD was exceeded at the high and/or mid-doses in several studies. The incidence of tumors in high doses was lower when compared to the low and mid-doses of both sexes. Thus, we recommend that the high dose in male mice should not exceed one-half of the estimated MTD (EMTD), as it is currently chosen, and the next dose should be one-fourth of the EMTD. Because females were less sensitive to decrements in BWG, the high dose in female mice should not exceed two-third of EMTD and the next dose group should be one-third of EMTD. If needed, a third dose group should be set at one-eighth EMTD in males and one-sixth EMTD in females. In addition, for compounds that do not show toxicity in the range finding studies, a limit dose should be applied for the 26-week carcinogenicity studies. © 2014 by The Author(s).

  3. Short-term digestive tolerance of different doses of NUTRIOSE FB, a food dextrin, in adult men.

    Science.gov (United States)

    van den Heuvel, E G H M; Wils, D; Pasman, W J; Bakker, M; Saniez, M-H; Kardinaal, A F M

    2004-07-01

    To determine the tolerance of increasing dosages of an incompletely hydrolysed and/or incompletely absorbed food dextrin coming from wheat starch, NUTRIOSE FB, at daily levels of 10 and 15 g up to 60 and 80 g, respectively. A randomized, double-blind, multiple dose, placebo-controlled, combined crossover and parallel trial. The metabolic ward of TNO Nutrition and Food Research. A total of 20 healthy men (age 31.7 +/- 9.1 y; BMI 24.5 +/- 2.9 kg/m2). One group of 10 subjects consumed on top of their diet 10, 30 and 60 g of NUTRIOSE FB or maltodextrin (placebo) daily. The other group of 10 subjects consumed 15, 45 and 80 g daily. Each dose was consumed for 7 days. Compared with placebo, flatulence occurred more frequently over the last 6 days on 30, 60 or 80 g/day of NUTRIOSE FB (P FB, the frequency of flatulence was even higher (P FB, the frequency of defecation decreased (P FB (P FB resulted in diarrhoea. Compared to baseline levels, breath H2 excretion, which was only measured after a week with 10 and 15 g of NUTRIOSE FB daily, increased (P FB is a fermentable carbohydrate and is well tolerated up to a dose of 45 g daily. Higher daily dosages (60 and 80 g) may result in flatulence, but does not result in diarrhoea. TNO Nutrition and Food Research was assigned by Roquette Frères to perform the study.

  4. Allergenicity evaluation of p-chloro-m-cresol and p-chloro-m-xylenol by non-radioactive murine local lymph-node assay and multiple-dose guinea pig maximization test

    International Nuclear Information System (INIS)

    Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu

    2003-01-01

    p-Chloro-m-cresol (PCMC) and p-chloro-m-xylenol (PCMX) are known to cause allergic contact dermatitis. For risk assessment of skin sensitizers, information on dose-response profiles in the induction and elicitation phases and cross-reactivity with analogous chemicals are important. In the non-radioactive local lymph-node assay (LLNA) using 5-bromo-2'-deoxyuridine instead of 3 H-methyl thymidine, significant effect on lymph node cell proliferation was detected at 10% PCMC and 25% PCMX, while in the multiple-dose guinea pig maximization test (GPMT) at least one animal tested in the group was sensitized at a 5 ppm induction dose of either chemical. When mean skin reaction score in an animal group maximally sensitized with each allergen with the GPMT was plotted against log challenge concentration, linear regression lines with high correlations were obtained in both cases. The calculated elicitation threshold was lower for PCMC than PCMX. The area under the linear regression line between the threshold point and 1% of the elicitation concentration, another index of relative elicitation potency, was also greater for PCMC. Bidirectional cross-reactivity between PCMX and PCMC was detected in the GPMT. PCMC was thus identified in both LLNA and GPMT as a stronger sensitizer than PCMX in both the induction and elicitation phases. These results suggest that the non-radioactive LLNA is a simple and useful method for evaluating allergenicity in the induction phase, while the GPMT using a maximally sensitized animal group is more suitable for assessing the dose-response profile and cross-reactivity in the elicitation phase

  5. First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors

    DEFF Research Database (Denmark)

    Dienstmann, Rodrigo; Lassen, Ulrik; Cebon, Jonathan

    2016-01-01

    V600-mutated advanced solid tumors. PATIENTS AND METHODS: Patients received RG7256 orally over 8 dose levels from 200 mg once a day (QD) to 2400 mg twice a day (BID) (50-, 100- and 150-mg tablets) using a classic 3 + 3 dose escalation design. RESULTS: In total, 45 patients were enrolled; most (87...... %) had advanced melanoma (94 % BRAF V600E). RG7256 was rapidly absorbed, with limited accumulation and dose-proportional increase in exposure up to 1950 mg BID. The maximal tolerated dose (MTD) was not reached. The most common drug-related adverse events (AEs) were dyspepsia (20 %), dry skin (18 %), rash...

  6. Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose in Future Studies. A Response to the Counterpoints.

    Science.gov (United States)

    Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

    2016-01-01

    We recently conducted a retrospective analysis of data collected from 29 Tg.rasH2 carcinogenicity studies conducted at our facility to determine how successful was the strategy of choosing the high dose of the 26-week studies based on an estimated maximum tolerated dose (MTD). As a result of our publication, 2 counterviews were expressed. Both counterviews illustrate very valid points in their interpretation of our data. In this article, we would like to highlight clarifications based on several points and issues they have raised in their papers, namely, the dose-level selection, determining if MTD was exceeded in 26-week studies, and a discussion on the number of dose groups to be used in the studies. © The Author(s) 2015.

  7. Design of spray dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose.

    Science.gov (United States)

    Ung, Keith T; Rao, Nagaraja; Weers, Jeffry G; Huang, Daniel; Chan, Hak-Kim

    2016-09-25

    Inhaled drugs all too often deliver only a fraction of the emitted dose to the target lung site due to deposition in the extrathoracic region (i.e., mouth and throat), which can lead to increased variation in lung exposure, and in some instances increases in local and systemic side effects. For aerosol medications, improved targeting to the lungs may be achieved by tailoring the micromeritic properties of the particles (e.g., size, density, rugosity) to minimize deposition in the mouth-throat and maximize the total lung dose. This study evaluated a co-solvent spray drying approach to modulate particle morphology and dose delivery characteristics of engineered powder formulations of insulin microparticles. The binary co-solvent system studied included water as the primary solvent mixed with an organic co-solvent, e.g., ethanol. Factors such as the relative rate of evaporation of each component of a binary co-solvent mixture, and insulin solubility in each component were considered in selecting feedstock compositions. A water-ethanol co-solvent mixture with a composition range considered suitable for modulating particle shell formation during drying was selected for experimental investigation. An Alberta Idealized Throat model was used to evaluate the in vitro total lung dose of a series of spray dried insulin formulations engineered with different bulk powder properties and delivered with two prototype inhalers that fluidize and disperse powder using different principles. The in vitro total lung dose of insulin microparticles was improved and favored for powders with low bulk density and small primary particle size, with reduction of deposition in the extrathoracic region. The results demonstrated that a total lung dose >95% of the delivered dose can be achieved with engineered particles, indicating a high degree of lung targeting, almost completely bypassing deposition in the mouth-throat. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Evaluation of the clinical maxim: "If it ain't broke, don't fix it".

    Science.gov (United States)

    Howell-Duffy, Chris; Hrynchak, Patricia K; Irving, Elizabeth L; Mouat, Graham S V; Elliott, David B

    2012-01-01

    A significant number of patients return to optometric practice dissatisfied with their spectacles. An important question is whether any of these cases are preventable. There are several different clinical maxims that are used to modify the subjective refraction when determining the refractive prescription. These maxims aim to improve patient comfort and adaptation and thereby reduce patient dissatisfaction with new spectacles. They are not based on research evidence, but rather on expert opinion gained from clinical experience. The aim of this study was to retrospectively analyze a large number of case records of dissatisfied patients to assess the possible usefulness of the prescribing maxim "if it ain't broke, don't fix it." Three hundred eighteen non-tolerance cases from a university-based Canadian optometric clinic were categorized by a focus group of optometrists. Three prescribing categories were defined and comprised cases in which application of the proposed maxim may have prevented the recheck eye examination; a more limited application of the maxim for one working distance may have been appropriate; and finally scenarios in which the maxim did not work in that the practitioner was judged to have initially followed the maxim, yet patient dissatisfaction was still reported. The remaining unallocated records comprised prescribing situations outside the scope of this study. Approximately 32% of non-tolerance cases were judged to have been preventable by use of the proposed maxim. Furthermore, an additional 10% reduction in recheck cases may have been possible by a more liberal interpretation of the maxim. Conversely, 4% of cases were deemed to comprise scenarios in which the maxim was followed yet the patient returned later to report problems with their spectacles. The prescribing maxim "if it ain't broke, don't fix it" appears to have a role in reducing recheck eye examinations and improving patient satisfaction with new spectacles.

  9. Effect of a simple dose-escalation schedule on tramadol tolerability : assessment in the clinical setting.

    Science.gov (United States)

    Tagarro, I; Herrera, J; Barutell, C; Díez, M C; Marín, M; Samper, D; Busquet, C; Rodríguez, M J

    2005-01-01

    To assess the effect of a very simple dose-escalation schedule on tramadol tolerability in clinical practice. This schedule consists of starting treatment with sustained-release tramadol 50mg twice daily, and escalating the dose around 7 days later to 100mg twice daily. Data from 1925 outpatients with non-malignant chronic pain were collected in this multicentre, prospective, comparative, non-randomised, open, observational study. A total of 1071 patients (55.6%) were included in the dose-escalation group (50mg group) and 854 patients (44.4%) in the control group (sustained-release tramadol 100mg twice daily; 100mg group). The proportion of patients who interrupted tramadol treatment due to the occurrence of adverse reactions was significantly lower in the 50mg group (5.6%) than in the 100mg group (12.6%) [p = 0.001]. In line with this, the proportion of patients who experienced at least one adverse reaction was significantly lower in the 50mg group (18.4%) than in the 100mg group (30.4%) [p = 0.001] and, interestingly, the two most frequently reported adverse reactions, nausea and dizziness, were found with a significantly lower frequency in the 50mg group (p < 0.001). Multivariate analysis showed that the risk of safety-related treatment cessations was 2.3 times higher in the 100mg group than in the 50mg group, and 2.2 times higher in females than in males. The two treatments were equally effective in reducing pain intensity (p = 0.121), measured as a reduction in pain score obtained by means of a visual analogue scale. The instauration of tramadol treatment, starting with sustained-release 50mg capsules twice daily and escalating the dose some days later to 100mg twice daily, was shown to be an effective and easy way to improve tramadol tolerability in clinical practice, whilst maintaining its analgesic efficacy.

  10. Tailored solar optics for maximal optical tolerance and concentration

    Energy Technology Data Exchange (ETDEWEB)

    Goldstein, Alex [Department of Solar Energy and Environmental Physics, Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus (Israel); Gordon, Jeffrey M. [Department of Solar Energy and Environmental Physics, Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus (Israel); The Pearlstone Center for Aeronautical Engineering Studies, Department of Mechanical Engineering, Ben-Gurion University of the Negev, Beersheva (Israel)

    2011-02-15

    Recently identified fundamental classes of dual-mirror double-tailored nonimaging optics have the potential to satisfy the pragmatic exigencies of concentrator photovoltaics. Via a comprehensive survey of their parameter space, including raytrace verification, we identify champion high-concentration high-efficiency designs that offer unprecedented optical tolerance (i.e., sensitivity to off-axis orientation) - a pivotal figure-of-merit with a basic bound that depends on concentration, exit angle, and effective solar angular radius. For comparison, results for the best corresponding dual-mirror aplanatic concentrators are also presented. (author)

  11. Maximization of bremsstrahlung and K-series production efficiencies in flash x-ray tubes

    International Nuclear Information System (INIS)

    Krehl, P.

    1986-01-01

    Historically, x-ray output of flash x-ray tubes was maximized empirically by changing the electrode geometry and varying the capacitance of the pulse generator. With the advent of high-voltage, low-impedance transmission lines, short-duration, high-current pulses could be generated with ease. An appropriate line scaling should assure that dose maximization is not reached at the expense of pulse prolongation which would reduce stop motion capability, but rather that dose rate should be maximized. Additionally, anode evaporation in the arc phase should be minimized to enhance tube life

  12. Orchid flowers tolerance to gamma-radiation

    International Nuclear Information System (INIS)

    Kikuchi, Olivia Kimiko

    2000-01-01

    Cut flowers are fresh goods that may be treated with fumigants such as methyl bromide to meet the needs of the quarantine requirements of importing countries. Irradiation is a non-chemical alternative to substitute the methyl bromide treatment of fresh products. In this research, different cut orchids were irradiated to examine their tolerance to gamma-rays. A 200 Gy dose did inhibit the Dendrobium palenopsis buds from opening, but did not cause visible damage to opened flowers. Doses of 800 and 1000 Gy were damaging because they provoked the flowers to drop from the stem. Cattleya irradiated with 750 Gy did not show any damage, and were therefore eligible for the radiation treatment. Cymbidium tolerated up to 300 Gy and above this dose dropped prematurely. On the other hand, Oncydium did not tolerate doses above 150 Gy.(author)

  13. Orchid flowers tolerance to gamma-radiation

    Energy Technology Data Exchange (ETDEWEB)

    Kikuchi, Olivia Kimiko E-mail: okikuchi@net.ipen.br

    2000-03-01

    Cut flowers are fresh goods that may be treated with fumigants such as methyl bromide to meet the needs of the quarantine requirements of importing countries. Irradiation is a non-chemical alternative to substitute the methyl bromide treatment of fresh products. In this research, different cut orchids were irradiated to examine their tolerance to gamma-rays. A 200 Gy dose did inhibit the Dendrobium palenopsis buds from opening, but did not cause visible damage to opened flowers. Doses of 800 and 1000 Gy were damaging because they provoked the flowers to drop from the stem. Cattleya irradiated with 750 Gy did not show any damage, and were therefore eligible for the radiation treatment. Cymbidium tolerated up to 300 Gy and above this dose dropped prematurely. On the other hand, Oncydium did not tolerate doses above 150 Gy.(author)

  14. Biochemical Tolerance During Low Dose Propylene Glycol Exposure in Neonates: A Formulation-Controlled Evaluation

    Directory of Open Access Journals (Sweden)

    Aida Kulo

    2012-07-01

    Full Text Available Background and purpose of the study: Propylene glycol (PG is a frequently co-administered solvent in formulations administered to neonates, but reports on its (intolerance are limited. We aimed to report on renal, metabolic and hepatic tolerance before, during and following intravenous (iv PG-paracetamol exposure and compared these data with similar datasets reported in literature on neonates exposed to PG without paracetamol or paracetamol without PG.Methods: Renal (diuresis, creatinemia, sodium, metabolic (Base Excess, Anion Gap, lactate, bicarbonate and hepatic (liver enzymes, bilirubinemia indicators before, during and following iv paracetamol-PG exposure in neonates as included in the PARANEO (paracetamol in neonates study (intra-individual trends, ANOVA were collected and analysed.Comparison with observations collected in cases exposed to either iv phenobarbital-PG or iv paracetamol-mannitol (inter-individual comparison, Mann Whitney-U test were made. Results: PG exposure (median 34.1 mg/kg/24 h did not affect postnatal renal, metabolic and hepatic adaptations in 60 cases exposed to paracetamol-PG. These indicators were similar when compared to 29 cases exposed to phenobarbital- PG or 172 cases exposed to paracetamol-mannitol.Major conclusion: Based on observations in 89 neonates, low dose PG exposure was tolerated well. Studies on PG pharmacokinetics and its covariates are needed to estimate the upper level of PG tolerance in neonates.

  15. Efficacy and tolerability of a high loading dose (25,000 IU weekly) vitamin D3 supplementation in obese children with vitamin D insufficiency/deficiency

    NARCIS (Netherlands)

    Radhakishun, Nalini N E; van Vliet, Mariska; Poland, Dennis C W; Weijer, Olivier; Beijnen, Jos H; Brandjes, Dees P M; Diamant, Michaela; von Rosenstiel, Ines A

    2014-01-01

    BACKGROUND: The recommended dose of vitamin D supplementation of 400 IU/day might be inadequate to treat obese children with vitamin D insufficiency. Therefore, we tested the efficacy and tolerability of a high loading dose vitamin D3 supplementation of 25,000 IU weekly in multiethnic obese

  16. Open-label, dose-titration tolerability study of atomoxetine hydrochloride in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Takahashi, Michihiro; Goto, Taro; Takita, Yasushi; Chung, Sang-Keun; Wang, Yufeng; Gau, Susan Shur-Fen

    2014-03-01

    The primary objective of this study was to assess the overall safety and tolerability of atomoxetine in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder (ADHD). A total of 44 patients aged ≥18 years who met the Conners' Adult ADHD Diagnostic Interview for DSM-IV diagnostic criteria for ADHD were enrolled from China, Korea, and Taiwan. In this open-label, dose-escalation study, patients received atomoxetine orally once daily over a period of eight weeks, starting at 40 mg/day (one week) up to a maximum dosage of 120 mg/day. Tolerability was evaluated by rate of discontinuation due to adverse events. Safety was assessed by recording all adverse events, laboratory tests, vital signs, and electrocardiograms. ADHD symptoms were evaluated by the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) for efficacy assessment. Thirty-four patients (77.3%) completed the study. Atomoxetine was well tolerated with a discontinuation rate of 2.3% (1/44) due to adverse events. The most commonly reported adverse events were nausea, dizziness, and somnolence. The mean change from baseline to endpoint in CAARS-Inv:SV total ADHD symptom score was -12.5 (P atomoxetine clinical trial in adult patients with ADHD in China, Korea, and Taiwan. Atomoxetine was well tolerated in doses of up to 120 mg/day with no unknown safety concerns. Copyright © 2012 Blackwell Publishing Asia Pty Ltd.

  17. OEDIPE, a software for personalized Monte Carlo dosimetry and treatment planning optimization in nuclear medicine: absorbed dose and biologically effective dose considerations

    International Nuclear Information System (INIS)

    Petitguillaume, A.; Broggio, D.; Franck, D.; Desbree, A.; Bernardini, M.; Labriolle Vaylet, C. de

    2014-01-01

    For targeted radionuclide therapies, treatment planning usually consists of the administration of standard activities without accounting for the patient-specific activity distribution, pharmacokinetics and dosimetry to organs at risk. The OEDIPE software is a user-friendly interface which has an automation level suitable for performing personalized Monte Carlo 3D dosimetry for diagnostic and therapeutic radionuclide administrations. Mean absorbed doses to regions of interest (ROIs), isodose curves superimposed on a personalized anatomical model of the patient and dose-volume histograms can be extracted from the absorbed dose 3D distribution. Moreover, to account for the differences in radiosensitivity between tumoral and healthy tissues, additional functionalities have been implemented to calculate the 3D distribution of the biologically effective dose (BED), mean BEDs to ROIs, isoBED curves and BED-volume histograms along with the Equivalent Uniform Biologically Effective Dose (EUD) to ROIs. Finally, optimization tools are available for treatment planning optimization using either the absorbed dose or BED distributions. These tools enable one to calculate the maximal injectable activity which meets tolerance criteria to organs at risk for a chosen fractionation protocol. This paper describes the functionalities available in the latest version of the OEDIPE software to perform personalized Monte Carlo dosimetry and treatment planning optimization in targeted radionuclide therapies. (authors)

  18. Overcoming beta-agonist tolerance: high dose salbutamol and ipratropium bromide. Two randomised controlled trials

    Directory of Open Access Journals (Sweden)

    Haney Sarah

    2007-03-01

    Full Text Available Abstract Background Asthmatics treated with long-acting beta-agonists have a reduced bronchodilator response to moderate doses of inhaled short acting beta-agonists during acute bronchoconstriction. It is not known if the response to higher doses of nebulised beta-agonists or other bronchodilators is impaired. We assessed the effect of long-acting beta-agonist treatment on the response to 5 mg nebulised salbutamol and to ipratropium bromide. Methods Two double-blind, placebo-controlled, crossover studies of inhaled formoterol 12 μg twice daily in patients with asthma. High-dose salbutamol: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled methacholine to produce a 20% fall in FEV1. Salbutamol 5 mg was then administered via nebuliser and the FEV1 was monitored for 20 minutes. Ipratropium: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled 4.5% saline to produce a 20% fall in FEV1. Salbutamol 200 μg or ipratropium bromide 40 μg was then inhaled and the FEV1 was monitored for 30 minutes. Four study arms compared the response to each bronchodilator after formoterol and placebo. Analyses compared the area under the bronchodilator response curves, adjusting for changes in pre-challenge FEV1, dose of provocational agent and FEV1 fall during the challenge procedure. Results The response to nebulised salbutamol was 15% lower after formoterol therapy compared to placebo (95% confidence 5 to 25%, p = 0.008. The response to ipratropium was unchanged. Conclusion Long-acting beta-agonist treatment induces tolerance to the bronchodilator effect of beta-agonists, which is not overcome by higher dose nebulised salbutamol. However, the bronchodilator response to ipratropium bromide is unaffected.

  19. Design and assessment of a 6 ps-resolution time-to-digital converter with 5 MGy gamma-dose tolerance for nuclear instrumentation

    International Nuclear Information System (INIS)

    Cao, Y.; Leroux, P.; De Cock, W.; Steyaert, M.

    2011-01-01

    Time-to-Digital Converters (TDCs) are key building blocks in time-based mixed-signal systems, used for the digitization of analog signals in time domain. A short survey on state-of-the-art TDCs is given. In order to realize a TDC with picosecond time resolution as well as multi MGy gamma-dose radiation tolerance, a novel multi-stage noise-shaping (MASH) delta-sigma (ΔΣ) TDC structure is proposed. The converter, implemented in 0.13 μm, achieves a time resolution of 5.6 ps and an ENOB of 11 bits, when the over sampling ratio (OSR) is 250. The TDC core consumes only 1.7 mW, and occupies an area of 0.11 mm 2 . Owing to the usage of circuit level radiation hardened-by-design techniques, such as passive RC oscillators and constant-g m biasing, the TDC exhibits enhanced radiation tolerance. At a low dose rate of 1.2 kGy/h, the frequency of the counting clock in the TDC remains constant up to at least 160 kGy. Even after a total dose of 3.4 MGy at a high dose rate of 30 kGy/h, the TDC still achieves a time resolution of 10.5 ps with an OSR of 250. (authors)

  20. Design and assessment of a 6 ps-resolution time-to-digital converter with 5 MGy gamma-dose tolerance for nuclear instrumentation

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Y. [ESAT-MICAS Div., Katholieke Universiteit Leuven, B-3001 Heverlee (Belgium); SCK.CEN, Belgian Nuclear Research Centre, B-2400 Mol (Belgium); Leroux, P. [ESAT-MICAS Div., Katholieke Universiteit Leuven, B-3001 Heverlee (Belgium); ICT-RELIC Div., Katholieke Hogeschool Kempen, B-2440 Geel (Belgium); De Cock, W. [SCK.CEN, Belgian Nuclear Research Centre, B-2400 Mol (Belgium); Steyaert, M. [ESAT-MICAS Div., Katholieke Universiteit Leuven, B-3001 Heverlee (Belgium)

    2011-07-01

    Time-to-Digital Converters (TDCs) are key building blocks in time-based mixed-signal systems, used for the digitization of analog signals in time domain. A short survey on state-of-the-art TDCs is given. In order to realize a TDC with picosecond time resolution as well as multi MGy gamma-dose radiation tolerance, a novel multi-stage noise-shaping (MASH) delta-sigma ({Delta}{Sigma}) TDC structure is proposed. The converter, implemented in 0.13 {mu}m, achieves a time resolution of 5.6 ps and an ENOB of 11 bits, when the over sampling ratio (OSR) is 250. The TDC core consumes only 1.7 mW, and occupies an area of 0.11 mm{sup 2}. Owing to the usage of circuit level radiation hardened-by-design techniques, such as passive RC oscillators and constant-g{sub m} biasing, the TDC exhibits enhanced radiation tolerance. At a low dose rate of 1.2 kGy/h, the frequency of the counting clock in the TDC remains constant up to at least 160 kGy. Even after a total dose of 3.4 MGy at a high dose rate of 30 kGy/h, the TDC still achieves a time resolution of 10.5 ps with an OSR of 250. (authors)

  1. The effects of low and moderate doses of caffeine supplementation on upper and lower body maximal voluntary concentric and eccentric muscle force.

    Science.gov (United States)

    Tallis, Jason; Yavuz, Harley C M

    2018-03-01

    Despite the growing quantity of literature exploring the effect of caffeine on muscular strength, there is a dearth of data that directly explores differences in erogenicity between upper and lower body musculature and the dose-response effect. The present study sought to investigate the effects of low and moderate doses of caffeine on the maximal voluntary strength of the elbow flexors and knee extensors. Ten nonspecifically strength-trained, recreationally active participants (aged 21 ± 0.3 years) completed the study. Using a randomised, counterbalanced, and double-blind approach, isokinetic concentric and eccentric strength was measured at 60 and 180°/s following administration of a placebo, 3 mg·kg -1 body mass caffeine, and 6 mg·kg -1 body mass caffeine. There was no effect of caffeine on the maximal voluntary concentric and eccentric strength of the elbow flexors, or the eccentric strength of the knee extensors. Both 3 and 6 mg·kg -1 body mass caffeine caused a significant increase in peak concentric force of the knee extensors at 180°/s. No difference was apparent between the 2 concentrations. Only 6 mg·kg -1 body mass caused an increase in peak concentric force during repeated contractions. The results infer that the effective caffeine concentration to evoke improved muscle performance may be related to muscle mass and contraction type. The present work indicates that a relatively low dose of caffeine treatment may be effective for improving lower body muscular strength, but may have little benefit for the strength of major muscular groups of the upper body.

  2. A new dose of maximal-intensity interval training in hypoxia to improve body composition and hemoglobin and hematocrit levels: a pilot study.

    Science.gov (United States)

    Camacho-Cardenosa, Marta; Camacho-Cardenosa, Alba; Martínez Guardado, Ismael; Marcos-Serrano, Marta; Timon, Rafael; Olcina, Guillermo

    2017-01-01

    This pilot study had the aim to determine the effects of a new dose of maximal-intensity interval training in hypoxia in active adults. Twenty-four university student volunteers were randomly assigned to three groups: hypoxia group, normoxia group or control group. The eight training sessions consisted of 2 sets of 5 repeated sprints of 10 seconds with a recovery of 20 seconds between sprints and a recovery period of 10 minutes between sets. Body composition was measured following standard procedures. A blood sample was taken for an immediate hematocrit (HCT) and hemoglobin (Hb) concentration assessment. An all-out 3-ute test was performed to evaluate ventilation parameters and power. HCT and Hb were significantly higher for the hypoxia group in Post- and Det- (P=0.01; P=0.03). Fat mass percentage was significantly lower for the hypoxia group in both assessments (P=0.05; P=0.05). The hypoxia group underwent a significant increase in mean power after the recovery period. A new dose of 8 sessions of maximal-intensity interval training in hypoxia is enough to decrease the percentage of fat mass and to improve HCT and Hb parameters and mean muscle power in healthy and active adults.

  3. A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

    NARCIS (Netherlands)

    C.M.L. Herpen (Carla); F.A.L.M. Eskens (Ferry); M.J.A. de Jonge (Maja); I.M.E. Desar (Ingrid); L. Hooftman (Leon); E. Bone (Elisabeth); J.N.H. Timmerbonte (Johanna); J. Verweij (Jaap)

    2010-01-01

    textabstractBackground: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with

  4. Dry powder dosing in liquid vehicles: ocular tolerance and scintigraphic evaluation of a perfluorocarbon suspension.

    Science.gov (United States)

    Zhu, Y; Wilson, C G; Meadows, D; Olejnik, O; Frier, M; Washington, N; Musson, R

    1999-11-30

    The ocular tolerance and precorneal disposition of 99mTc-labelled sterile carbon-perfluorodecalin (PFD) and carbon-aqueous suspensions were examined in a cohort of healthy volunteers. Formulations were prepared in PFD or saline using charcoal particles, radiolabelled with [99mTc]diethylenetriaminepentaacetic acid (DTPA) under GMP conditions. Colloidal silicon dioxide was used as a suspending agent. Ocular tolerance was examined following the instillation of each formulation to the eyes of 12 volunteers. The precorneal distribution of both formulations in man was monitored using gamma scintigraphy. Dynamic and static data acquisitions were taken over a period of 150 min after dosing. Carbon particulates suspended in PFD did not show any irritation to the eye. Administration of PFD formulation in man produced a significant increase in ocular retention over a saline formulation (mean residence time (MRT)=157+/-42 and 0.29+/-0.08 min, respectively, P=0.0001). Distribution of the carbon in man followed the same pattern as in a previous reported study in animals. The carbon deposited uniformly along the lid margin in the case of the PFD vehicle, whereas it agglomerated following dosing in the saline vehicle and was ejected from the eye. The novel non-aqueous vehicle system is able to significantly improve the ocular retention of charcoal particles in man and provides a unique distribution of the particles in the eye, which suggests a potential for the PFD system for the treatment of periocular diseases.

  5. A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours.

    NARCIS (Netherlands)

    Herpen, C.M.L. van; Eskens, F.A.; Jonge, M. de; Desar, I.M.E.; Hooftman, L.; Bone, E.A.; Timmer-Bonte, J.N.H.; Verweij, J.

    2010-01-01

    BACKGROUND: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel. METHODS:

  6. Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Ana M. C. Faria

    2006-01-01

    Full Text Available Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10 and Th3 (TGF-β regulatory T cells (Tregs plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB, Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE, uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral, formulation, mucosal adjuvants, combination therapy and early therapy.

  7. Normal tissue tolerance to external beam radiation therapy: Esophagus; Dose de tolerance a l'irradiation des tissus sains: l'oesophage

    Energy Technology Data Exchange (ETDEWEB)

    Bera, G.; Pointreau, Y. [Clinique d' oncologie-radiotherapie, centre Henry-S.-Kaplan, hopital Bretonneau, CHU de Tours, 37 - Tours (France); Denis, F.; Dupuis, O. [Centre Jean-Bernard, clinique Victor-Hugo, 72 - Le-Mans (France); Orain, I. [Service d' anatomie et cytologie pathologiques, hopital Trousseau, CHU de Tours, 37 - Tours (France); Crehange, G. [Departement de radiotherapie, centre Georges-Francois-Leclerc, 21 - Dijon (France)

    2010-07-15

    The esophagus is a musculo-membranous tube through which food passes from the pharynx to the stomach. Due to its anatomical location, it can be exposed to ionizing radiation in many external radiotherapy indications. Radiation-induced esophageal mucositis is clinically revealed by dysphagia and odynophagia, and usually begins 3 to 4 weeks after the start of radiation treatment. With the rise of multimodality treatments (e.g., concurrent chemoradiotherapy, dose escalation and accelerated fractionation schemes), esophageal toxicity has become a significant dose-limiting issue. Understanding the predictive factors of esophageal injury may improve the optimal delivery of treatment plans. It may help to minimize the risks, hence increasing the therapeutic ratio. Based on a large literature review, our study describes both early and late radiation-induced esophageal injuries and highlights some of the predictive factors for cervical and thoracic esophagus toxicity. These clinical and dosimetric parameters are numerous but none is consensual. The large number of dosimetric parameters strengthens the need of an overall analysis of the dose/volume histograms. The data provided is insufficient to recommend their routine use to prevent radiation-induced esophagitis. Defining guidelines for the tolerance of the esophagus to ionizing radiation remains essential for a safe and efficient treatment. (authors)

  8. A novel dose uncertainty model and its application for dose verification

    International Nuclear Information System (INIS)

    Jin Hosang; Chung Heetaek; Liu Chihray; Palta, Jatinder; Suh, Tae-Suk; Kim, Siyong

    2005-01-01

    Based on statistical approach, a novel dose uncertainty model was introduced considering both nonspatial and spatial dose deviations. Non-space-oriented uncertainty is mainly caused by dosimetric uncertainties, and space-oriented dose uncertainty is the uncertainty caused by all spatial displacements. Assuming these two parts are independent, dose difference between measurement and calculation is a linear combination of nonspatial and spatial dose uncertainties. Two assumptions were made: (1) the relative standard deviation of nonspatial dose uncertainty is inversely proportional to the dose standard deviation σ, and (2) the spatial dose uncertainty is proportional to the gradient of dose. The total dose uncertainty is a quadratic sum of the nonspatial and spatial uncertainties. The uncertainty model provides the tolerance dose bound for comparison between calculation and measurement. In the statistical uncertainty model based on a Gaussian distribution, a confidence level of 3σ theoretically confines 99.74% of measurements within the bound. By setting the confidence limit, the tolerance bound for dose comparison can be made analogous to that of existing dose comparison methods (e.g., a composite distribution analysis, a γ test, a χ evaluation, and a normalized agreement test method). However, the model considers the inherent dose uncertainty characteristics of the test points by taking into account the space-specific history of dose accumulation, while the previous methods apply a single tolerance criterion to the points, although dose uncertainty at each point is significantly different from others. Three types of one-dimensional test dose distributions (a single large field, a composite flat field made by two identical beams, and three-beam intensity-modulated fields) were made to verify the robustness of the model. For each test distribution, the dose bound predicted by the uncertainty model was compared with simulated measurements. The simulated

  9. Microbiological efficacy and tolerability of a single-dose regimen of 1 g of ceftriaxone in men with gonococcal urethritis.

    Science.gov (United States)

    Ito, Shin; Yasuda, Mitsuru; Hatazaki, Kyoko; Mizutani, Kosuke; Tsuchiya, Tomohiro; Yokoi, Shigeaki; Nakano, Masahiro; Deguchi, Takashi

    2016-09-01

    We treated men with gonococcal urethritis with a single-dose regimen of 1 g of ceftriaxone, which is recommended as the first-line treatment for gonorrhoea in Japan, to determine its microbiological outcomes and tolerability. We enrolled 255 men with gonococcal urethritis and treated them with a single-dose regimen of 1 g of ceftriaxone. We evaluated its microbiological outcomes and tolerability. We also determined ceftriaxone MICs for pretreatment isolates of Neisseria gonorrhoeae collected from the patients. The microbiological efficacy of the ceftriaxone regimen, which was determined between 5 and 9 days after treatment in 111 men based on the Japanese guideline for clinical research on antimicrobial agents in urogenital infections, was 100%. In the 194 men who returned to the clinic between 2 and 41 days after treatment, 191 (98.5%; 95% CI 96.8%-100%) were negative for N. gonorrhoeae after treatment. Ceftriaxone MICs determined for 136 pretreatment isolates obtained from these 194 men ranged from 0.001 to 0.25 mg/L. One isolate persisting after treatment exhibited a ceftriaxone MIC of 0.008 mg/L. For two isolates persisting after treatment, ceftriaxone MICs were not determined. Seven adverse events were observed in 7 (3.2%) of the 220 men treated with the ceftriaxone regimen. Four men had diarrhoea classified as grade 1. Three had urticaria during ceftriaxone administration, with one event classified as grade 1 and two events classified as grade 3. A single-dose regimen of 1 g of ceftriaxone was microbiologically effective against gonococcal urethritis and was safe and tolerable. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors

    Directory of Open Access Journals (Sweden)

    Jappe Annette

    2011-01-01

    Full Text Available Abstract Background This phase I, randomized, multicenter, open-label study investigated the pharmacokinetics, safety, and efficacy of the oral mammalian target of rapamycin inhibitor everolimus in Chinese patients with advanced solid tumors. Methods A total of 24 patients with advanced breast cancer (n = 6, gastric cancer (n = 6, non-small cell lung cancer (n = 6, or renal cell carcinoma (n = 6 who were refractory to/unsuitable for standard therapy were randomized 1:1 to oral everolimus 5 or 10 mg/day. Primary end points were pharmacokinetic parameters and safety and tolerability. Pharmacokinetic 24-h profiles were measured on day 15; trough level was measured on days 2, 8, 15, 16, and 22. Tolerability was assessed continuously. This final analysis was performed after all patients had received 6 months of study drug or had discontinued. Results Everolimus was absorbed rapidly; median Tmax was 3 h (range, 1-4 and 2 h (range, 0.9-6 in the 5 and 10 mg/day groups, respectively. Pharmacokinetic parameters increased dose proportionally from the 5 and 10 mg/day doses. Steady-state levels were achieved by day 8 or earlier. The most common adverse events suspected to be related to everolimus therapy were increased blood glucose (16.7% and 41.7% and fatigue (16.7% and 33.3% in the everolimus 5 and 10 mg/day dose cohorts, respectively. Best tumor response was stable disease in 10 (83% and 6 (50% patients in the 5 and 10 mg/day groups, respectively. Conclusions Everolimus 5 or 10 mg/day was well tolerated in Chinese patients with advanced solid tumors. The observed safety and pharmacokinetic profile of everolimus from this study were consistent with previous studies. Trial registration Chinese Health Authorities 2008L09346

  11. Dose effect comparisons between HFR and BMRR irradiated dogs with respect to healthy tissue tolerance

    International Nuclear Information System (INIS)

    Huiskamp, R.; Philipp, K.H.I.; Gavin, P.R.; Wheeler, F.J.; Siefert, A.

    1993-01-01

    Epithermal neutron beams are being developed for the application of boron neutron capture therapy (BNCT) of deep seated tumors, like glioblastoma and astrocytomas, through the intact skin. Epithermal neutrons will be moderated by the tissue mass between skin and tumour to produce the thermal neutrons necessary for the 10 B(n,α) 7 Li reaction in the target tissue. Although the neutron capture cross-sections of elements in normal tissue are several orders of magnitude lower that for boron, the high abundance of hydrogen and nitrogen will cause a significant contribution to the total absorbed radiation dose through the 1 H(n,γ) 2 H and the 14 N(n,p) 14 C reaction, respectively. Due to inevitable incomplete filtration, an epithermal beam will also contain a fast neutron component, i.e. neutrons with energies ≥ 10 keV, and a γ-photon component originating from the reactor and produced in structural and filter materials. Therefore, the resultant radiation consists of a complex of low and high LET radiation of which the constitutents vary rapidly with depth in tissue. Based on the ongoing canine healthy tissue tolerance study at the Brookhaven Medical Research Reactor (BMRR) using the epithermal beam without BSH, the relative biological effectiveness (RBE) of the fast neutron beam component has been determined for skin reactions. In addition, a open-quotes compound factorclose quotes, i.e geometry x RBE, for the 10 B(n,α) 7 Li reaction was derived for dogs irradiated at the BMRR with the epithermal beam and BSH (Gavin et al.). Currently, a healthy tissue tolerance study with BSH is being carried out at the HB11 epithermal beam of the High Flux Reactor at Petten. The present paper describes preliminary dose effect comparisons between High Flux Reactor (HFR) and BMRR irradiated dogs with respect to healthy tissue tolerance in order to refine the BSH compound factors and the fast neutron RBE for skin and brain

  12. In vitro antioxidant, hypoglycemic and oral glucose tolerance test of banana peels

    Directory of Open Access Journals (Sweden)

    V.V. Navghare

    2017-08-01

    Full Text Available Banana fruit is claimed to have antidiabetic effects despite its high calorie content, and its peels also contain vital phytoconstituents including gallocatechin. Previously banana pulp has been studied for antihyperglycemic effects, and in the present investigation antihyperglycemic effect of ethanolic extract of inner peels of Musa sapientum (EMS, Musa paradisiaca (EMP, Musa cavendish (EMC and Musa acuminata (EMA fruit was evaluated using oral glucose tolerance test in normoglycemic rats. In vitro antioxidant study was conducted using DPPH, H2O2 radical scavenging assay and ferric reducing power assay. Wistar rats were divided into fourteen groups and twelve groups received different doses of aforementioned extracts, while control group received gum acacia solution and remaining group received standard drug, glimepiride. All the rats received glucose load at a dose of 2 g/kg body weight. Groups treated with EMC and EMA showed significant decrease in glucose level (p < 0.01 at 150 min as compared to control group. In hypoglycemic study, only EMP 500 mg/kg, p.o. treated group revealed a significant decrease (p < 0.05 in glucose level at 120 min, while other groups did not show any sign of hypoglycemia. In glucose tolerance test, animals treated with EMC and EMA depicted dose dependent antihyperglycemic effect at 150 min while EMS and EMP showed significant reduction in plasma glucose at higher doses. In a similar fashion, EMA i.e. M. acuminata demonstrated highest antioxidant activity followed by EMC against DPPH radical. In ferric reducing power and H2O2 scavenging assay, EMA demonstrated maximal antioxidant activity when compared with other extracts.

  13. The impact of central lung distance, maximal heart distance, and radiation technique on the volumetric dose of the lung and heart for intact breast radiation

    International Nuclear Information System (INIS)

    Kong, F.-M.; Klein, Eric E.; Bradley, Jeffrey D.; Mansur, David B.; Taylor, Marie E.; Perez, Carlos A.; Myerson, Robert J.; Harms, William B.

    2002-01-01

    Purpose: To investigate the impact of radiographic parameter and radiation technique on the volumetric dose of lung and heart for intact breast radiation. Methods and Materials: Forty patients with both two-dimensional (2D) and computed tomographic (CT) simulations were enrolled in the study. Central lung distance (CLD), maximal heart distance (MHD), and maximal heart length (MHL) were measured under virtual simulation. Four plans were compared for each patient. Plan A used a traditional 2D tangential setup. Plan B used clinical target volume (CTV) based three-dimensional (3D) planning. Both plans C and D used a combination of a medial breast field with shallow tangents. Plan D is a further modification of plan C. Results: Under the traditional tangential setup, the mean ipsilateral lung dose and volume at 20, 30, and 40 Gy correlated linearly with CLD (R = 0.85∼0.91). The mean ipsilateral lung dose (Gy) approximated 4 times the CLD value (cm), whereas the percentage volume (%) of ipsilateral lung at 20, 30, and 40 Gy was about 10 times the CLD (cm). The mean heart dose and percentage volume at 20, 30, and 40 Gy correlated with MHD (R = 0.76∼0.80) and MHL (R 0.65∼0.75). The mean heart dose (Gy) approximated 3 times the MHD value (cm), and the percentage volume (%) of the heart at 10, 20, 30, and 40 Gy was about 6 times MHD (cm). Radiation technique impacted lung and heart dose. The 3D tangential plan (plan B) failed to reduce the volumetric dose of lung and heart from that of the 2D plan (plan A). The medial breast techniques (plans C and D) significantly decreased the volume of lung and heart receiving high doses (30 and 40 Gy). Plan D further decreased the 20 Gy volumes. By use of the medial breast technique, the lung and heart dose were not impacted by original CLD and MHD/MHL. Therefore, the improvement from the tangential technique was more remarkable for patients with CLD ≥ 3.0 cm (p<0.001). Conclusions: The CLD and MHD impact the volumetric dose of

  14. A Phase I randomized clinical trial testing the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy volunteers.

    Science.gov (United States)

    Haass-Koffler, Carolina L; Goodyear, Kimberly; Long, Victoria M; Tran, Harrison H; Loche, Antonella; Cacciaglia, Roberto; Swift, Robert M; Leggio, Lorenzo

    2017-11-15

    Preclinical work suggests that the metabotropic glutamate receptor subtype 5 (mGlu5) may represent a novel target to treat neuropsychiatric disorders, including alcohol use disorder and obesity. The goal of this first-in-man study was to evaluate the safety, tolerability and pharmacokinetics (PK) of GET 73 (PubChem SID: 329974174), a novel mGluR5 negative allosteric modulator. This was a double-blind, placebo-controlled, ascending dose, Phase I study conducted in healthy male volunteers in two experiments. GET 73 was administered as single ascending doses (N=48; Experiment 1; 10, 30, 100, 300, 450, 600-mg) or multiple ascending doses (N=32; Experiment 2; 100, 300, 450, 450-mg twice a day). Primary endpoints were the incidence of adverse events (AEs) among drug conditions and drug tolerability. The secondary endpoints were the PK parameters of GET 73 and its metabolite MET 2. Single GET 73 doses of up to 600-mg and repeated ascending doses of up to 450-mg twice/day were safe and well-tolerated. There were no serious or severe AEs. All AEs were mild or moderate in severity. Total GET 73 exposure increased with each increased GET 73 dose. A dose-related increase in mean maximum plasma drug concentration was observed after repeated dosing. Maximum plasma drug concentrations occurred between 0.5 and 2.05h after administration in all groups for both single and repeated doses. This first-in-human study indicates that GET 73, as single or multiple ascending doses, is safe and well-tolerated when administered to healthy male volunteers. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Reversal of oxycodone and hydrocodone tolerance by diazepam.

    Science.gov (United States)

    Gonek, Maciej; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L

    2017-11-01

    The Centers for Disease Control has declared opioid abuse to be an epidemic. Overdose deaths are largely assumed to be the result of excessive opioid consumption. In many of these cases, however, opioid abusers are often polydrug abusers. Benzodiazepines are one of the most commonly co-abused substances and pose a significant risk to opioid users. In 2016, the FDA required boxed warnings - the FDA's strongest warning - for prescription opioid analgesics and benzodiazepines about the serious risks associated with using these medications at the same time. The point of our studies was to evaluate the interactions between these two classes of drugs. We investigated whether diazepam adds to the depressant effects of opioids or do they alter the levels of tolerance to opioids. In the present study, we have found that the antinociceptive tolerance that developed to repeated administration of oxycodone was reversed by an acute dose of diazepam. Antinociceptive tolerance to hydrocodone was also reversed by acute injection of diazepam; however, a fourfold higher dose of diazepam was required when compared to reversal of oxycodone-induced tolerance. These doses of diazepam did not potentiate the acute antinociceptive effect of either opioid. The same dose of diazepam that reversed oxycodone antinociceptive tolerance also reversed oxycodone locomotor tolerance while having no potentiating effects. These studies show that diazepam does not potentiate the acute effect of prescription opioids but reverses the tolerance developed after chronic administration of the drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. An overview of the report: Correlation between carcinogenic potency and the maximum tolerated dose: Implications for risk assessment

    International Nuclear Information System (INIS)

    Krewski, D.; Gaylor, D.W.; Soms, A.P.; Szyszkowicz, M.

    1993-01-01

    Current practice in carcinogen bioassay calls for exposure of experimental animals at doses up to and including the maximum tolerated dose (MTD). Such studies have been used to compute measures of carcinogenic potency such as the TD 50 as well as unit risk factors such as q 1 for predicting low-dose risks. Recent studies have indicated that these measures of carcinogenic potency are highly correlated with the MTD. Carcinogenic potency has also been shown to be correlated with indicators of mutagenicity and toxicity. Correlation of the MTDs for rats and mice implies a corresponding correlation in TD 50 values for these two species. The implications of these results for cancer risk assessment are examined in light of the large variation in potency among chemicals known to induce tumors in rodents. 119 refs., 2 figs., 4 tabs

  17. Normal tissue tolerance to external beam radiation therapy: Adult bone; Dose de tolerance a l'irradiation des tissus sains: l'os chez l'adulte

    Energy Technology Data Exchange (ETDEWEB)

    Sargos, P.; Mamou, N.; Dejean, C.; Henriques de Figueiredo, B.; Kantor, G. [Departement de radiotherapie, Centre regional de lutte contre le cancer, institut Bergonie, 33 - Bordeaux (France); Huchet, A. [Departement de radiotherapie, hopital Saint-Andre, 33 - Bordeaux (France); Italiano, A. [Service d' oncologie medicale, Centre regional de lutte contre le cancer, institut Bergonie, 33 - Bordeaux (France)

    2010-07-15

    Radiation tolerance for bone tissue has been mostly evaluated with regard to bone fracture. Main circumstances are mandibula osteoradionecrosis, hip and costal fracture, and patent or radiologic fractures in the treated volume. After radiation therapy of bone metastasis, the analysis of related radiation fracture is difficult to individualize from a pathologic fracture. Frequency of clinical fracture is less than 5% in the large series or cohorts and is probably under-evaluated for the asymptomatic lesions. Women older than 50 years and with osteoporosis are probably the main population at risk. Dose-effect relations are difficult to qualify in older series. Recent models evaluating radiations toxicity on diaphysa suggest an important risk after 60 Gy, for high dose-fraction and for a large volume. (authors)

  18. Dataset for Phase I randomized clinical trial for safety and tolerability of GET 73 in single and repeated ascending doses including preliminary pharmacokinetic parameters

    Directory of Open Access Journals (Sweden)

    Carolina L. Haass-Koffler

    2017-12-01

    Full Text Available The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled “Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers” (Haass-Koffler et al., 2017 [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET 73. Keywords: Glutamate receptor subtype 5 (mGlu5, Allosteric modulator, GET 73, Safety, Tolerability

  19. 77 FR 3617 - Etoxazole; Pesticide Tolerances

    Science.gov (United States)

    2012-01-25

    ... similar doses, indicating that systemic effects (mainly liver effects) occur at similar dose levels... chromatography/mass selective detection (GC/MSD) methods) are available to enforce the tolerance expression. The...

  20. Optimizing bevacizumab dosing in glioblastoma: less is more.

    Science.gov (United States)

    Ajlan, Abdulrazag; Thomas, Piia; Albakr, Abdulrahman; Nagpal, Seema; Recht, Lawrence

    2017-10-01

    Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below maximum tolerated dose. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of 10 mg/kg every other week for glioma patients, there has not been much prior work examining whether the relatively high complication rates reported with this agent can be decreased by lowering the dose without impairing efficacy. We assessed charts from 80 patients who received BEV for glioblastoma to survey the incidence of complications relative to BEV dose. All patients were treated with standard upfront chemoradiation. The toxicity was graded based on the NCI CTCAE, version 4.03. The rate of BEV serious related adverse events was 12.5% (n = 10/80). There were no serious adverse events (≥grade 3) when the administered dose was (<3 mg/kg/week), compared to a 21% incidence in those who received higher doses (≥3 mg/kg/week) (P < 0.01). Importantly, the three patient deaths attributable to BEV administration occurred in patients receiving higher doses. Patients who received lower doses also had a better survival rate, although this did not reach statistical significance [median OS 39 for low dose group vs. 17.3 for high dose group (P = 0.07)]. Lower rates of serious BEV related toxicities are noted when lower dosages are used without diminishing positive clinical impact. Further work aimed at optimizing BEV dosage is justified.

  1. Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications

    Science.gov (United States)

    Shen, Jie; Goodkin, Margot L; Tong, Warren; Attar, Mayssa

    2017-01-01

    Purpose Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed. Methods New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve. Results Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6–8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation. Conclusion Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties

  2. Haloperidol Disrupts Opioid-Antinociceptive Tolerance and Physical Dependence

    Science.gov (United States)

    Yang, Cheng; Chen, Yan; Tang, Lei

    2011-01-01

    Previous studies from our laboratory and others have implicated a critical role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in opioid tolerance and dependence. Translational research targeting the CaMKII pathway is challenging, if not impossible, because of a lack of selective inhibitors. We discovered in a preliminary study that haloperidol, a butyrophenone antipsychotic drug, inhibited CaMKII, which led us to hypothesize that haloperidol can attenuate opioid tolerance and dependence by inhibiting CaMKII. The hypothesis was tested in two rodent models of opioid tolerance and dependence. Pretreatment with haloperidol (0.2–1.0 mg/kg i.p.) prevented the development of morphine tolerance and dependence in a dose-dependent manner. Short-term treatment with haloperidol (0.06–0.60 mg/kg i.p.) dose-dependently reversed the established morphine-antinociceptive tolerance and physical dependence. Correlating with behavioral effects, pretreatment or short-term treatment with haloperidol dose-dependently inhibited morphine-induced up-regulation of supraspinal and spinal CaMKIIα activity. Moreover, haloperidol given orally was also effective in attenuating morphine-induced CaMKIIα activity, antinociceptive tolerance, and physical dependence. Taken together, these data suggest that haloperidol attenuates opioid tolerance and dependence by suppressing CaMKII activity. Because haloperidol is a clinically used drug that can be taken orally, we propose that the drug may be of use in attenuating opioid tolerance and dependence. PMID:21436292

  3. Amino acid tolerance test using L-β-phenylalanine-125I

    International Nuclear Information System (INIS)

    Hafiez, A.A.; Megahed, Y.M.; Ismail, A.A.; Abdel-Wahab, M.F.; Khater, R.A.

    1978-01-01

    An amino acid tolerance test is described. L-β-phenylalanine- 125 I was used as representative of L-amino acids. The change in radioactivity of the blood after giving a test dose of tagged L-β-phenylalanine was also investigated. L-β-phenylalanine- 125 I tolerance curves were found to be irreproducible when the test dose was given without a carrier. The addition of 2.5 g untagged phenylalanine as a carrier to the test dose allowed a reproducible and precise type of tolerance curves. Metformin in a dose of 0.5 g t.d.s. for three days induced an inhibitory effect on amino acid absorption in normal persons. (author)

  4. Phase I dose escalation safety study of nanoparticulate paclitaxel (CTI 52010) in normal dogs.

    Science.gov (United States)

    Axiak, Sandra M; Selting, Kim A; Decedue, Charles J; Henry, Carolyn J; Tate, Deborah; Howell, Jahna; Bilof, K James; Kim, Dae Y

    2011-01-01

    Paclitaxel is highly effective in the treatment of many cancers in humans, but cannot be routinely used in dogs as currently formulated due to the exquisite sensitivity of this species to surfactant-solubilizing agents. CTI 52010 is a formulation of nanoparticulate paclitaxel consisting of drug and normal saline. Our objectives were to determine the maximally tolerated dose, dose-limiting toxicities, and pharmacokinetics of CTI 52010 administered intravenously to normal dogs. Three normal adult hound dogs were evaluated by physical examination, complete blood count, chemistry profile, and urinalysis. Dogs were treated with staggered escalating dosages of CTI 52010 with a 28-day washout. All dogs were treated with a starting dosage of 40 mg/m(2), and subsequent dosages were escalated at 50% (dog 1), 100% (dog 2), or 200% (dog 3) with each cycle, to a maximum of 240 mg/m(2). Dogs were monitored by daily physical assessment and weekly laboratory evaluation. Standard criteria were used to grade adverse events. Plasma was collected at regular intervals to determine pharmacokinetics. Dogs were euthanized humanely, and necropsy was performed one week after the last treatment. The dose-limiting toxicity was grade 4 neutropenia and the maximum tolerated dosage was 120 mg/m(2). Grade 1-2 gastrointestinal toxicity was noted at higher dosages. Upon post mortem evaluation, no evidence of organ (liver, kidney, spleen) toxicity was noted. CTI 52010 was well tolerated when administered intravenously to normal dogs. A starting dosage for a Phase I/II trial in tumor-bearing dogs is 80 mg/m(2).

  5. [Fixed-dose combination fluticasone propionate/formoterol for the treatment of asthma: a review of its pharmacology, efficacy and tolerability].

    Science.gov (United States)

    Quintano Jiménez, J A; Ginel Mendoza, L; Entrenas Costa, L M; Polo García, J

    2016-02-01

    The fixed-dose combination fluticasone propionate/formoterol (FPF) is a novel combination of a widely known and used inhaled glucocorticoid (IGC) and a long-acting β2-adrenergic agonist (LABA), available for the first time in a single device. This fixed-dose combination of FPF has a demonstrated efficacy and safety profile in clinical trials compared with its individual components and other fixed-dose combinations of IGC/LABA and is indicated for the treatment of persistent asthma in adults and adolescents. FPF is available in a wide range of doses that can adequately cover the therapeutic steps recommended by treatment guidelines, constituting a fixed-dose combination of GCI/LABA that is effective, rapid, well tolerated and with a reasonable acquisition cost. Various assessment agencies of the Spanish Autonomous Communities consider this combination to be an appropriate alternative therapy for asthma in the primary care setting. Copyright © 2016 Elsevier España, S.L.U. y Sociedad Española de Medicina Rural y Generalista (SEMERGEN). All rights reserved.

  6. Single- and Multiple-Dose Study To Determine the Safety, Tolerability, Pharmacokinetics, and Food Effect of Oral MRX-I versus Linezolid in Healthy Adult Subjects.

    Science.gov (United States)

    Eckburg, Paul B; Ge, Yigong; Hafkin, Barry

    2017-04-01

    A multipart phase 1 study was conducted to determine the safety, tolerability, pharmacokinetics, and food effect of the novel oral oxazolidinone, MRX-I, in healthy adults, as well as the tolerability of longer-term exposure of both oral MRX-I and linezolid. Thirty subjects in part 1 received single ascending doses of MRX-I or placebo under fasting or fed condition in a double-blind crossover design. Twelve subjects in part 2 received MRX-I at 800 mg every 12 h (q12h) for 14 days in a double-blind, placebo-controlled design. In part 3, 24 subjects were randomized to receive 28 days of MRX-I at 800 mg q12h or oral linezolid at 600 mg q12h for 28 days in a double-blind, double-dummy design. Oral MRX-I was associated with a greater bioavailability and exposure when administered with food, and minimal accumulation of MRX-I occurred after multiple-dose administration. Oral MRX-I was well tolerated at single doses of up to 1,200 and 800 mg q12h for up to 28 days; all adverse events were mild to moderate in severity, and there was no drug discontinuation due to adverse events. These data support further clinical development of oral MRX-I in the treatment of resistant Gram-positive bacterial infections. Copyright © 2017 American Society for Microbiology.

  7. Tolerance and efficacy of a low dose of the calcimimetic agent cinacalcet in controlling moderate to severe secondary hyperparathyroidism in hemodialysis patients.

    Science.gov (United States)

    Bashir, Salah O; Omer, Hayder A; Aamer, Mahmoud A; Somialy, Rashid; Morsy, Mohamed D

    2015-11-01

    Secondary hyperparathyroidism is almost a constant feature in chronic kidney disease (CKD) patients maintained on hemodialysis (HD). Calcimimetic agents appear to offer an alternative to surgery in controlling secondary hyperparathyroidism in these patients. Recent studies provide conflicting data on the benefits, efficacy and tolerance of cinacalcet as first-line therapy for the treatment of secondary hyperparathyroidism in CKD. This study was designed to investigate the efficacy and tolerance of a low dose of the calcimimetic agent cinacalcet in patients on long-term HD having moderate to severe secondary hyperparathyroidism. Twenty five adult male patients on HD for more than three years were included in the study. All had moderate to severe secondary hyperparathyroidism with serum intact parathyroid hormone (iPTH) >50 pmol/L, resistant to conventional treatment. We used the targets of Chronic Kidney Disease: Outcomes Quality Initiative (K/DOQI) clinical guidelines as optimal target of serum iPTH, calcium and phosphate. Patients were administered cinacalcet as a single oral daily dose of 30 mg and were followed-up for six months. Cinacalcet treatment for six months resulted in a significant reduction in the serum phosphate and iPTH levels while the serum calcium levels remained unchanged. Thirty-six percent of the patients attained the recommended serum iPTH levels, 40% achieved significant reduction of the serum iPTH levels and 24% showed no favorable response. Only one patient dropped out because of severe gastrointestinal symptoms. Our results suggest that treatment of CKD patients, having moderate to severe secondary hyperparathyroidism, with low-dose cinacalcet is effective and well tolerated.

  8. Tolerance to and cross tolerance between ethanol and nicotine.

    Science.gov (United States)

    Collins, A C; Burch, J B; de Fiebre, C M; Marks, M J

    1988-02-01

    Female DBA mice were subjected to one of four treatments: ethanol-containing or control diets, nicotine (0.2, 1.0, 5.0 mg/kg/hr) infusion or saline infusion. After removal from the liquid diets or cessation of infusion, the animals were challenged with an acute dose of ethanol or nicotine. Chronic ethanol-fed mice were tolerant to the effects of ethanol on body temperature and open field activity and were cross tolerant to the effects of nicotine on body temperature and heart rate. Nicotine infused animals were tolerant to the effects of nicotine on body temperature and rotarod performance and were cross tolerant to the effects of ethanol on body temperature. Ethanol-induced sleep time was decreased in chronic ethanol- but not chronic nicotine-treated mice. Chronic drug treatment did not alter the elimination rate of either drug. Chronic ethanol treatment did not alter the number or affinity of brain nicotinic receptors whereas chronic nicotine treatment elicited an increase in the number of [3H]-nicotine binding sites. Tolerance and cross tolerance between ethanol and nicotine is discussed in terms of potential effects on desensitization of brain nicotinic receptors.

  9. Tri-maximal vs. bi-maximal neutrino mixing

    International Nuclear Information System (INIS)

    Scott, W.G

    2000-01-01

    It is argued that data from atmospheric and solar neutrino experiments point strongly to tri-maximal or bi-maximal lepton mixing. While ('optimised') bi-maximal mixing gives an excellent a posteriori fit to the data, tri-maximal mixing is an a priori hypothesis, which is not excluded, taking account of terrestrial matter effects

  10. Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials.

    Science.gov (United States)

    Lee, Shing M; Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

    2016-04-20

    The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. © 2016 by American Society of Clinical Oncology.

  11. Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

    Science.gov (United States)

    Krishnaswami, Sriram; Boy, Mary; Chow, Vincent; Chan, Gary

    2015-03-01

    Tofacitinib is an oral Janus kinase inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs. © 2014, The American College of Clinical Pharmacology.

  12. Quantitative comparison of the results obtained by the multiple-dose guinea pig maximization test and the non-radioactive murine local lymph-node assay for various biocides.

    Science.gov (United States)

    Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu

    2005-07-01

    We compared the results of the multiple-dose guinea pig maximization test (GPMT) and the non-radioactive murine local lymph-node assay (LLNA) for various biocides. Thirteen out of 17 positive biocides in the GPMT gave positive results in the LLNA. In the GPMT, the minimum first induction doses ranged over four orders (0.00005-0.5%), while elicitation-threshold doses, which were evaluated using an optimally sensitized group of animals in the multiple-dose studies, ranged over five orders (0.00006-2.8%). In the LLNA, minimum induction doses ranged over more than three orders (0.01-30%). With respect to 13 biocides that were positive in both the GPMT and the LLNA, results were quantitatively compared. When compared after conversion to corresponding area doses (microg/cm), the minimum doses required to elicit skin reaction in guinea pigs were always lower than that for induction in mice with all biocides. Correlation between minimum induction doses from the GPMT and the LLNA seemed poor (r=0.57), while that between minimum induction doses in the LLNA and elicitation-threshold doses in the GPMT was relatively good (r=0.73). The results suggest the possibility to estimate human elicitation-threshold doses, which are definitely lacking in the process of risk assessment for skin-sensitizers, from the data of the LLNA.

  13. Quantitative comparison of the results obtained by the multiple-dose guinea pig maximization test and the non-radioactive murine local lymph-node assay for various biocides

    International Nuclear Information System (INIS)

    Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu

    2005-01-01

    We compared the results of the multiple-dose guinea pig maximization test (GPMT) and the non-radioactive murine local lymph-node assay (LLNA) for various biocides. Thirteen out of 17 positive biocides in the GPMT gave positive results in the LLNA. In the GPMT, the minimum first induction doses ranged over four orders (0.00005-0.5%), while elicitation-threshold doses, which were evaluated using an optimally sensitized group of animals in the multiple-dose studies, ranged over five orders (0.00006-2.8%). In the LLNA, minimum induction doses ranged over more than three orders (0.01-30%). With respect to 13 biocides that were positive in both the GPMT and the LLNA, results were quantitatively compared. When compared after conversion to corresponding area doses (μg/cm), the minimum doses required to elicit skin reaction in guinea pigs were always lower than that for induction in mice with all biocides. Correlation between minimum induction doses from the GPMT and the LLNA seemed poor (r = 0.57), while that between minimum induction doses in the LLNA and elicitation-threshold doses in the GPMT was relatively good (r = 0.73). The results suggest the possibility to estimate human elicitation-threshold doses, which are definitely lacking in the process of risk assessment for skin-sensitizers, from the data of the LLNA

  14. Ergogenic effect of varied doses of coffee-caffeine on maximal ...

    African Journals Online (AJOL)

    Endurance performance index (VO2 max, run time & number of exercise laps) were measured and recorded. Result: Repeated measures ANOVA was used to assess the level of significant difference between caffeine doses and placebo dose in VO2 max, run time and number of exercise laps. The result showed no ...

  15. Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications

    Directory of Open Access Journals (Sweden)

    Shen J

    2017-09-01

    Full Text Available Jie Shen,1 Margot L Goodkin,2 Warren Tong,2 Mayssa Attar3 1Clinical Pharmacology, 2Clinical Development, 3Clinical Pharmacology, Metabolism and Immunology, Allergan plc, Irvine, CA, USA Purpose: Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP, but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed.Methods: New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve.Results: Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6–8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans, suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation.Conclusion: Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid

  16. Dose-escalated total body irradiation and autologous stem cell transplantation for refractory hematologic malignancy

    International Nuclear Information System (INIS)

    McAfee, Steven L.; Powell, Simon N.; Colby, Christine; Spitzer, Thomas R.

    2002-01-01

    Purpose: To evaluate the feasibility of dose escalation of total body irradiation (TBI) above the previously reported maximally tolerated dose, we have undertaken a Phase I-II trial of dose-escalated TBI with autologous peripheral blood stem cell transplantation (PBSCT) for chemotherapy-refractory lymphoma. Methods and Materials: Nine lymphoma patients with primary refractory disease (PRD) or in resistant relapse (RR) received dose-escalated TBI and PBSCT. The three dose levels of fractionated TBI (200 cGy twice daily) were 1,600 cGy, 1,800 cGy, and 2,000 cGy. Lung blocks were used to reduce the TBI transmission dose by 50%, and the chest wall dose was supplemented to the prescribed dose using electrons. Shielding of the kidneys was performed to keep the maximal renal dose at 1,600 cGy. Three patients, two with non-Hodgkin's lymphoma (NHL) in RR and one with PRD Hodgkin's disease, received 1,600 cGy + PBSCT, three patients (two NHL in RR, one PRD) received 1,800 cGy + PBSCT, and three patients with NHL (two in RR, one PRD) received 2,000 cGy + PBSCT. Results: Toxicities associated with this high-dose TBI regimen included reversible hepatic veno-occlusive disease in 1 patient, Grade 2 mucositis requiring narcotic analgesics in 8 patients, and neurologic toxicities consisting of a symmetrical sensory neuropathy (n=4) and Lhermitte's syndrome (n=1). Interstitial pneumonitis developed in 1 patient who received 1,800 cGy after receiving recombinant α-interferon (with exacerbation after rechallenge with interferon). Six (66%) patients achieved a response. Four (44%) patients achieved complete responses, three of which were of a duration greater than 1 year, and 2 (22%) patients achieved a partial response. One patient remains disease-free more than 5 years posttransplant. Corticosteroid-induced gastritis and postoperative infection resulted in the death of 1 patient in complete response, 429 days posttransplant. Conclusion: TBI in a dose range 1,600-2,000 cGy as

  17. [Comparative study on the tolerance and efficacy of high doses of metoclopramide and clebopride in vomiting induced by cisplatin].

    Science.gov (United States)

    Martín, M; Díaz-Rubio, E

    1989-06-10

    Forty-one patients treated with cisplatin (100-120 mg/m2), alone or associated with vindesine (3 mg/m2), were included in a randomized crossover pilot study which compared 3 different doses of intravenous clebopride with intravenous metoclopramide. The patients were randomly assigned to receive clebopride in the first chemotherapy course in one of the three dose levels used (0.5 mg/kg, 21 patients; 0.75 mg/kg, 11 patients; 1 mg/kg, 10 patients) or metoclopramide (10 mg/kg). In the second course of the same chemotherapy the patients received the alternative antiemetic, and thus each patient was his own control. The total dose of both antiemetic drugs was infused in 5 intravenous fractions given every 2 hours. The antiemetic activity of clebopride was moderately lower to that of metoclopramide with the first two tested doses (overall doses of 0.5 and 0.75 mg/kg) and similar with the last dose (1 mg/kg). Clebopride was reasonably well tolerated at the used dosages, inducing sedation in 20% of cases (versus 24% with metoclopramide) and diarrhea in 37% (versus 20% with metoclopramide). Extrapyramidal reactions developed in 17% of the courses which included metoclopramide and in none including clebopride. This difference was statistically significant.

  18. Commercialization of radiation tolerant camera

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yong Bum; Choi, Young Soo; Kim, Sun Ku; Lee, Jong Min; Cha, Bung Hun; Lee, Nam Ho; Byun, Eiy Gyo; Yoo, Seun Wook; Choi, Bum Ki; Yoon, Sung Up; Kim, Hyun Gun; Sin, Jeong Hun; So, Suk Il

    1999-12-01

    In this project, radiation tolerant camera which tolerates 10{sup 6} - 10{sup 8} rad total dose is developed. In order to develop radiation tolerant camera, radiation effect of camera components was examined and evaluated, and camera configuration was studied. By the result of evaluation, the components were decided and design was performed. Vidicon tube was selected to use by image sensor and non-browning optics and camera driving circuit were applied. The controller needed for CCTV camera system, lens, light, pan/tilt controller, was designed by the concept of remote control. And two type of radiation tolerant camera were fabricated consider to use in underwater environment or normal environment. (author)

  19. Commercialization of radiation tolerant camera

    International Nuclear Information System (INIS)

    Lee, Yong Bum; Choi, Young Soo; Kim, Sun Ku; Lee, Jong Min; Cha, Bung Hun; Lee, Nam Ho; Byun, Eiy Gyo; Yoo, Seun Wook; Choi, Bum Ki; Yoon, Sung Up; Kim, Hyun Gun; Sin, Jeong Hun; So, Suk Il

    1999-12-01

    In this project, radiation tolerant camera which tolerates 10 6 - 10 8 rad total dose is developed. In order to develop radiation tolerant camera, radiation effect of camera components was examined and evaluated, and camera configuration was studied. By the result of evaluation, the components were decided and design was performed. Vidicon tube was selected to use by image sensor and non-browning optics and camera driving circuit were applied. The controller needed for CCTV camera system, lens, light, pan/tilt controller, was designed by the concept of remote control. And two type of radiation tolerant camera were fabricated consider to use in underwater environment or normal environment. (author)

  20. Relative safety profiles of high dose statin regimens

    Directory of Open Access Journals (Sweden)

    Carlos Escobar

    2008-06-01

    Full Text Available Carlos Escobar, Rocio Echarri, Vivencio BarriosDepartment of Cardiology, Hospital Ramón y Cajal, Madrid, SpainAbstract: Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.Keywords: statins, high doses, tolerability, liver, muscle

  1. Dose-response relationship in the treatment of gastrointestinal disorders.

    Science.gov (United States)

    Weihrauch, T R; Demol, P

    1989-08-01

    Numerous clinical studies have been performed to establish efficacy and safety of drugs in gastroenterological disorders. Only in a few if any of these studies, however, the rationale for the optimal dose and the dose regimens, respectively, have been addressed. Adequate and well-controlled dose finding studies play a key role in the clinical assessment of new drugs and in the evaluation of new indications. Hereby the range from the minimal effective dose to the maximal effective and well tolerated dose can be assessed and thus the optimal dose-range and dosage regimen be determined. Meaningful pharmacodynamic studies can be performed in the gastrointestinal tract also in healthy volunteers provided that a method with a high predictability for the desired therapeutic effect is available such as measurement of gastric acid secretion and its inhibition by a drug. Dose finding studies in gastroenterology can be carried out under two main aspects: First, to assess the pharmacodynamic and therapeutic effect of a compound on the gastrointestinal tract (e.g. anti-ulcer drug). Second, to evaluate the side effects of a drug on the gastrointestinal tract (e.g. gastric mucosal damage by non-steroidal anti-inflammatory drugs). For the evaluation of new drugs in gastrointestinal therapy a number of methods are available which yield accurate and reproducible data. While careful clinical-pharmacological dose-response studies using these methods have been carried out already more than a decade ago, it is surprising that therapeutic dose finding studies have become available only during the past few years. For scientific as well as for ethical reasons more trials which determine the optimal therapeutic dose are warranted.

  2. Tolerance of cut flowers to gamma-radiation

    International Nuclear Information System (INIS)

    Kikuchi, O.K.; Wiendl, F.M.; Arthur, V.

    1999-01-01

    Cut flowers were gamma-irradiated with doses of 0, 200, 400, 600, and 1000 Gy. Dianthuscaryophyllus (Caryophyllaceae), Gypsophila paniculata (Caryophyllaceae), Freesia sp (Iridaceae), Limonium sinuatum Mill. (Plumbaginaceae), L. latifolium Kuntze (Plumbaginaceae), Narcissus tazetta L. (Amaryllidaceae), Helichrysum bracteatum Andr. (Compositae) and Rhodanthe manglesii Lindl (Compositae) were tolerant up to 1000 Gy, without visible negative changes after irradiation and during the vase-life. Callistephus chinensis (Compositae) and Lilium longiflorum Thunb. (Liliaceae) were moderately tolerant, but were modified by high doses. Anthurium sp (Araceae), Strelitzia sp (Musaceae), Matthiola incana R. Br. (Cruciferae), Aechmea distichanta (Bromeliaceae), Consolida ajacis Niew (Ranunculaceae), Ranunculus sp (Ranunculaceae), Dendrobium phalenopsis (Orchidaceae) and Gerbera sp (Compositae) were not tolerant to a dose of 200 Gy. The most adequate flowers to be submitted to irradiation treatment for disinfestation purpose were those of the Caryophillaceae family and those which can be used as dried flowers, such as members of the Rhodanthe, Helichrysum and Limmonium genera. (author)

  3. Assessment of cardiovascular reflexes is of limited value in predicting maximal +Gz-tolerance

    NARCIS (Netherlands)

    van Lieshout, E. J.; van Lieshout, J. J.; Krol, J.; Simons, M.; Karemaker, J. M.

    1992-01-01

    The importance of +Gz-induced loss of consciousness as a major cause of inflight incapacitation emphasizes the need for predicting +Gz-tolerance and investigating its possible determinants. The cardiovascular changes from +Gz-stress are initially counteracted reflexly by the cardiovascular autonomic

  4. A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.

    Science.gov (United States)

    Palmer, Melissa; Jennings, Lee; Silberg, Debra G; Bliss, Caleb; Martin, Patrick

    2018-03-16

    Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat. Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids. All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0-4) to 2 (0-8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of - 0.70 mmol/L (range - 2.8 to 0.4) and - 0.6990

  5. Attenuation of morphine tolerance and dependence by thymoquinone in mice

    Directory of Open Access Journals (Sweden)

    Hossein Hosseinzadeh

    2016-01-01

    Full Text Available Objectives: Dependence and tolerance are major restricting factors in the clinical use of opioid analgesics. In the present study, the effects of thymoquinone, the major constituent of Nigella sativa seeds, on morphine dependence and tolerance were investigated in mice. Materials and Methods: Male adult NMRI mice were made tolerant and dependent by repeated injections of morphine (50, 50, and 75 mg/kg, i.p. on 9 a.m., 1 p.m., and 5 p.m., respectively during a 3-day administration schedule. The hot-plate test was used to assess tolerance to the analgesic effects of morphine. Naloxone (2 mg/kg, i.p. was injected to precipitate withdrawal syndrome in order to assess the morphine dependence. To evaluate the effects of thymoquinone on tolerance and dependence to morphine, different single or repeated doses of thymoquinone were administered in mice. Rotarod was used to assess the motor coordination. Results: Administration of single or repeated doses of thymoquinone (20 and 40 mg/kg, i.p. significantly decreased the number of jumps in morphine dependent animals. Repeated administration of thymoquinone (20 and 40 mg/kg, for 3 days and also single injection of thymoquinone (40 mg/kg, on the fourth day attenuated tolerance to the analgesic effect of morphine. None of the thymoquinone doses (10, 20, and 40 mg/kg produced any antinociceptive effects on their own. Motor coordination of animals was impaired by the high dose of thymoquinone (40 mg/kg. Conclusion: Based on these results, it can be concluded that thymoquinone prevents the development of tolerance and dependence to morphine.

  6. Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A.; Trofimov, Alexei [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 (United States)

    2013-05-15

    Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor

  7. Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

    International Nuclear Information System (INIS)

    Zeng Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A.; Trofimov, Alexei

    2013-01-01

    Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor

  8. Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions.

    Science.gov (United States)

    Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A; Trofimov, Alexei

    2013-05-01

    Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability

  9. Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.

    Science.gov (United States)

    Pegram, Mark D; Borges, Virginia F; Ibrahim, Nuhad; Fuloria, Jyotsna; Shapiro, Charles; Perez, Susan; Wang, Karen; Schaedli Stark, Franziska; Courtenay Luck, Nigel

    2009-01-01

    . Repeated iv administration of AS1402 was well tolerated, with a maximum tolerated dose (MTD) exceeding 16 mg/kg, the highest dose administered in this study. The half-life and exposure of AS1402 were such that weekly dosing could achieve plasma concentrations corresponding to the maximal ADCC activity observed in vitro. A phase II study is ongoing to evaluate the clinical activity of AS1402 in patients with advanced breast cancer. ClinicalTrials.gov Identifier: NCT00096057.

  10. 75 FR 53586 - Bifenazate; Pesticide Tolerances

    Science.gov (United States)

    2010-09-01

    ... characterized and were seen at dose(s) that produce evidence of overt systemic toxicity. These effects included... system, and these findings may be due to secondary effect of overt systemic toxicity. Further, there is... Adequate enforcement methodology is available to enforce the tolerance expression. High-performance liquid...

  11. Intravascular ultrasound based dose assessment in endovascular brachytherapy

    International Nuclear Information System (INIS)

    Catalano, Gianpiero; Tamburini, Vittorio; Colombo, Antonio; Nishida, Takahiro; Parisi, Giovanni; Mazzetta, Chiara; Orecchia, Roberto

    2003-01-01

    Background: the role of endovascular brachytherapy in restenosis prevention is well documented. Dose is usually prescribed at a fixed distance from the source axis by angiographic quantification of vessel diameter. Recently, intravascular ultrasound (IVUS) was introduced in dose prescription, allowing a better evaluation of the vessel anatomy. This study retrospectively explores the difference between prescription following angiographic vessel sizing and delivered dose calculated with IVUS. Methods and results: Seventeen lesions were studied with IVUS, identifying on irradiated segment, three sections on which measuring minimal and maximal distance from the centre of IVUS catheter to the adventitia; using dedicated software, corresponding doses were calculated. The dose ranged widely, with maximal and minimal values of 71.6 and 4.9 Gy; furthermore, heterogeneity in dose among different sections was observed. In the central section, the maximal dose was 206% of the one prescribed with the QCA model at 2 mm from the source axis, while the minimal dose was 96%. In proximal and distal sections, respective values were 182, 45, 243, and 122%. Conclusions: Our analysis confirmed the dose inhomogeneity delivered with an angiographic fixed-dose prescription strategy. A dose variation was found along the irradiated segment due to the differences in vessel thickness. IVUS emerged as an important tool in endovascular brachytherapy, especially for irregular-shaped vessels

  12. A fixed-dose combination tablet of gemigliptin and metformin sustained release has comparable pharmacodynamic, pharmacokinetic, and tolerability profiles to separate tablets in healthy subjects.

    Science.gov (United States)

    Park, Sang-In; Lee, Howard; Oh, Jaeseong; Lim, Kyoung Soo; Jang, In-Jin; Kim, Jeong-Ae; Jung, Jong Hyuk; Yu, Kyung-Sang

    2015-01-01

    In type 2 diabetes mellitus, fixed-dose combination (FDC) can provide the complementary benefits of correction of multiple pathophysiologic defects such as dysfunctions in glycemic or metabolic control while improving compliance compared with separate tablets taken together. The objective of the study reported here was to compare the pharmacodynamic (PD), pharmacokinetic (PK), and tolerability profiles of gemigliptin and extended-release metformin (metformin XR) between FDC and separate tablets. A randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 28 healthy male volunteers. Two FDC tablets of gemigliptin/metformin 25/500 mg or separate tablets of gemigliptin (50 mg ×1) and metformin XR (500 mg ×2) were orally administered in each period. Serial blood samples were collected up to 48 hours post-dose to determine dipeptidyl peptidase 4 (DPP-4) activity using spectrophotometric assay and concentrations of gemigliptin and metformin using tandem mass spectrometry. Geometric mean ratios (GMRs) of FDC to separate tablet formulations and their 90% confidence intervals (CIs) were calculated to compare the PD and PK parameters between the two formulations. Tolerability was assessed throughout the study. The plasma DPP-4 activity-time curves of the FDC and the separate tablets almost overlapped, leading to a GMR (90% CI) of the FDC to separate tablets for the plasma DPP-4 activity and its maximum inhibition of 1.00 (0.97-1.04) and 0.92 (0.82-1.05), respectively. Likewise, all of the GMRs (90% CIs) of FDC to separate tablets for the area under the plasma concentration-time curve and maximum plasma concentration of gemigliptin and metformin fell entirely within the conventional bioequivalence range of 0.80-1.25. Both the FDC and separate tablets were well tolerated. The PD, PK, and tolerability profiles of gemigliptin and metformin XR in FDC and separate tablets were found to be comparable. The FDC tablet of gemigliptin and metformin

  13. Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study

    Directory of Open Access Journals (Sweden)

    Xu HR

    2016-05-01

    Full Text Available Hongrong Xu,1,* Lei Sheng,1,* Weili Chen,1 Fei Yuan,1 Mengjie Yang,1 Hui Li,1 Xuening Li,1 John Choi,2 Guiyu Zhao,2 Tianxin Hu,2 Yongguo Li,2 Yi Zhang,2 Li Chen2 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 2Department of Clinical Research & Development, Hua Medicine, Shanghai, People’s Republic of China *These authors have contributed equally to this work Background: HMS5552, a novel fourth-generation glucokinase (GK activator, has demonstrated promising effects on glycemic control in preclinical models of type 2 diabetes. This single ascending dose study was conducted to investigate the safety, tolerability, pharmacokinetics (PK, and pharmacodynamics (PD of HMS5552 during its first-in-human exposure.Methods: Sixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg, ten subjects were randomized with eight subjects receiving the same cohort-dose of HMS5552 and two receiving placebo. Plasma HMS5552 exposure, glucose, and insulin were measured repeatedly during fasting and after a standardized meal. Assessment included safety, PK, and PD endpoints.Results: HMS5552 showed dose-proportional increases in area under the curve 0 to the last quantifiable concentration (AUC0–t and maximum plasma concentration (Cmax. Slopes estimated by linear regression for AUC0–t and Cmax were ~1.0 (0.932 and 0.933, respectively. Geometric mean elimination half-life ranged from 4.48 to 7.51 hours and apparent clearance ranged from 11.5 to 13.1 L/h across all doses. No significant sex effect was observed in PK parameters. HMS5552 also demonstrated dose-related PD responses in terms of maximum glucose change from baseline (% and mean glucose area under effect curve 0–4 hours change from baseline (% (P<0.001. Fifteen adverse events were reported by nine subjects (ten with HMS5552 and five with the placebo. All adverse events were mild in intensity and resolved without any treatment

  14. Phenomenology of maximal and near-maximal lepton mixing

    International Nuclear Information System (INIS)

    Gonzalez-Garcia, M. C.; Pena-Garay, Carlos; Nir, Yosef; Smirnov, Alexei Yu.

    2001-01-01

    The possible existence of maximal or near-maximal lepton mixing constitutes an intriguing challenge for fundamental theories of flavor. We study the phenomenological consequences of maximal and near-maximal mixing of the electron neutrino with other (x=tau and/or muon) neutrinos. We describe the deviations from maximal mixing in terms of a parameter ε(equivalent to)1-2sin 2 θ ex and quantify the present experimental status for |ε| e mixing comes from solar neutrino experiments. We find that the global analysis of solar neutrino data allows maximal mixing with confidence level better than 99% for 10 -8 eV 2 ∼ 2 ∼ -7 eV 2 . In the mass ranges Δm 2 ∼>1.5x10 -5 eV 2 and 4x10 -10 eV 2 ∼ 2 ∼ -7 eV 2 the full interval |ε| e mixing in atmospheric neutrinos, supernova neutrinos, and neutrinoless double beta decay

  15. Effects of Insulin on Brain Glucose Metabolism in Impaired Glucose Tolerance

    Science.gov (United States)

    Hirvonen, Jussi; Virtanen, Kirsi A.; Nummenmaa, Lauri; Hannukainen, Jarna C.; Honka, Miikka-Juhani; Bucci, Marco; Nesterov, Sergey V.; Parkkola, Riitta; Rinne, Juha; Iozzo, Patricia; Nuutila, Pirjo

    2011-01-01

    OBJECTIVE Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance. RESEARCH DESIGN AND METHODS We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [18F]fluorodeoxyglucose (for brain glucose metabolism) and [15O]H2O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling. RESULTS The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group. CONCLUSIONS We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance. PMID:21270256

  16. Estimation of dependence between mean of fractionation of photons and neutrons dose and intensity of post-irradiation reaction of mouse large intestine

    International Nuclear Information System (INIS)

    Gasinska, A.

    1995-01-01

    The aim of the work was verification of mouse large intestine tolerance on fractionated 250 kV X-rays and 2.3 MeV neutrons doses. Two cm of large intestine of mouse CBA/HT strain were irradiated with various fraction doses: from 0.25 to 35 Gy of X-rays and 0.05-12 Gy of neutrons. The measure of injury was handicap of intestine function. Early post-irradiation reaction was measured by loss of body weight (2-3 weeks after irradiation) and mouse mortality (till 2 months after irradiation, LD50/2). The late reaction was measured on the base of maximal body weight in 1 year period after irradiation, deformation of excrements (after 10 months) and death of animals (till 12. month after irradiation, LD50/12). Fractionation of X-ray dose influenced on decrease of intensification of late irradiation effects. After fractionation of neutrons this effect has not been observed. α/β coefficient for X-rays was 19.9 Gy [15.2; 27.0] for body weight nadir, 13.4 Gy [9.3; 19.5] for early mortality (LD50/2), 6.4 Gy [3.6;11.0] for maximal body weight and 6.9 [4.2; 10.8] for late mortality (LD50/12). Analysis of influence of low doses of photons 90.25-4 Gy) and neutrons (0.05-0.8 Gy) showed trend to reduction α/β for photons only (LD50/2=5.4 Gy; LD50/12=4.6 Gy). α/β coefficient for neutrons was defined by LQ model only for maximal body weight and was 19.9 Gy [9.5; 61.0]. In application of graphic method α/β for neutrons was 230 Gy for early and 48 Gy for late effects. Lower values of α/β coefficient for late irradiation effects for photon radiation demonstrate the big influence of fractionation of photons dose on large intestine tolerance (decrease intensity in all biological effects). Author did not observe increase of intestine tolerance in fractionation of neutrons dose. Effect of irradiation damages repair in interfraction pauses, measured by percent of regenerated dose (F r ) was much bigger for photons. For X-rays it was 50% for early and 63% for late effects. In case of

  17. The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome

    KAUST Repository

    Hurst, Laurence D.; Ghanbarian, Avazeh T.; Forrest, Alistair R. R.; Huminiecki, Lukasz

    2015-01-01

    to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia

  18. Indexes of carbohydrate exchange (CE) and results of toleration test to glucose after effect of low dose of ionizing radiation in late periods

    International Nuclear Information System (INIS)

    Akhmetov, E.A.

    1997-01-01

    The indexes of tolerance test to glucose and values of generalized criterion (GC) being information index of CE system status were determined for 100 liquidators of Chernobyl accident with purpose of study of carbohydrate exchange (CE) status. Analysis of these mean values was carried out according to participation data in liquidation works, exposition duration, rate of radioactive contamination of zone, absorbed dose of external irradiation and age of examined persons. Contribution of each studied components of radiation factor on CE status is estimated. It is determined that both the absorbed dose and the exposition duration are main factors influencing on CE. In examined group there were 32 men with disorders of CE , 20 of them (GC=18.33±0.48) were placed to group of higher risk, 9 men have high tolerance of organism to glucose (GC=32.84±1.37) and 3 men have diabetes of II type (GC=68.6±2.16). Frequency of cases of liquidators' of Chernobyl accident CE disorders allows to made conclusion that ills have dis-function of endocrine section of pancreas

  19. Caffeine tolerance: behavioral, electrophysiological and neurochemical evidence

    International Nuclear Information System (INIS)

    Chou, D.T.; Khan, S.; Forde, J.; Hirsh, K.R.

    1985-01-01

    The development of tolerance to the stimulatory action of caffeine upon mesencephalic reticular neurons and upon spontaneous locomotor activity was evaluated in rats after two weeks of chronic exposure to low doses of caffeine (5-10 mg/kg/day via their drinking water). These doses are achievable through dietary intake of caffeine-containing beverages in man. Concomitant measurement of [ 3 H]-CHA binding in the mesencephalic reticular formation was also carried out in order to explore the neurochemical basis of the development of tolerance. Caffeine, 2.5 mg/kg i.v., markedly increased the firing rate of reticular neurons in caffeine naive rats but failed to modify the neuronal activity in a group exposed chronically to low doses of caffeine. In addition, in spontaneous locomotor activity studies, the data show a distinct shift to the right of the caffeine dose-response curve in caffeine pretreated rats. These results clearly indicate that tolerance develops to the stimulatory action of caffeine upon the reticular formation at the single neuronal activity level as well as upon spontaneous locomotor activity. Furthermore, in chronically caffeine exposed rats, an increase in the number of binding sites for [ 3 H]-CHA was observed in reticular formation membranes without any change in receptor affinity. 28 references, 4 figures

  20. In vivo assessment of the tolerance dose of small liver volumes after single-fraction HDR irradiation

    International Nuclear Information System (INIS)

    Ricke, Jens; Seidensticker, Max; Luedemann, Lutz; Pech, Maciej; Wieners, Gero; Hengst, Susanne; Mohnike, Konrad; Cho, Chie Hee; Lopez Haenninen, Enrique; Al-Abadi, Hussain; Felix, Roland; Wust, Peter

    2005-01-01

    Purpose: To prospectively assess a dose-response relationship for small volumes of liver parenchyma after single-fraction irradiation. Methods and Materials: Twenty-five liver metastases were treated by computed tomography (CT)-guided interstitial brachytherapy. Magnetic resonance imaging was performed 1 day before and 3 days and 6, 12, and 24 weeks after therapy. MR sequences included T1-w gradient echo (GRE) enhanced by hepatocyte-targeted gadobenate dimeglumine. All MRI data sets were merged with 3D dosimetry data and evaluated by two radiologists. The reviewers indicated the border of hyperintensity on T2-w images (edema) or hypointensity on T1-w images (loss of hepatocyte function). Based on the total 3D data, a dose-volume histogram was calculated. We estimated the threshold dose for either edema or function loss as the D 90 , i.e., the dose achieved in at least 90% of the pseudolesion volume. Results: Between 3 days and 6 weeks, the extension of the edema increased significantly from the 12.9 Gy isosurface to 9.9 Gy (standard deviation [SD], 3.3 and 2.6). No significant change was detected between 6 and 12 weeks. After 24 weeks, the edematous tissue had shrunk significantly to 14.7 Gy (SD, 4.2). Three days postbrachytherapy, the D 90 for hepatocyte function loss reached the 14.9 Gy isosurface (SD, 3.9). At 6 weeks, the respective zone had increased significantly to 9.9 Gy (SD, 2.3). After 12 and 24 weeks, the dysfunction volume had decreased significantly to the 11.9 Gy and 15.2 Gy isosurface, respectively (SD, 3 and 4.1). Conclusions: The 95% interval from 7.6 to 12.2 Gy found as the minimal hepatocyte tolerance after 6 weeks accounts for the radiobiologic variations found in CT-guided brachytherapy, including heterogeneous dose rates by variable catheter arrays

  1. Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial.

    Science.gov (United States)

    Takahashi, Fumihiro; Morita, Satoshi

    2018-02-08

    Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.

  2. Oxycodone recycling: a novel hypothesis of opioid tolerance development in humans.

    Science.gov (United States)

    Linares, Oscar A; Fudin, Jeffrey; Schiesser, William E; Linares, Annemarie Daly; Boston, Raymond C

    2014-09-01

    We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC's exposure to local μ-opioid receptors (μORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is TΩ. TΩ estimates OC's tolerance recovery in days; It is defined as the rate of recovery of OC's pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t1/2 = 4.5h)-after which time steady-state was assumed. Repetitive OC dose TΩ fell 61% compared to single OC dose TΩ (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p = 0.001). The fall in TΩ was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravascular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of μORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface μOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance

  3. On dose distribution comparison

    International Nuclear Information System (INIS)

    Jiang, Steve B; Sharp, Greg C; Neicu, Toni; Berbeco, Ross I; Flampouri, Stella; Bortfeld, Thomas

    2006-01-01

    In radiotherapy practice, one often needs to compare two dose distributions. Especially with the wide clinical implementation of intensity-modulated radiation therapy, software tools for quantitative dose (or fluence) distribution comparison are required for patient-specific quality assurance. Dose distribution comparison is not a trivial task since it has to be performed in both dose and spatial domains in order to be clinically relevant. Each of the existing comparison methods has its own strengths and weaknesses and there is room for improvement. In this work, we developed a general framework for comparing dose distributions. Using a new concept called maximum allowed dose difference (MADD), the comparison in both dose and spatial domains can be performed entirely in the dose domain. Formulae for calculating MADD values for various comparison methods, such as composite analysis and gamma index, have been derived. For convenience in clinical practice, a new measure called normalized dose difference (NDD) has also been proposed, which is the dose difference at a point scaled by the ratio of MADD to the predetermined dose acceptance tolerance. Unlike the simple dose difference test, NDD works in both low and high dose gradient regions because it considers both dose and spatial acceptance tolerances through MADD. The new method has been applied to a test case and a clinical example. It was found that the new method combines the merits of the existing methods (accurate, simple, clinically intuitive and insensitive to dose grid size) and can easily be implemented into any dose/intensity comparison tool

  4. Maximally effective dosing regimens of meropenem in patients with septic shock

    DEFF Research Database (Denmark)

    Sjövall, Fredrik; Alobaid, Abdulaziz S; Wallis, Steven C

    2018-01-01

    was required for both empirical and targeted treatment. In patients with a CL CR of ≤ 100 mL/min, successful concentration targets could be reached with intermittent dosing of 1000 mg/8 h. Conclusions: In patients with septic shock and possible augmented renal clearance, doses should be increased and...

  5. Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

    International Nuclear Information System (INIS)

    Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya; Hirose, Takahisa; Kawamori, Ryuzo; Fujitani, Yoshio; Watada, Hirotaka

    2009-01-01

    Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

  6. Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

    Energy Technology Data Exchange (ETDEWEB)

    Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan); Fujitani, Yoshio, E-mail: fujitani@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan)

    2009-12-18

    Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

  7. A comparison of the development of tolerance to ethanol and cross-tolerance to nicotine after chronic ethanol treatment in long- and short-sleep mice.

    Science.gov (United States)

    de Fiebre, C M; Collins, A C

    1993-09-01

    Previous studies have shown that inbred mouse strains differ in the development of tolerance to both nicotine and ethanol, indicating that genetic factors regulate tolerance development. Those mouse strains that are most sensitive to an acute challenge dose of either drug develop the most tolerance to that drug. The ethanol-sensitive long-sleep (LS) mice are more sensitive to several behavioral and physiological effects of nicotine than are the ethanol-resistant short-sleep (SS) mice. The experiments reported here assessed whether the LS and SS mice develop tolerance to ethanol after chronic treatment with ethanol-containing liquid diets and whether cross-tolerance to nicotine also developed. Tolerance and cross-tolerance were measured by assessing the effects of acute challenge doses of drug on Y-maze crossing and rearing activities, heart rate and body temperature. The LS mice developed tolerance to ethanol's effects on three of the four measures and were cross-tolerant to nicotine on all of the measures. In contrast, the SS mice developed tolerance to ethanol for only two of the measures, but failed to develop cross-tolerance to any action of nicotine. These findings support the hypothesis that ethanol and nicotine share sites of action and that common genes regulate responses to these two drugs. Evidence suggests that tolerance to nicotine may be related to an up-regulation of brain nicotinic receptors, at least in some inbred mouse strains, but chronic ethanol treatment did not reproducibly change either [3H]nicotine or alpha-[125I]bungarotoxin binding. Therefore, other mechanisms must underlie the tolerance and cross-tolerance that was seen.

  8. Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

    Science.gov (United States)

    2011-01-01

    Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p.) 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.). IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v.) prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical) given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA. PMID:22114930

  9. Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

    Directory of Open Access Journals (Sweden)

    Mayado Andrea

    2011-11-01

    Full Text Available Abstract Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p. 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.. IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v. prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA.

  10. 76 FR 22045 - Fluopicolide; Pesticide Tolerances

    Science.gov (United States)

    2011-04-20

    ... regulation establishes tolerances for residues of fluopicolide and its metabolites in or on multiple... occurred at dose levels where significant maternal toxicity (severe body weight gain decrements and...

  11. Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. Need for a better dosing regimen.

    Science.gov (United States)

    Lobel, H O; Bernard, K W; Williams, S L; Hightower, A W; Patchen, L C; Campbell, C C

    1991-01-16

    To measure the effectiveness and tolerance of long-term malaria prophylaxis with mefloquine, the incidence of Plasmodium falciparum malaria and of adverse reactions was compared in Peace Corps volunteers in West Africa who took mefloquine every 2 weeks and in volunteers who took chloroquine phosphate weekly. Mefloquine was only 63% more effective than chloroquine; the monthly incidence of P falciparum infections was one case per 100 volunteers who took mefloquine and 2.7 cases per 100 volunteers who took chloroquine. Using daily proguanil (chloroguanide) hydrochloride in addition to chloroquine did not provide additional protection. All mefloquine prophylaxis failures occurred during the second week of the every-2-weeks dosing regimen in volunteers who had used mefloquine for more than 2 months. Blood concentrations of mefloquine were lower during the second week of the alternate-week regimen than during the first week, suggesting that blood levels are too low during the second week to suppress parasitemia. No serious adverse reactions were observed. The results indicate that a dosing regimen of 250 mg of mefloquine weekly should be considered for travelers to areas with chloroquine-resistant P falciparum malaria.

  12. Pretreatment with low-dose gamma irradiation enhances tolerance to the stress of cadmium and lead in Arabidopsis thaliana seedlings.

    Science.gov (United States)

    Qi, Wencai; Zhang, Liang; Wang, Lin; Xu, Hangbo; Jin, Qingsheng; Jiao, Zhen

    2015-05-01

    Heavy metals are important environmental pollutants with negative impact on plant growth and development. To investigate the physiological and molecular mechanisms of heavy metal stress mitigated by low-dose gamma irradiation, the dry seeds of Arabidopsis thaliana were exposed to a Cobalt-60 gamma source at doses ranging from 25 to 150Gy before being subjected to 75µM CdCl2 or 500µM Pb(NO3)2. Then, the growth parameters, and physiological and molecular changes were determined in response to gamma irradiation. Our results showed that 50-Gy gamma irradiation gave maximal beneficial effects on the germination index and root length in response to cadmium/lead stress in Arabidopsis seedlings. The hydrogen peroxide and malondialdehyde contents in seedlings irradiated with 50-Gy gamma rays under stress were significantly lower than those of controls. The antioxidant enzyme activities and proline levels in the irradiated seedlings were significantly increased compared with the controls. Furthermore, a transcriptional expression analysis of selected genes revealed that some components of heavy metal detoxification were stimulated by low-dose gamma irradiation under cadmium/lead stress. Our results suggest that low-dose gamma irradiation alleviates heavy metal stress, probably by modulating the physiological responses and gene expression levels related to heavy metal resistance in Arabidopsis seedlings. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Dietary lecithin potentiates thermal tolerance and cellular stress protection of milk fish (Chanos Chanos) reared under low dose endosulfan-induced stress.

    Science.gov (United States)

    Kumar, Neeraj; Minhas, P S; Ambasankar, K; Krishnani, K K; Rana, R S

    2014-12-01

    Endosulfan is an organochlorine pesticide commonly found in aquatic environments that has been found to reduce thermal tolerance of fish. Lipotropes such as the food additive, Lecithin has been shown to improve thermal tolerance in fish species. This study was conducted to evaluate the role of lipotropes (lecithin) for enhancing the thermal tolerance of Chanos chanos reared under sublethal low dose endosulfan-induced stress. Two hundred and twenty-five fish were distributed randomly into five treatments, each with three replicates. Four isocaloric and isonitrogenous diets were prepared with graded levels of lecithin: normal water and fed with control diet (En0/L0), endosulfan-treated water and fed with control diet (En/L0), endosulfan-treated water and fed with 1% (En/L1%), 1.5% (En/L 1.5%) and 2% (En/L 2%) lecithin supplemented feed. The endosulfan in treated water was maintained at the level of 1/40th of LC50 (0.52ppb). At the end of the five weeks, critical temperature maxima (CTmax), lethal temperature maxima (LTmax), critical temperature minima (CTmin) and lethal temperature minima (LTmin) were Determined. There was a significant (Plecithin on temperature tolerance (CTmax, LTmax, CTmin and LTmin) of the groups fed with 1, 1.5 and 2% lecithin-supplemented diet compared to control and endosulfan-exposed groups. Positive correlations were observed between CT max and LTmax (R(2)=0.934) as well as between CTmin and LTmin (R(2)=0.9313). At the end of the thermal tolerance study, endosulfan-induced changes in cellular stress enzymes (Catalase, SOD and GST in liver and gill and neurotansmitter enzyme, brain AChE) were significantly (plecithin. We herein report the role of lecithin in enhancing the thermal tolerance and protection against cellular stress in fish exposed to an organochlorine pesticide. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Radiation tolerance of the WorldFIP fieldbus interface

    CERN Document Server

    Wijnands, Thijs

    2006-01-01

    This paper summarises on radiation tests on the main components for the WorldFIP fieldbus interface. The chipset based on 0.6 \\mu­m technology has a total dose tolerance of 100 Gy (Co-60) and in standalone mode, no functional interrupts from single events have been observed during proton irradiation (60 MeV). The chipset based on 0.5 \\mu­m technology has a total dose tolerance of 150 Gy (Co-60) but shows a sharp increase in the single event cross section after a dose of 70 Gy. Finally, it was found that the chipset based on 0.5 \\mu­m technology operates reliable in standalone mode in a magnetic field up to 4.6 kGauss.

  15. Pharmacokinetics of detomidine administered to horses at rest and after maximal exercise.

    Science.gov (United States)

    Hubbell, J A E; Sams, R A; Schmall, L M; Robertson, J T; Hinchcliff, K W; Muir, W W

    2009-05-01

    Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses. To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest. Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatography-mass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis. Median back-extrapolated time zero plasma concentration was significantly lower and median plasma half-life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations. Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect.

  16. Maximal Bell's inequality violation for non-maximal entanglement

    International Nuclear Information System (INIS)

    Kobayashi, M.; Khanna, F.; Mann, A.; Revzen, M.; Santana, A.

    2004-01-01

    Bell's inequality violation (BIQV) for correlations of polarization is studied for a product state of two two-mode squeezed vacuum (TMSV) states. The violation allowed is shown to attain its maximal limit for all values of the squeezing parameter, ζ. We show via an explicit example that a state whose entanglement is not maximal allow maximal BIQV. The Wigner function of the state is non-negative and the average value of either polarization is nil

  17. Radiation tolerance of the cervical spinal cord: incidence and dose-volume relationship of symptomatic and asymptomatic late effects following high dose irradiation of paraspinal tumors

    International Nuclear Information System (INIS)

    Liu, Mitchell C.C.; Munzenrider, John E.; Finkelstein, Dianne; Liebsch, Norbert; Adams, Judy; Hug, Eugen B.

    1997-01-01

    changes was between 2 and 8.5 months after radiation therapy. Two risk factors appeared to have significant impact when all incidences were considered: proton portion of tumor dose > 55 CGE (p=.023), and spinal cord surface dose ≥ 60 CGE (p=.045). For patients receiving 55 CGE to >1.5cc of spinal cord, the risk of developing imaging changes was significantly higher (p=.0074). Age < 40 years was found to be correlated with higher incidence of Lhermitt's syndrome (p=.002). No variable was significant for predicting incidence of sensory or motor deficits. Conclusions: For chordomas and chondrosarcomas of the cervical spine, requiring high radiation doses, the guidelines of limiting maximum spinal cord surface dose to ≤ 64 CGE and maximum spinal cord center dose to ≤ 53 CGE appears safe. For the patients who had been treated within the above tolerance dose, none of them had developed motor deficits. Both a significant dose response relationship as well as volume effect for symptomatic or asymptomatic spinal cord changes were observed. The incidence of 1 patient, who developed motor damage after higher radiation doses to the spinal cord than generally allowed, emphasizes the importance of strict guidelines for critical, normal tissues in high dose, conformal radiation treatment

  18. 78 FR 60715 - Sedaxane; Pesticide Tolerances

    Science.gov (United States)

    2013-10-02

    ... 28-day dermal study did not show systemic toxicity at the limit dose of 1,000 milligrams/kilogram/day... Enforcement Methodology Adequate enforcement methodology is available to enforce the tolerance expression. A...

  19. Maximizing and customer loyalty: Are maximizers less loyal?

    Directory of Open Access Journals (Sweden)

    Linda Lai

    2011-06-01

    Full Text Available Despite their efforts to choose the best of all available solutions, maximizers seem to be more inclined than satisficers to regret their choices and to experience post-decisional dissonance. Maximizers may therefore be expected to change their decisions more frequently and hence exhibit lower customer loyalty to providers of products and services compared to satisficers. Findings from the study reported here (N = 1978 support this prediction. Maximizers reported significantly higher intentions to switch to another service provider (television provider than satisficers. Maximizers' intentions to switch appear to be intensified and mediated by higher proneness to regret, increased desire to discuss relevant choices with others, higher levels of perceived knowledge of alternatives, and higher ego involvement in the end product, compared to satisficers. Opportunities for future research are suggested.

  20. Application of Key Events Dose Response Framework to defining the upper intake level of leucine in young men.

    Science.gov (United States)

    Pencharz, Paul B; Russell, Robert M

    2012-12-01

    Leucine is sold in large doses in health food stores and is ingested by weight-training athletes. The safety of ingestion of large doses of leucine is unknown. Before designing chronic high-dose leucine supplementation experiments, we decided to determine the effect of graded doses of leucine in healthy participants. The Key Events Dose Response Framework is an organizational and analytical framework that dissects the various biologic steps (key events) that occur between exposure to a substance and an eventual adverse effect. Each biologic event is looked at for its unique dose-response characteristics. For nutrients, there are a number of biologic homeostatic mechanisms that work to keep circulating/tissue levels in a safe, nontoxic range. If a response mechanism at a particular key event is especially vulnerable and easily overwhelmed, this is known as a determining event, because this event drives the overall slope or shape of the dose-response relationship. In this paper, the Key Events Dose Framework has been applied to the problem of leucine toxicity and leucine's tolerable upper level. After analyzing the experimental data vis a vis key events for leucine leading to toxicity, it became evident that the rate of leucine oxidation was the determining event. A dose-response study has been conducted to graded intakes of leucine in healthy human adult male volunteers. All participants were started at the mean requirement level of leucine [50 mg/(kg · d)] and the highest leucine intake was 1250 mg/( kg · d), which is 25 times the mean requirement. No gut intolerance was seen. Blood glucose fell progressively but remained within normal values without any changes in plasma insulin. Maximal leucine oxidation levels occurred at an intake of 550 mg leucine/( kg · d), after which plasma leucine progressively increased and plasma ammonia also increased in response to leucine intakes >500 mg/( kg · d). Thus, the "key determining event" appears to be when the

  1. High-Dose Atomoxetine Treatment of ADHD in Youths with Limited Response to Standard Doses

    Science.gov (United States)

    Kratochvil, Christopher J.; Michelson, David; Newcorn, Jeffrey H.; Weiss, Margaret D.; Busner, Joan; Moore, Rodney J.; Ruff, Dustin D.; Ramsey, Janet; Dickson, Ruth; Turgay, Atilla; Saylor, Keith E.; Luber, Stephen; Vaughan, Brigette; Allen, Albert J.

    2007-01-01

    Objective: To assess the utility and tolerability of higher than standard atomoxetine doses to treat attention-deficit/hyperactivity disorder (ADHD). Method: Two randomized, double-blind trials of atomoxetine nonresponders ages 6 to 16 years were conducted comparing continued treatment with same-dose atomoxetine to treatment using greater than…

  2. State of art in radiation tolerant camera

    Energy Technology Data Exchange (ETDEWEB)

    Choi; Young Soo; Kim, Seong Ho; Cho, Jae Wan; Kim, Chang Hoi; Seo, Young Chil

    2002-02-01

    Working in radiation environment such as nuclear power plant, RI facility, nuclear fuel fabrication facility, medical center has to be considered radiation exposure, and we can implement these job by remote observation and operation. However the camera used for general industry is weakened at radiation, so radiation-tolerant camera is needed for radiation environment. The application of radiation-tolerant camera system is nuclear industry, radio-active medical, aerospace, and so on. Specially nuclear industry, the demand is continuous in the inspection of nuclear boiler, exchange of pellet, inspection of nuclear waste. In the nuclear developed countries have been an effort to develop radiation-tolerant cameras. Now they have many kinds of radiation-tolerant cameras which can tolerate to 10{sup 6}-10{sup 8} rad total dose. In this report, we examine into the state-of-art about radiation-tolerant cameras, and analyze these technology. We want to grow up the concern of developing radiation-tolerant camera by this paper, and upgrade the level of domestic technology.

  3. Risk of low-doses in radiodiagnosis; Risque des faibles doses en radiodiagnostic. Mythes, reglementation et rationalite

    Energy Technology Data Exchange (ETDEWEB)

    Cordoliani, Y.S.; Sarrazin, J.L.; Le Frian, G.; Soulie, D.; Leveque, C. [Hopital d`Instruction des Armees du Val-de-Grace, 75 - Paris (France)

    1997-12-31

    The effect of low doses of X-rays is inferred from the indubitable effects of high doses in human carcinogenesis, Genetic and teratogenic effects are mainly inferred from animal experimentation because clinical surveys of irradiated pregnant women have failed to demonstrate such consequences in the children, except for mental retardation after Japanese atomic bombing. Since no evidence of carcinogenic effect has been produced by epidemiological studies for doses lower than 500 mSv. the estimation of the risk due to low doses has been extrapolated from the linear relation between dose and cancers at high doses. Such an extrapolation gives a maximal risk which is falsely used as a probability of cancer. The actual risk lies between zero and this maximal number, and many epidemiologic surveys in people receiving doses much higher than the mean level of background irradiation failed to demonstrate higher rate of cancer. The explanation of this fact, which is supported by the most recent biological data, is the efficacy of the DNA repair system at low level of exposure to ionizing radiations. We expose the principles of regulation of radioprotection for workers, and give estimations of the doses delivered to the patients and the personnel by diagnostic investigations, by comparing these doses with those of natural irradiation. Practical aspect for conventional and computed radiology are exposed for patients and workers. (authors)

  4. Dataset for Phase I randomized clinical trial for safety and tolerability of GET 73 in single and repeated ascending doses including preliminary pharmacokinetic parameters.

    Science.gov (United States)

    Haass-Koffler, Carolina L; Goodyear, Kimberly; Long, Victoria M; Tran, Harrison H; Loche, Antonella; Cacciaglia, Roberto; Swift, Robert M; Leggio, Lorenzo

    2017-12-01

    The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled "Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers" (Haass-Koffler et al., 2017) [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK) parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET 73.

  5. Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides

    Science.gov (United States)

    Schuchardt, Christiane; Kulkarni, Harshad R.; Shahinfar, Mostafa; Singh, Aviral; Glatting, Gerhard; Baum, Richard P.; Beer, Ambros J.

    2016-01-01

    In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25−29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1–3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the

  6. Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer's Disease: Results from a Double-Blind, Placebo-Controlled Trial.

    Science.gov (United States)

    Decourt, Boris; Drumm-Gurnee, Denise; Wilson, Jeffrey; Jacobson, Sandra; Belden, Christine; Sirrel, Sherye; Ahmadi, Michael; Shill, Holly; Powell, Jessica; Walker, Aaron; Gonzales, Amanda; Macias, Mimi; Sabbagh, Marwan N

    2017-01-01

    To date there is no cure for Alzheimer's disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aβ levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects. This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support.

    Science.gov (United States)

    Elias, A D; Wheeler, C; Ayash, L J; Schwartz, G; Ibrahim, J; Mills, L; McCauley, M; Coleman, N; Warren, D; Schnipper, L; Antman, K H; Teicher, B A; Frei, E

    1998-06-01

    Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain

  8. Single-dose pharmacokinetics and tolerability of oral delta-9- tetrahydrocannabinol in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Joerger, Markus; Wilkins, Justin; Fagagnini, Stefania; Baldinger, Reto; Brenneisen, Rudolf; Schneider, Ursula; Goldman, Bea; Weber, Markus

    2012-06-01

    Cannabinoids exert neuroprotective and symptomatic effects in amyotrophic lateral sclerosis (ALS). We assessed the pharmacokinetics (PK) and tolerability of delta-9-tetrahydrocannabinol (THC) in ALS patients. Nine patients received THC single oral doses of 5mg and 10mg, separated by a wash-out period of two weeks. Blood samples for the determination of THC, 11-nor-9-carboxy-THC (THC-COOH) and hydroxy-THC (THC-OH) were taken up to 8 hours after intake. Adverse events were assessed by visual analogue scales (VAS). Plasma concentrations of the active metabolite THC-OH were submitted to sequential pharmacokinetic-pharmacodynamic population modeling on individual heart rate as a proxy for THC's cardiovasculatory effects. Drowsiness, euphoria, orthostasis, sleepiness, vertigo and weakness were significantly more frequent in patients receiving 10mg compared to 5 mg THC. A marked interindividual variability was found for the absorption of oral THC (84%) and elimination of THC-COOH (45%). PK data did not support any clinically relevant deviation from linear PK in the investigated range of concentrations. Plasma concentrations of THC-OH were positively correlated with the individual heart rate. An E(max-model) was successfully fitted to individual heart rate, with a THC-OH plasma concentration of 3.2 x 10(-4) μmol/L for EC(50) and an E(max) of 93 bpm for heart rate. The higher 10mg dose of THC was dose-limiting in patients with ALS. High interindividual PK variability requires individuell titration of THC for potential therapeutic use in patients with ALS.

  9. Habituation of Salmonella spp. at Reduced Water Activity and Its Effect on Heat Tolerance

    Science.gov (United States)

    Mattick, K. L.; Jørgensen, F.; Legan, J. D.; Lappin-Scott, H. M.; Humphrey, T. J.

    2000-01-01

    The effect of habituation at reduced water activity (aw) on heat tolerance of Salmonella spp. was investigated. Stationary-phase cells were exposed to aw 0.95 in broths containing glucose-fructose, sodium chloride, or glycerol at 21°C for up to a week prior to heat challenge at 54°C. In addition, the effects of different aws and heat challenge temperatures were investigated. Habituation at aw 0.95 resulted in increased heat tolerance at 54°C with all solutes tested. The extent of the increase and the optimal habituation time depended on the solute used. Exposure to broths containing glucose-fructose (aw 0.95) for 12 h resulted in maximal heat tolerance, with more than a fourfold increase in D54 values. Cells held for more than 72 h in these conditions, however, became as heat sensitive as nonhabituated populations. Habituation in the presence of sodium chloride or glycerol gave rise to less pronounced but still significant increases in heat tolerance at 54°C, and a shorter incubation time was required to maximize tolerance. The increase in heat tolerance following habituation in broths containing glucose-fructose (aw 0.95) was RpoS independent. The presence of chloramphenicol or rifampin during habituation and inactivation did not affect the extent of heat tolerance achieved, suggesting that de novo protein synthesis was probably not necessary. These data highlight the importance of cell prehistory prior to heat inactivation and may have implications for food manufacturers using low-aw ingredients. PMID:11055944

  10. New approach for food allergy management using low-dose oral food challenges and low-dose oral immunotherapies.

    Science.gov (United States)

    Yanagida, Noriyuki; Okada, Yu; Sato, Sakura; Ebisawa, Motohiro

    2016-04-01

    A number of studies have suggested that a large subset of children (approximately 70%) who react to unheated milk or egg can tolerate extensively heated forms of these foods. A diet that includes baked milk or egg is well tolerated and appears to accelerate the development of regular milk or egg tolerance when compared with strict avoidance. However, the indications for an oral food challenge (OFC) using baked products are limited for patients with high specific IgE values or large skin prick test diameters. Oral immunotherapies (OITs) are becoming increasingly popular for the management of food allergies. However, the reported efficacy of OIT is not satisfactory, given the high frequency of symptoms and requirement for long-term therapy. With food allergies, removing the need to eliminate a food that could be consumed in low doses could significantly improve quality of life. This review discusses the importance of an OFC and OIT that use low doses of causative foods as the target volumes. Utilizing an OFC or OIT with a low dose as the target volume could be a novel approach for accelerating the tolerance to causative foods. Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  11. 78 FR 46267 - Trifluralin; Pesticide Tolerance

    Science.gov (United States)

    2013-07-31

    ...), trifluralin was tested up to the limit dose (1000 mg/kg/day) and caused no systemic toxicity. Handler exposure... detection (ECD)) is available to enforce the tolerance expression. The method may be requested from: Chief...

  12. Phase I clinical trial of parenteral hydroxyurea in combination with pelvic and para-aortic external radiation and brachytherapy for patients with advanced squamous cell cancer of the uterine cervix

    International Nuclear Information System (INIS)

    Beitler, Jonathan J.; Anderson, Patrick; Haynes, Hilda; Sood, Brij; Fields, Abbi; Goldberg, Gary; Vikram, Bhadrasain; Runowicz, Carolyn D.; Wadler, Scott

    2002-01-01

    Purpose: Oral hydroxyurea (HU) is a potent radiation sensitizer, but in vitro studies have suggested that prolonged exposure to HU by way of continuous parenteral infusion would enhance clinical efficacy. The objective of this study was to determine the maximal tolerated dose and identify the toxicities of continuous infusion HU in combination with pelvic and para-aortic external beam radiotherapy (RT) and intrauterine brachytherapy in patients with locally advanced carcinoma of the uterine cervix. Methods: This Phase I study of concomitant RT was designed with an escalating dose schedule of HU administered by continuous infusion. HU was administered parenterally as a continuous infusion, 5 d/wk, during the first 21 days of external radiation, during the final 5 days of external beam RT, followed by another 5-day infusion schedule bracketing the single fraction of brachytherapy. The maximal tolerated dose was defined as the highest dose level at which 3 of 3 or 5 of 6 patients could be treated without dose-limiting toxicity. Results: At dose level 1 (0.25 mg/m 2 /min), 0 of 4 patients experienced Grade 4 toxicities and 2 patients experienced Grade 3 hematologic toxicities that were not considered dose-limiting. One of the first 4 patients at level 2 (0.375 mg/m 2 /min) had Grade 3 diarrhea, but the 3 subsequent patients tolerated the dose. At level 3 (0.5 mg/m 2 /min), 4 of 5 patients failed to complete therapy without a >7-day interruption in HU. Conclusions: The maximal tolerated dose of parenteral HU was 0.375 mg/m 2 /min when administered with concomitant RT. The most common toxicities were hematologic. A new trial, incorporating concurrent cisplatin, HU, and RT is planned

  13. Evaluating the Safety and Tolerability of Sacubitril/Valsartan for HFrEF Managed Within a Pharmacist Clinic.

    Science.gov (United States)

    Pogge, Elizabeth K; Davis, Lindsay E

    2018-04-01

    The objective of this research was to describe the use of pharmacist-managed sacubitril/valsartan therapy in a multi-center, outpatient cardiac group. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNi), is a novel agent for the treatment of heart failure. An ARNi is recommended by national guidelines to be used in place of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy for patients who remain symptomatic. A retrospective chart review was performed to identify patients initiated and fully titrated on sacubitril/valsartan therapy from July 7, 2015 to March 7, 2017. Fifty-two of the 72 symptomatic heart failure with reduced ejection fraction (HFrEF) patients prescribed sacubitril/valsartan during the 21-month period were included in this analysis. The average ejection fraction was 26%. The average age was 69 years. At baseline, 26.9% of patients were not on ACEi/ARB therapy and 13.5% were on target-dose therapy. After completing the uptitration process, the maximally tolerated dose of sacubitril/valsartan was 5.8% low-dose, 7.7% mid-dose, and 86.5% target-dose. Loop and thiazide diuretic use decreased significantly. There was a significant mean reduction in systolic blood pressure of 6 mmHg with no significant changes in serum creatinine, blood urea nitrogen, or potassium levels. With close monitoring and follow-up, ARNi therapy was a safe alternative to ACEi/ARB therapy for chronic symptomatic HFrEF when initiated within a pharmacist clinic.

  14. Inducing rat brain CYP2D with nicotine increases the rate of codeine tolerance; predicting the rate of tolerance from acute analgesic response.

    Science.gov (United States)

    McMillan, Douglas M; Tyndale, Rachel F

    2017-12-01

    Repeated opioid administration produces analgesic tolerance, which may lead to dose escalation. Brain CYP2D metabolizes codeine to morphine, a bioactivation step required for codeine analgesia. Higher brain, but not liver, CYP2D is found in smokers and nicotine induces rat brain, but not liver, CYP2D expression and activity. Nicotine induction of rat brain CYP2D increases acute codeine conversion to morphine, and analgesia, however the role of brain CYP2D on the effects of repeated codeine exposure and tolerance is unknown. Rats were pretreated with nicotine (brain CYP2D inducer; 1mg/kg subcutaneously) or vehicle (saline; 1ml/kg subcutaneously). Codeine (40-60mg/kg oral-gavage) or morphine (20-30mg/kg oral-gavage) was administered daily and analgesia was assessed daily using the tail-flick reflex assay. Nicotine (versus saline) pretreatment increased acute codeine analgesia (1.32-fold change in AUC 0-60 min ; pnicotine did not alter acute morphine analgesia (1.03-fold; p>0.8), or the rate of morphine tolerance (8.1%/day versus 7.6%; p>0.9). The rate of both codeine and morphine tolerance (loss in peak analgesia from day 1 to day 4) correlated with initial analgesic response on day 1 (R=0.97, p<001). Increasing brain CYP2D altered initial analgesia and subsequent rate of tolerance. Variation in an individual's initial response to analgesic (e.g. high initial dose, smoking) may affect the rate of tolerance, and thereby the risk for dose escalation and/or opioid dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458).

    Science.gov (United States)

    Shaib, Walid L; Hawk, Natalyn; Cassidy, Richard J; Chen, Zhengjia; Zhang, Chao; Brutcher, Edith; Kooby, David; Maithel, Shishir K; Sarmiento, Juan M; Landry, Jerome; El-Rayes, Bassel F

    2016-10-01

    A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

    International Nuclear Information System (INIS)

    Shaib, Walid L.; Hawk, Natalyn; Cassidy, Richard J.; Chen, Zhengjia; Zhang, Chao; Brutcher, Edith; Kooby, David; Maithel, Shishir K.; Sarmiento, Juan M.; Landry, Jerome; El-Rayes, Bassel F.

    2016-01-01

    Purpose: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

  17. A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

    Energy Technology Data Exchange (ETDEWEB)

    Shaib, Walid L.; Hawk, Natalyn [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Cassidy, Richard J. [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Chen, Zhengjia; Zhang, Chao [Department of Biostatistics, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Brutcher, Edith [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Kooby, David; Maithel, Shishir K.; Sarmiento, Juan M. [Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Landry, Jerome [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); El-Rayes, Bassel F., E-mail: bassel.el-rayes@emoryhealthcare.org [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States)

    2016-10-01

    Purpose: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

  18. Hanford Dose Overview Program. Comparison of AIRDOS-EPA and Hanford site dose codes

    International Nuclear Information System (INIS)

    Aaberg, R.L.; Napier, B.A.

    1985-11-01

    Radiation dose commitments for persons in the Hanford environs calculated using AIRDOS-EPA were compared with those calculated using a suite of Hanford codes: FOOD, PABLM, DACRIN, and KRONIC. Dose commitments to the population and to the maximally exposed individual (MI) based on annual releases of eight radionuclides from the N-Reactor, were calculated by these codes. Dose commitments from each pathway to the total body, lung, thyroid, and lower large intestine (LLI) are given for the population and MI, respectively. 11 refs., 25 tabs

  19. Phase I dose escalation safety study of nanoparticulate paclitaxel (CTI 52010 in normal dogs

    Directory of Open Access Journals (Sweden)

    Axiak SM

    2011-10-01

    Full Text Available Sandra M Axiak1, Kim A Selting1, Charles J Decedue2, Carolyn J Henry1,3, Deborah Tate1, Jahna Howell2, K James Bilof1, Dae Y Kim4 1Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, USA; 2CritiTech Inc, Lawrence, KS, USA; 3Department of Internal Medicine, Division of Hematology and Oncology; 4Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA Background: Paclitaxel is highly effective in the treatment of many cancers in humans, but cannot be routinely used in dogs as currently formulated due to the exquisite sensitivity of this species to surfactant-solubilizing agents. CTI 52010 is a formulation of nanoparticulate paclitaxel consisting of drug and normal saline. Our objectives were to determine the maximally tolerated dose, dose-limiting toxicities, and pharmacokinetics of CTI 52010 administered intravenously to normal dogs. Methods: Three normal adult hound dogs were evaluated by physical examination, complete blood count, chemistry profile, and urinalysis. Dogs were treated with staggered escalating dosages of CTI 52010 with a 28-day washout. All dogs were treated with a starting dosage of 40 mg/m2, and subsequent dosages were escalated at 50% (dog 1, 100% (dog 2, or 200% (dog 3 with each cycle, to a maximum of 240 mg/m2. Dogs were monitored by daily physical assessment and weekly laboratory evaluation. Standard criteria were used to grade adverse events. Plasma was collected at regular intervals to determine pharmacokinetics. Dogs were euthanized humanely, and necropsy was performed one week after the last treatment. Results: The dose-limiting toxicity was grade 4 neutropenia and the maximum tolerated dosage was 120 mg/m2. Grade 1–2 gastrointestinal toxicity was noted at higher dosages. Upon post mortem evaluation, no evidence of organ (liver, kidney, spleen toxicity was noted. Conclusion: CTI 52010 was well tolerated when administered intravenously to normal dogs. A starting

  20. EMP Attachment 3 DOE-SC PNNL Site Dose Assessment Guidance

    Energy Technology Data Exchange (ETDEWEB)

    Snyder, Sandra F.

    2011-12-21

    This Dose Assessment Guidance (DAG) describes methods to use to determine the Maximally-Exposed Individual (MEI) location and to estimate dose impact to that individual under the U.S. Department of Energy Office of Science (DOE-SC) Pacific Northwest National Laboratory (PNNL) Site Environmental Monitoring Plan (EMP). This guidance applies to public dose from radioactive material releases to the air from PNNL Site operations. This document is an attachment to the Pacific Northwest National Laboratory (PNNL) Environmental Monitoring Plan (EMP) and describes dose assessment guidance for radiological air emissions. The impact of radiological air emissions from the U.S. Department of Energy Office of Science (DOE-SC) PNNL Site is indicated by dose estimates to a maximally exposed member of the public, referred to as the maximally exposed individual (MEI). Reporting requirements associated with dose to members of the public from radiological air emissions are in 40 CFR Part 61.94, WAC 246-247-080, and DOE Order 458.1. The DOE Order and state standards for dose from radioactive air emissions are consistent with U.S. Environmental Protection Agency (EPA) dose standards in 40 CFR 61.92 (i.e., 10 mrem/yr to a MEI). Despite the fact that the current Contract Requirements Document (CRD) for the DOE-SC PNNL Site operations does not include the requirement to meet DOE CRD 458.1, paragraph 2.b, public dose limits, the DOE dose limits would be met when EPA limits are met.

  1. Post-closure radiation dose assessment for Yucca Mountain repository

    International Nuclear Information System (INIS)

    Jia Mingyan; Zhang Xiabin; Yang Chuncai

    2006-01-01

    A brief introduction of post-closure long-term radiation safety assessment results was represented for the yucca mountain high-level waste geographic disposal repository. In 1 million years after repository closure, for the higher temperature repository operating mode, the peak annual dose would be 150 millirem (120 millirem under the lower-temperature operating mode) to a reasonably maximally exposed individual approximately 18 kilometers (11 miles) from the repository. The analysis of a drilling intrusion event occurring at 30,000 years indicated a peak of the mean annual dose to the reasonably maximally exposed individual approximately 18 kilometers (11 miles) downstream of the repository would be 0.002 millirem. The analysis of an igneous activity scenario, including a volcanic eruption event and igneous intrusion event indicated a peak of the mean annual dose to the reasonably maximally exposed individual approximately 18 kilometers downstream of the repository would be 0.1 millirem. (authors)

  2. Principles of maximally classical and maximally realistic quantum ...

    Indian Academy of Sciences (India)

    Principles of maximally classical and maximally realistic quantum mechanics. S M ROY. Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400 005, India. Abstract. Recently Auberson, Mahoux, Roy and Singh have proved a long standing conjecture of Roy and Singh: In 2N-dimensional phase space, ...

  3. Dose response relationship in local radiotherapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Park, Hee Chul; Seong, Jin Sil; Han, Kwang Hyub; Chon, Chae Yoon; Moon, Young Myoung; Song, Jae Seok; Suh, Chang Ok

    2001-01-01

    In this study, it was investigated whether dose response relation existed or not in local radiotherapy for primary hepatocellular carcinoma. From January 1992 to March 2000, 158 patients were included in present study. Exclusion criteria included the presence of extrahepatic metastasis, liver cirrhosis of Child's class C, tumors occupying more than two thirds of the entire liver, and performance status on the ECOG scale of more than 3. Radiotherapy was given to the field including tumor with generous margin using 6, 10-MV X-ray. Mean tumor dose was 48.2±7.9 Gy in daily 1.8 Gy fractions. Tumor response was based on diagnostic radiologic examinations such as CT scan, MR imaging, hepatic artery angiography at 4-8 weeks following completion of treatment. Statistical analysis was done to investigate the existence of dose response relationship of local radiotherapy when it was applied to the treatment of primary hepatocellular carcinoma. An objective response was observed in 106 of 158 patients, giving a response rate of 67. 1%. Statistical analysis revealed that total dose was the most significant factor in relation to tumor response when local radiotherapy was applied to the treatment of primary hepatocellular carcinoma. Only 29.2% showed objective response in patients treated with dose less than 40 Gy, while 68.6% and 77.1 % showed major response in patients with 40-50 Gy and more than 50 Gy, respectively. Child-Pugh classification was significant factor in the development of ascites, overt radiation induced liver disease and gastroenteritis. Radiation dose was an important factor for development of radiation induced gastroduodenal ulcer. Present study showed the existence of dose response relationship in local radiotherapy for primary hepatocellular carcinoma. Only radiotherapy dose was a significant factor to predict the objective response. Further study is required to predict the maximal tolerance dose in consideration of liver function and non-irradiated liver

  4. Effectiveness and tolerability of fixed-dose combination enalapril plus nitrendipine in hypertensive patients: results of the 3-month observational, post-marketing, multicentre, prospective CENIT study.

    Science.gov (United States)

    Sierra, Alejandro de la; Roca-Cusachs, Alejandro; Redón, Josep; Marín, Rafael; Luque, Manuel; Figuera, Mariano de la; Garcia-Garcia, Margarida; Falkon, Liliana

    2009-01-01

    Monotherapy with any class of antihypertensive drug effectively controls blood pressure (BP) in only about 50% of patients. Consequently, the majority of patients with hypertension require combined therapy with two or more medications. This study aimed to evaluate the effectiveness (systolic BP [SBP]/diastolic BP [DBP] control) and tolerability of the fixed-dose combination enalapril/nitrendipine 10 mg/20 mg administered as a single daily dose in hypertensive patients. This was a post-authorization, multicentre, prospective, observational study conducted in primary care with a 3-month follow-up. Patients throughout Spain with uncontrolled hypertension (> or =140/90 mmHg for patients without diabetes mellitus, or > or =130/85 mmHg for patients with diabetes) on monotherapy or with any combination other than enalapril + nitrendipine, or who were unable to tolerate their previous antihypertensive therapy, were recruited. Change from previous to study treatment was according to usual clinical practice. BP was measured once after 5 minutes of rest in the sitting position. Therapeutic response was defined as follows: 'controlled' meant controlled BP ( or =20 mmHg and in DBP of > or =10 mmHg. The main laboratory test parameters were documented at baseline and after 3 months. Patients aged >65 years, with diabetes, with isolated systolic hypertension (ISH; SBP > or =140 mmHg for patients without diabetes, SBP > or =130 mmHg for patients with diabetes) and who were obese (body mass index [BMI] > or =30 kg/m2) were analysed separately. Of 6537 patients included, 5010 and 6354 patients were assessed in effectiveness and tolerability analyses, respectively. In the tolerability analysis population, there were 3023 men (47.6%) and 3321 women (52.4%). The mean (+/- SD) age of the tolerability analysis group was 62.8 (+/- 10.7) years. A total of 71.1% of the patients presented at least one clinical cardiovascular risk factor other than hypertension, with the most frequent being

  5. Radiation tolerance of NPN bipolar technology with 30 GHz Ft

    International Nuclear Information System (INIS)

    Flament, O.; Synold, S.; Pontcharra, J. de; Niel, S.

    1999-01-01

    The ionizing dose and neutron radiation tolerance of Si QSA bipolar technology has been investigated. The transistors exhibit good radiation tolerance up to 100 krad and 5 10 13 n/cm 2 without any special fabrication steps to harden the technology to the studied effects. (authors)

  6. Dual specific oral tolerance induction using interferon gamma for IgE-mediated anaphylactic food allergy and the dissociation of local skin allergy and systemic oral allergy: tolerance or desensitization?

    Science.gov (United States)

    Noh, G; Jang, E H

    2014-01-01

    Specific oral tolerance induction (SOTI) for IgE-mediated food allergy (IFA) can be successfully achieved using interfero gamma (classic SOTI). In this study, a tolerable dose was introduced during tolerance induction with interferon gamma (dual SOTI), and its effectiveness was evaluated. The study population comprised 25 IFA patients. Blood samples were taken for analysis, including complete blood count with differential counts of eosinophils, serum total IgE levels, and specific IgE for allergenic foods. Skin prick tests were conducted with the allergens. Oral food challenges were performed to diagnose IFA. Ten patients received dual SOTI, 5 received classic SOTI, 5 received SOTI without interferon gamma (original SOTI), and 5 were not treated (controls). Patients treated with dual SOTI and classic SOTI using interferon gamma became tolerant to the allergenic food. The tolerable dose was introduced successfully in dual SOTI. It was difficult to proceed with the same dosing protocol used for classic SOTI in cases treated with original SOTI. Following dual SOTI, the systemic reaction to oral intake subsided, but the local skin reaction to contact with the allergenic food persisted. Dual SOTI is an improved protocol for SOTI using interferon gamma for IFA.The local skin reaction and systemic reaction to oral intake were dissociated following dual SOTI. In cases of food allergy, tolerance appears to result from desensitization to allergens.

  7. Role of adenosine receptors in caffeine tolerance

    International Nuclear Information System (INIS)

    Holtzman, S.G.; Mante, S.; Minneman, K.P.

    1991-01-01

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity

  8. Role of adenosine receptors in caffeine tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Holtzman, S.G.; Mante, S.; Minneman, K.P. (Emory Univ. School of Medicine, Atlanta, GA (USA))

    1991-01-01

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity.

  9. Profit maximization mitigates competition

    DEFF Research Database (Denmark)

    Dierker, Egbert; Grodal, Birgit

    1996-01-01

    We consider oligopolistic markets in which the notion of shareholders' utility is well-defined and compare the Bertrand-Nash equilibria in case of utility maximization with those under the usual profit maximization hypothesis. Our main result states that profit maximization leads to less price...... competition than utility maximization. Since profit maximization tends to raise prices, it may be regarded as beneficial for the owners as a whole. Moreover, if profit maximization is a good proxy for utility maximization, then there is no need for a general equilibrium analysis that takes the distribution...... of profits among consumers fully into account and partial equilibrium analysis suffices...

  10. Implications of maximal Jarlskog invariant and maximal CP violation

    International Nuclear Information System (INIS)

    Rodriguez-Jauregui, E.; Universidad Nacional Autonoma de Mexico

    2001-04-01

    We argue here why CP violating phase Φ in the quark mixing matrix is maximal, that is, Φ=90 . In the Standard Model CP violation is related to the Jarlskog invariant J, which can be obtained from non commuting Hermitian mass matrices. In this article we derive the conditions to have Hermitian mass matrices which give maximal Jarlskog invariant J and maximal CP violating phase Φ. We find that all squared moduli of the quark mixing elements have a singular point when the CP violation phase Φ takes the value Φ=90 . This special feature of the Jarlskog invariant J and the quark mixing matrix is a clear and precise indication that CP violating Phase Φ is maximal in order to let nature treat democratically all of the quark mixing matrix moduli. (orig.)

  11. B cells in operational tolerance.

    Science.gov (United States)

    Chesneau, M; Danger, R; Soulillou, J-P; Brouard, S

    2018-02-16

    Transplantation is currently the therapy of choice for endstage organ failure even though it requires long-term immunosuppresive therapy, with its numerous side effects, for acceptance of the transplanted organ. In rare cases however, patients develop operational tolerance, that is, graft survival without immunosuppression. Studies conducted on these patients reveal genetic, phenotypic, and functional signatures. They provide a better understanding of the immunological mechanisms involved in operational tolerance and define biomarkers that could be used to adapt immunosuppressive treatment to the individual, safely reduce immunosuppression doses, and ideally and safely guide immunosuppression withdrawal. This review summarizes studies that suggest a role for B cells as biomarkers of operational tolerance and discusses the use of B cells as a predictive tool for immunologic risk. Copyright © 2018. Published by Elsevier Inc.

  12. Morphine tolerance offers protection from radiogenic performance deficits

    International Nuclear Information System (INIS)

    Mickley, G.A.; Stevens, K.E.; Burrows, J.M.; White, G.A.; Gibbs, G.L.

    1983-01-01

    When rats are exposed to a sufficiently large dose of ionizing radiation they exhibit lethargy, hypokinesia, and deficits in performance. These and other behavioral changes parallel those often observed in this species after a large dose of morphine. Since the release of endogenous opiates has been implicated in some stress reactions, we sought to determine if they might play a part in radiogenic behavioral deficits. Rats were trained to criterion on a signaled avoidance task. Some subjects were then implanted with a pellet containing 75 mg of morphine. Other animals received placebo implants. Over a number of days, morphine tolerance was evaluated by measurement of body temperature changes. Prior to 2500 rad 60 Co exposure or sham irradiation, morphine (or placebo) pellets were removed. Twenty-four hours later rats were retested to assess their performance on the avoidance task. Morphine-tolerant subjects performed significantly better than the irradiated placebo-implanted group and no differently than morphine-tolerant/sham-irradiated animals. Morphine tolerance seems to provide a degree of behavioral radiation resistance. These data are consistent with the hypothesis that endogenous opiate hyperexcretion may play some part in the behavioral deficits often observed after irradiation

  13. Sodium phenylbutyrate in Huntington's disease: a dose-finding study.

    Science.gov (United States)

    Hogarth, Penelope; Lovrecic, Luca; Krainc, Dimitri

    2007-10-15

    Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de-escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose-response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well-tolerated in human HD. 2007 Movement Disorder Society

  14. Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer.

    Science.gov (United States)

    Weiss, Glen J; Donehower, Ross C; Iyengar, Tara; Ramanathan, Ramesh K; Lewandowski, Karen; Westin, Eric; Hurt, Karla; Hynes, Scott M; Anthony, Stephen P; McKane, Scott

    2013-02-01

    This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m(2). LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.

  15. Improvement of CMOS VLSI rad tolerance by processing technics

    International Nuclear Information System (INIS)

    Guyomard, D.; Desoutter, I.

    1986-01-01

    The following study concerns the development of integrated circuits for fields requiring only relatively low radiation tolerance levels, and especially for the civil spatial district area. Process modifications constitute our basic study. They have been carried into effects. Our work and main results are reported in this paper. Well known 2.5 and 3 μm CMOS technologies are under our concern. A first set of modifications enables us to double the cumulative dose tolerance of a 4 Kbit SRAM, keeping at the same time the same kind of damage. We obtain memories which tolerate radiation doses as high as 16 KRad(Si). Repetitivity of the results, linked to the quality assurance of this specific circuit, is reported here. A second set of modifications concerns the processing of gate array. In particular, the choice of the silicon substrate type, (epitaxy substrate), is under investigation. On the other hand, a complete study of a test vehicule allows us to accurately measure the rad tolerance of various components of the Cell library [fr

  16. Tolerance of retroperitoneal structures to intraoperative radiation

    International Nuclear Information System (INIS)

    Sindelar, W.F.; Tepper, J.; Travis, E.L.; Terrill, R.

    1982-01-01

    In conjunction with the clinical development of intraoperative radiotherapy, a study was undertaken in dogs to define the tolerance of normal anatomic structures in the retroperitoneum to radiation delivered during operation. Twenty adult dogs were subjected to laparotomy and intraoperative 11 MeV electron irradiation in single doses ranging from 0.to 5000 rad. Animals were followed regularly with clinical observation, blood count, serum chemistries, pyelography, and angiography. Animals were sacrificed and autopsied at regular intervals up to 12 months following treatment to assess radiation-induced complications or tissue damage. Irradiation field in all dogs consisted of a 4 X 15 cm rectangle extending in the retroperitoneum from the level of the renal vessels to the bifurcation of aorta and vena cava. The field included aorta, vena cava, inferior portion of left kidney, and distal portion of left ureter. No complications or histologic changes occurred in any animal given doses of 2000 rad, with a follow-up in excess of 18 months. A dose of 3000 rad was well tolerated, except for left ureteral occlusion in one animal. Mild vascular fibrosis was present inthe aorta and vena cava, and significant ureteral fibrosis developed by six months after doses of 4000 or 5000 rad. All animals that received 5000 rad died of radiation-related complications, including ureteral obstruction and rectal perforation. It was concluded that major vessels tolerate intraoperative irradiation well up to and including 3000 rad and that no clinically significant vascular problems develop after 4000 and 5000 rad, although some fibrosis does occur. The ureter and kidney appear to be the most radiosensitive structures inthe retroperitoneum, showing progressive changes at 300 rad or greater and showing the potential for serious complications after doses of 4000 rad or more

  17. Onset of efficacy and tolerability following the initiation dosing of long-acting paliperidone palmitate: post-hoc analyses of a randomized, double-blind clinical trial

    Directory of Open Access Journals (Sweden)

    Fu Dong-Jing

    2011-05-01

    Full Text Available Abstract Background Paliperidone palmitate is a long-acting injectable atypical antipsychotic for the acute and maintenance treatment of adults with schizophrenia. The recommended initiation dosing regimen is 234 mg on Day 1 and 156 mg on Day 8 via intramuscular (deltoid injection; followed by 39 to 234 mg once-monthly thereafter (deltoid or gluteal. These post-hoc analyses addressed two commonly encountered clinical issues regarding the initiation dosing: the time to onset of efficacy and the associated tolerability. Methods In a 13-week double-blind trial, 652 subjects with schizophrenia were randomized to paliperidone palmitate 39, 156, or 234 mg (corresponding to 25, 100, or 150 mg equivalents of paliperidone, respectively or placebo (NCT#00590577. Subjects randomized to paliperidone palmitate received 234 mg on Day 1, followed by their randomized fixed dose on Day 8, and monthly thereafter, with no oral antipsychotic supplementation. The onset of efficacy was defined as the first timepoint where the paliperidone palmitate group showed significant improvement in the Positive and Negative Syndrome Scale (PANSS score compared to placebo (Analysis of Covariance [ANCOVA] models and Last Observation Carried Forward [LOCF] methodology without adjusting for multiplicity using data from the Days 4, 8, 22, and 36 assessments. Adverse event (AE rates and relative risks (RR with 95% confidence intervals (CI versus placebo were determined. Results Paliperidone palmitate 234 mg on Day 1 was associated with greater improvement than placebo on Least Squares (LS mean PANSS total score at Day 8 (p = 0.037. After the Day 8 injection of 156 mg, there was continued PANSS improvement at Day 22 (p ≤ 0.007 vs. placebo and Day 36 (p Conclusions Significantly greater symptom improvement was observed by Day 8 with paliperidone palmitate (234 mg on Day 1 compared to placebo; this effect was maintained after the 156 mg Day 8 injection, with a trend towards a dose

  18. 78 FR 13257 - Pyraflufen-ethyl; Pesticide Tolerances

    Science.gov (United States)

    2013-02-27

    .... months). No dermal or systemic toxicity was seen at the limit dose (1,000 mg/kg/day). [[Page 13260... enforcement methodology (gas chromatography-mass spectrometry (GC/MS)) is available to enforce the tolerance...

  19. Tolerance and immunity in mice infected with herpes simplex virus: studies on the mechanism of tolerance to delayed-type hypersensitivity.

    Science.gov (United States)

    Nash, A A; Phelan, J; Gell, P G; Wildy, P

    1981-06-01

    Tolerance to delayed-type hypersensitivity is produced in mice following an intravenous injection of herpes simplex virus. This form of tolerance is produced early on, following simultaneous injections of virus subcutaneously and intravenously, and is long lasting (greater than 100 days). The early tolerance mechanism is resistant to high doses of cyclophosphamide and is not transferable by serum or spleen cells taken after 7 days. However, spleen cells taken at 14 days onwards inhibit the induction of delayed hypersensitivity when transferred to normal syngeneic recipients. These cells are T lymphocytes and are specific for the herpes type used in the induction.

  20. Dose escalation of a curcuminoid formulation

    Directory of Open Access Journals (Sweden)

    Crowell James

    2006-03-01

    Full Text Available Abstract Background Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. Methods A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complex™, Sabinsa Corporation. Healthy volunteers were administered escalating doses from 500 to 12,000 mg. Results Seven of twenty-four subjects (30% experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. Conclusion The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.

  1. Maximizers versus satisficers

    Directory of Open Access Journals (Sweden)

    Andrew M. Parker

    2007-12-01

    Full Text Available Our previous research suggests that people reporting a stronger desire to maximize obtain worse life outcomes (Bruine de Bruin et al., 2007. Here, we examine whether this finding may be explained by the decision-making styles of self-reported maximizers. Expanding on Schwartz et al. (2002, we find that self-reported maximizers are more likely to show problematic decision-making styles, as evidenced by self-reports of less behavioral coping, greater dependence on others when making decisions, more avoidance of decision making, and greater tendency to experience regret. Contrary to predictions, self-reported maximizers were more likely to report spontaneous decision making. However, the relationship between self-reported maximizing and worse life outcomes is largely unaffected by controls for measures of other decision-making styles, decision-making competence, and demographic variables.

  2. An FMEA evaluation of intensity modulated radiation therapy dose delivery failures at tolerance criteria levels.

    Science.gov (United States)

    Faught, Jacqueline Tonigan; Balter, Peter A; Johnson, Jennifer L; Kry, Stephen F; Court, Laurence E; Stingo, Francesco C; Followill, David S

    2017-11-01

    The objective of this work was to assess both the perception of failure modes in Intensity Modulated Radiation Therapy (IMRT) when the linac is operated at the edge of tolerances given in AAPM TG-40 (Kutcher et al.) and TG-142 (Klein et al.) as well as the application of FMEA to this specific section of the IMRT process. An online survey was distributed to approximately 2000 physicists worldwide that participate in quality services provided by the Imaging and Radiation Oncology Core - Houston (IROC-H). The survey briefly described eleven different failure modes covered by basic quality assurance in step-and-shoot IMRT at or near TG-40 (Kutcher et al.) and TG-142 (Klein et al.) tolerance criteria levels. Respondents were asked to estimate the worst case scenario percent dose error that could be caused by each of these failure modes in a head and neck patient as well as the FMEA scores: Occurrence, Detectability, and Severity. Risk probability number (RPN) scores were calculated as the product of these scores. Demographic data were also collected. A total of 181 individual and three group responses were submitted. 84% were from North America. Most (76%) individual respondents performed at least 80% clinical work and 92% were nationally certified. Respondent medical physics experience ranged from 2.5 to 45 yr (average 18 yr). A total of 52% of individual respondents were at least somewhat familiar with FMEA, while 17% were not familiar. Several IMRT techniques, treatment planning systems, and linear accelerator manufacturers were represented. All failure modes received widely varying scores ranging from 1 to 10 for occurrence, at least 1-9 for detectability, and at least 1-7 for severity. Ranking failure modes by RPN scores also resulted in large variability, with each failure mode being ranked both most risky (1st) and least risky (11th) by different respondents. On average MLC modeling had the highest RPN scores. Individual estimated percent dose errors and severity

  3. Task Migration for Fault-Tolerance in Mixed-Criticality Embedded Systems

    DEFF Research Database (Denmark)

    Saraswat, Prabhat Kumar; Pop, Paul; Madsen, Jan

    2009-01-01

    In this paper we are interested in mixed-criticality embedded applications implemented on distributed architectures. Depending on their time-criticality, tasks can be hard or soft real-time and regarding safety-criticality, tasks can be fault-tolerant to transient faults, permanent faults, or have...... processors, such that the faults are tolerated, the deadlines for the hard real-time tasks are satisfied and the QoS for soft tasks is maximized. The proposed online adaptive approach has been evaluated using several synthetic benchmarks and a real-life case study....... no dependability requirements. We use Earliest Deadline First (EDF) scheduling for the hard tasks and the Constant Bandwidth Server (CBS) for the soft tasks. The CBS parameters determine the quality of service (QoS) of soft tasks. Transient faults are tolerated using checkpointing with roll- back recovery...

  4. Attenuation of a radiation-induced conditioned taste aversion after the development of ethanol tolerance

    International Nuclear Information System (INIS)

    Hunt, W.A.; Rabin, B.M.

    1988-01-01

    An attempt to reduce a radiation-induced conditioned taste aversion (CTA) was undertaken by rendering animals tolerant to ethanol. Ethanol tolerance, developed over 5 days, was sufficient to block a radiation-induced taste aversion, as well as an ethanol-induced CTA. Several intermittent doses of ethanol, which did not induce tolerance but removed the novelty of the conditioning stimulus, blocked an ethanol-induced CTA but not the radiation-induced CTA. A CTA induced by doses of radiation up to 500 rads was attenuated. These data suggest that radioprotection developing in association with ethanol tolerance is a result of a physiological response to the chronic presence of ethanol not to the ethanol itself

  5. Nickel-sulphate-induced contact dermatitis in the guinea pig maximization test

    DEFF Research Database (Denmark)

    Rohold, A E; Nielsen, G D; Andersen, Klaus Ejner

    1991-01-01

    Nickel sulphate is a sensitizer in guinea pigs, but the frequency of sensitization varies from study to study. The dose-response relationship for NiSO4.6H2O was evaluated in the guinea pig maximization test in this study. 6 intradermal (0.01%-3.0% aq.) and 6 topical (0.25%-10.0% pet.) concentrati...

  6. A Comparison of Four Indices for Combining Distance and Dose Differences

    International Nuclear Information System (INIS)

    Thomas, Simon J.; Cowley, Ian R.

    2012-01-01

    Purpose: When one is comparing two dose distributions, a number of methods have been published to combine dose difference and distance to agreement into a single measure. Some have been defined as pass/fail indices and some as numeric indices. We show that the pass/fail indices can all be used to derive numeric indices, and we compare the results of using these indices to evaluate one-dimensional (1D) and three-dimensional (3D) dose distributions, with the aim of selecting the most appropriate index for use in different circumstances. Methods and Materials: The indices compared are the gamma index, the kappa index, the index in International Commission on Radiation Units and Measurements Report 83, and a box index. Comparisons are made for 1D and 3D distributions. The 1D distribution is chosen to have a variety of dose gradients. The 3D distribution is taken from a clinical treatment plan. The effect of offsetting distributions by known distances and doses is studied. Results: The International Commission on Radiation Units and Measurements Report 83 index causes large discontinuities unless the dose gradient cutoff is set to equal the ratio of the dose tolerance to the distance tolerance. If it is so set, it returns identical results to the kappa index. Where the gradient is very high or very low, all the indices studied in this article give similar results for the same tolerance values. For moderate gradients, they differ, with the box index being the least strict, followed by the gamma index, and with the kappa index being the most strict. Conclusions: If the clinical tolerances are much greater than the uncertainties of the measuring system, the kappa index should be used, with tolerance values determined by the clinical tolerances. In cases where the uncertainties of the measuring system dominate, the box index will be best able to determine errors in the delivery system.

  7. Pharmacology of ayahuasca administered in two repeated doses.

    Science.gov (United States)

    Dos Santos, Rafael G; Grasa, Eva; Valle, Marta; Ballester, Maria Rosa; Bouso, José Carlos; Nomdedéu, Josep F; Homs, Rosa; Barbanoj, Manel J; Riba, Jordi

    2012-02-01

    Ayahuasca is an Amazonian tea containing the natural psychedelic 5-HT(2A/2C/1A) agonist N,N-dimethyltryptamine (DMT). It is used in ceremonial contexts for its visionary properties. The human pharmacology of ayahuasca has been well characterized following its administration in single doses. To evaluate the human pharmacology of ayahuasca in repeated doses and assess the potential occurrence of acute tolerance or sensitization. In a double-blind, crossover, placebo-controlled clinical trial, nine experienced psychedelic drug users received PO the two following treatment combinations at least 1 week apart: (a) a lactose placebo and then, 4 h later, an ayahuasca dose; and (b) two ayahuasca doses 4 h apart. All ayahuasca doses were freeze-dried Amazonian-sourced tea encapsulated to a standardized 0.75 mg DMT/kg bodyweight. Subjective, neurophysiological, cardiovascular, autonomic, neuroendocrine, and cell immunity measures were obtained before and at regular time intervals until 12 h after first dose administration. DMT plasma concentrations, scores in subjective and neurophysiological variables, and serum prolactin and cortisol were significantly higher after two consecutive doses. When effects were standardized by plasma DMT concentrations, no differences were observed for subjective, neurophysiological, autonomic, or immunological effects. However, we observed a trend to reduced systolic blood pressure and heart rate, and a significant decrease for growth hormone (GH) after the second ayahuasca dose. Whereas there was no clear-cut tolerance or sensitization in the psychological sphere or most physiological variables, a trend to lower cardiovascular activation was observed, together with significant tolerance to GH secretion.

  8. Cumulative high doses of inhaled formoterol have less systemic effects in asthmatic children 6-11 years-old than cumulative high doses of inhaled terbutaline

    DEFF Research Database (Denmark)

    Kaae, Rikke; Agertoft, Lone; Pedersen, Sören

    2004-01-01

    OBJECTIVES: To evaluate high dose tolerability and relative systemic dose potency between inhaled clinically equipotent dose increments of formoterol and terbutaline in children. METHODS: Twenty boys and girls (6-11 years-old) with asthma and normal ECGs were studied. Ten doses of formoterol (Oxi...

  9. Influence of irradiation upon neonative tolerance state induced in rabbit

    International Nuclear Information System (INIS)

    Servant, P.; Marquer, C.

    An attempt was made to determine the effect of whole-body irradiation on the establishment of a state of tolerance in new-born rabbits by the intraperitoneal injection of 1mg of human serum albumin. Simultaneous irradiation (doses of 200, 150, 100 rads) and antigen injections inhibited the establishment of this tolerance [fr

  10. The influence of dose fractionation and dose rate on normal tissue responses

    International Nuclear Information System (INIS)

    Barendsen, G.W.

    1982-01-01

    An analysis of responses of a variety of normal tissues in animals to fractionated irradiations has been made with the aim of developing a formalism for the prediction of tolerance doses as a function of the dose per fraction and the overall treatment time. An important feature of the formalism is that it is directly based on radiological insights and therefore provides a logical concept to account for the diversity of tissue responses. (Auth.)

  11. Using Microsoft Excel to compute the 5% overall site X/Q value and the 95th percentile of the distribution of doses to the nearest maximally exposed offsite individual (MEOI).

    Science.gov (United States)

    Vickers, Linda D

    2010-05-01

    This paper describes the method using Microsoft Excel (Microsoft Corporation One Microsoft Way Redmond, WA 98052-6399) to compute the 5% overall site X/Q value and the 95th percentile of the distribution of doses to the nearest maximally exposed offsite individual (MEOI) in accordance with guidance from DOE-STD-3009-1994 and U.S. NRC Regulatory Guide 1.145-1982. The accurate determination of the 5% overall site X/Q value is the most important factor in the computation of the 95th percentile of the distribution of doses to the nearest MEOI. This method should be used to validate software codes that compute the X/Q. The 95th percentile of the distribution of doses to the nearest MEOI must be compared to the U.S. DOE Evaluation Guide of 25 rem to determine the relative severity of hazard to the public from a postulated, unmitigated design basis accident that involves an offsite release of radioactive material.

  12. Developing maximal neuromuscular power: Part 1--biological basis of maximal power production.

    Science.gov (United States)

    Cormie, Prue; McGuigan, Michael R; Newton, Robert U

    2011-01-01

    This series of reviews focuses on the most important neuromuscular function in many sport performances, the ability to generate maximal muscular power. Part 1 focuses on the factors that affect maximal power production, while part 2, which will follow in a forthcoming edition of Sports Medicine, explores the practical application of these findings by reviewing the scientific literature relevant to the development of training programmes that most effectively enhance maximal power production. The ability of the neuromuscular system to generate maximal power is affected by a range of interrelated factors. Maximal muscular power is defined and limited by the force-velocity relationship and affected by the length-tension relationship. The ability to generate maximal power is influenced by the type of muscle action involved and, in particular, the time available to develop force, storage and utilization of elastic energy, interactions of contractile and elastic elements, potentiation of contractile and elastic filaments as well as stretch reflexes. Furthermore, maximal power production is influenced by morphological factors including fibre type contribution to whole muscle area, muscle architectural features and tendon properties as well as neural factors including motor unit recruitment, firing frequency, synchronization and inter-muscular coordination. In addition, acute changes in the muscle environment (i.e. alterations resulting from fatigue, changes in hormone milieu and muscle temperature) impact the ability to generate maximal power. Resistance training has been shown to impact each of these neuromuscular factors in quite specific ways. Therefore, an understanding of the biological basis of maximal power production is essential for developing training programmes that effectively enhance maximal power production in the human.

  13. Tissue tolerance under the combination treatment of maxillary cancer

    Energy Technology Data Exchange (ETDEWEB)

    Egawa, J [Teikyo Univ., Tokyo (Japan). Faculty of Medicine; Ono, I; Suzuki, K; Takeda, C; Ebihara, S

    1977-06-01

    The tissue tolerance doses of the maxillary sinus structures were estimated when they were subjected to treatment for maxillary cancer by the usual combination of surgery, radiotherapy, and regional arterial infusion of 5-fluorouracil. Equivalent single dose calculation was applied with irreversible tissue damage as an indicator. The retardation of epithelialization of the maxillary sinus operated upon appeared to be correlated with the dose delivered. The study indicated that 2,200 rad expressed by equivalent single dose is a safe dose level for sufficient epithelialization. The safety dose level for the bony structure, exposed by surgery, seemed to be at 1,800 rad.

  14. Radiation therapy and concurrent fixed dose amifostine with escalating doses of twice-weekly gemcitabine in advanced pancreatic cancer

    International Nuclear Information System (INIS)

    Yavuz, A. Aydin; Aydin, Fazil; Yavuz, Melek N.; Ilis, Esra; Ozdemir, Feyyaz

    2001-01-01

    Purpose: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of twice-weekly gemcitabine (TW-G) when administered in conjunction with fixed dose amifostine (A) during external radiotherapy (RT) in patients with advanced pancreatic cancer. Methods and Materials: Ten patients with previously untreated, locally advanced, or asymptomatic-metastatic pancreatic adenocarcinoma were enrolled in this study. RT was delivered by using the standard four-field technique (1.8 Gy daily fractions, 45 Gy followed by a boost of 5.4 Gy, in 5-1/2 weeks). The starting dose of TW-G was 60 mg/m 2 (i.v., 30-min infusion), which is equal to the upper limit of previously reported MTD of TW-G when given without A during RT. A was given just before the TW-G, at a fixed dose of 340 mg/m 2 (i.v., rapid infusion). TW-G doses were escalated by 30-mg/m 2 increments in successive cohorts of 3 to 6 additional patients until DLT was observed. Toxicities were graded using the Radiation Therapy Oncology Group and National Cancer Institute Common Toxicity Criteria, version 2.0. Results: In general, therapy was well tolerated in patients treated at the first two dose levels of 60 mg/m 2 and 90 mg/m 2 . The DLT of TW-G given in conjunction with A during RT were neutropenia, thrombocytopenia, and nausea/vomiting at the dose level of 120 mg/m 2 . Of the 10 patients eligible for a median follow-up of 10 months, 5 remain alive; 1 complete responder, 3 partial responders, and 1 with stable disease. Conclusion: A dose of TW-G at a level of 90 mg/m 2 produced tolerable toxicity and it may possess significant activity when delivered in conjunction with 340 mg/m 2 dose of A during RT of the upper abdomen. Due to the higher MTD of TW-G seen in our study, we consider that the A supplementation may optimize the therapeutic index of TW-G-based chemoradiotherapy protocols in patients with pancreatic carcinoma

  15. Predicting Neuroinflammation in Morphine Tolerance for Tolerance Therapy from Immunostaining Images of Rat Spinal Cord.

    Directory of Open Access Journals (Sweden)

    Shinn-Long Lin

    Full Text Available Long-term morphine treatment leads to tolerance which attenuates analgesic effect and hampers clinical utilization. Recent studies have sought to reveal the mechanism of opioid receptors and neuroinflammation by observing morphological changes of cells in the rat spinal cord. This work proposes a high-content screening (HCS based computational method, HCS-Morph, for predicting neuroinflammation in morphine tolerance to facilitate the development of tolerance therapy using immunostaining images for astrocytes, microglia, and neurons in the spinal cord. HCS-Morph first extracts numerous HCS-based features of cellular phenotypes. Next, an inheritable bi-objective genetic algorithm is used to identify a minimal set of features by maximizing the prediction accuracy of neuroinflammation. Finally, a mathematic model using a support vector machine with the identified features is established to predict drug-treated images to assess the effects of tolerance therapy. The dataset consists of 15 saline controls (1 μl/h, 15 morphine-tolerant rats (15 μg/h, and 10 rats receiving a co-infusion of morphine (15 μg/h and gabapentin (15 μg/h, Sigma. The three individual models of astrocytes, microglia, and neurons for predicting neuroinflammation yielded respective Jackknife test accuracies of 96.67%, 90.00%, and 86.67% on the 30 rats, and respective independent test accuracies of 100%, 90%, and 60% on the 10 co-infused rats. The experimental results suggest that neuroinflammation activity expresses more predominantly in astrocytes and microglia than in neuron cells. The set of features for predicting neuroinflammation from images of astrocytes comprises mean cell intensity, total cell area, and second-order geometric moment (relating to cell distribution, relevant to cell communication, cell extension, and cell migration, respectively. The present investigation provides the first evidence for the role of gabapentin in the attenuation of morphine tolerance from

  16. 76 FR 18899 - Indaziflam; Pesticide Tolerances

    Science.gov (United States)

    2011-04-06

    ... were generally observed in the available subchronic and chronic studies. No systemic toxicity was... limited to doses that also caused systemic toxicity in the adult. In the rat developmental toxicity study... to enforce the tolerance expression. The method is able to determine, separately, residues of...

  17. An analysis of tolerance levels in IMRT quality assurance procedures

    International Nuclear Information System (INIS)

    Basran, Parminder S.; Woo, Milton K.

    2008-01-01

    Increased use of intensity modulated radiation therapy (IMRT) has resulted in increased efforts in patient quality assurance (QA). Software and detector systems intended to streamline the IMRT quality assurance process often report metrics, such as percent discrepancies between measured and computed doses, which can be compared to benchmark or threshold values. The purpose of this work is to examine the relationships between two different types of IMRT QA processes in order to define, or refine, appropriate tolerances values. For 115 IMRT plans delivered in a 3 month period, we examine the discrepancies between (a) the treatment planning system (TPS) and results from a commercial independent monitor unit (MU) calculation program; (b) TPS and results from a commercial diode-array measurement system; and (c) the independent MU calculation and the diode-array measurements. Statistical tests were performed to assess significance in the IMRT QA results for different disease site and machine models. There is no evidence that the average total dose discrepancy in the monitor unit calculation depends on the disease site. Second, the discrepancies in the two IMRT QA methods are independent: there is no evidence that a better --or worse--monitor unit validation result is related to a better--or worse--diode-array measurement result. Third, there is marginal benefit in repeating the independent MU calculation with a more suitable dose point, if the initial IMRT QA failed a certain tolerance. Based on these findings, the authors conclude at some acceptable tolerances based on disease site and IMRT QA method. Specifically, monitor unit validations are expected to have a total dose discrepancy of 3% overall, and 5% per beam, independent of disease site. Diode array measurements are expected to have a total absolute dose discrepancy of 3% overall, and 3% per beam, independent of disease site. The percent of pixels exceeding a 3% and 3 mm threshold in a gamma analysis should be

  18. Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid.

    Science.gov (United States)

    Flanagan, Shawn; Fang, Edward; Muñoz, Kelly A; Minassian, Sonia L; Prokocimer, Philippe G

    2014-09-01

    Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate. Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. Ninety healthy volunteers. Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100-400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days. A dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1 μg/ml) and the area under the concentration-time curve (17.4-58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100-400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores. These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes. © 2014 Cubist Pharmaceuticals. Pharmacotherapy

  19. Effectiveness analysis of resistance and tolerance to infection

    Directory of Open Access Journals (Sweden)

    Detilleux Johann C

    2011-03-01

    Full Text Available Abstract Background Tolerance and resistance provide animals with two distinct strategies to fight infectious pathogens and may exhibit different evolutionary dynamics. However, few studies have investigated these mechanisms in the case of animal diseases under commercial constraints. Methods The paper proposes a method to simultaneously describe (1 the dynamics of transmission of a contagious pathogen between animals, (2 the growth and death of the pathogen within infected hosts and (3 the effects on their performances. The effectiveness of increasing individual levels of tolerance and resistance is evaluated by the number of infected animals and the performance at the population level. Results The model is applied to a particular set of parameters and different combinations of values. Given these imputed values, it is shown that higher levels of individual tolerance should be more effective than increased levels of resistance in commercial populations. As a practical example, a method is proposed to measure levels of animal tolerance to bovine mastitis. Conclusions The model provides a general framework and some tools to maximize health and performances of a population under infection. Limits and assumptions of the model are clearly identified so it can be improved for different epidemiological settings.

  20. Dose-volume complication analysis for visual pathway structures of patients with advanced paranasal sinus tumors

    International Nuclear Information System (INIS)

    Martel, Mary Kaye; Sandler, Howard M.; Cornblath, Wayne T.; Marsh, Lon H.; Hazuka, Mark B.; Roa, Wilson H.; Fraass, Benedict A.; Lichter, Allen S.

    1997-01-01

    Purpose: The purpose of the present work was to relate dose and volume information to complication data for visual pathway structures in patients with advanced paranasal sinus tumors. Methods and Materials: Three-dimensional (3D) dose distributions for chiasm, optic nerve, and retina were calculated and analyzed for 20 patients with advanced paranasal sinus malignant tumors. 3D treatment planning with beam's eye view capability was used to design beam and block arrangements, striving to spare the contralateral orbit (to lessen the chance of unilateral blindness) and frequently the ipsilateral orbit (to help prevent bilateral blindness). Point doses, dose-volume histogram analysis, and normal tissue complication probability (NTCP) calculations were performed. Published tolerance doses that indicate significant risk of complications were used as guidelines for analysis of the 3D dose distributions. Results: Point doses, percent volume exceeding a specified published tolerance dose, and NTCP calculations are given in detail for patients with complications versus patients without complications. Two optic nerves receiving maximum doses below the published tolerance dose sustained damage (mild vision loss). Three patients (of 13) without optic nerve sparing and/or chiasm sparing had moderate or severe vision loss. Complication data, including individual patient analysis to estimate overall risk for loss of vision, are given. Conclusion: 3D treatment planning techniques were used successfully to provide bilateral sparing of the globe for most patients. It was more difficult to spare the optic nerves, especially on the ipsilateral side, when prescription dose exceeded the normal tissue tolerance doses. NTCP calculations may be useful in assessing complication risk better than point dose tolerance criteria for the chiasm, optic nerve, and retina. It is important to assess the overall risk of blindness for the patient in addition to the risk for individual visual pathway

  1. Re-irradiation tolerance in the rat spinal cord

    International Nuclear Information System (INIS)

    Shun Wong, C.; Poon, J.K.; Hill, R.P.

    1993-01-01

    The influence of the level of initial radiation damage on the long term recovery and re-irradiation tolerance in the rat spinal cord was investigated. Rats were irradiated with 0, 10, 20, 30 and 36 daily fractions of 2.15 Gy initially representing 0, 25, 50, 75 and 90% of cord tolerance. After an interval of 20 weeks, retreatments were given using graded single doses of X-ray. The end-point was paralysis of the forelimbs due to white matter necrosis. Latent times to paralysis were inversely proportional to the level of initial injury and retreatment doses. The retreatment ED 50 s were 19.0, 17.0, 15.7, 14.0 and 11.8 Gy for the control animals and animals irradiated initially with 10. 20, 30 and 36 fractions of 2.15 Gy respectively. Using the extrapolated response dose (ERD) concept, α/β of 3.0 Gy, the retreatment of ED 50 s in % ERD were 81, 70, 58 and 42% after initial doses of 25, 50, 75 and 90% ERD respectively. The level of initial injury appeared to influence the proportion of residual injury. For an initial injury of 25 and 90% of ERD, the respective residual injury was 74 and 65% of the initial damage; for an initial injury of 50 and 75% ERD, the residual injury decreased to 59 and 57% respectively. It is concluded that there was significant long-term recovery in the rat spinal cord, and that the level of initial radiation damage influenced both the treatment tolerance and the time expression of injury. (author). tabs

  2. Influence of salicylic acid pre-treatment on cadmium tolerance and ...

    African Journals Online (AJOL)

    Dose-dependent changes in cadmium (Cd) tolerance, non-protein thiol (NP-SH) production and their relationship were investigated in sixteen-day-old flax (Linum usitatissimum L.) seedlings derived from seeds pre-soaked with various salicylic acid (SA) doses and grown hydroponically under increased Cd concentrations ...

  3. Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons From Preclinical Studies

    International Nuclear Information System (INIS)

    Medin, Paul M.; Boike, Thomas P.

    2011-01-01

    Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.

  4. 78 FR 20461 - Flumioxazin; Pesticide Tolerances

    Science.gov (United States)

    2013-04-05

    ... offspring were observed at doses lower than those that caused parental/systemic toxicity, and because the reproductive effects in offspring were considered to be more severe than the parental/systemic effects. 3... available to enforce the tolerance expression. The method may be requested from: Chief, Analytical Chemistry...

  5. A reversible albumin-binding growth hormone derivative is well tolerated and possesses a potential once-weekly treatment profile.

    Science.gov (United States)

    Rasmussen, Michael Højby; Olsen, Minna W Brændholt; Alifrangis, Lene; Klim, Søren; Suntum, Mette

    2014-10-01

    Human growth hormone (hGH) replacement therapy currently requires daily sc injections for years/lifetime, which may be both inconvenient and distressing for patients. NNC0195-0092 is a novel hGH derivative intended for once-weekly treatment of GH deficiency. A noncovalent albumin binding moiety is attached to the hGH backbone. Clearance is reduced as a consequence of a reversible binding to circulating serum albumin, which prolongs the pharmacodynamic (PD) effect. To evaluate safety, local tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose (SD) and multiple doses (MD) of NNC0195-0092. Randomized, single-center, placebo-controlled, double-blind, SD/MD, dose-escalation trial of 105 healthy male subjects. NNC0195-0092 sc administration: Five cohorts of eight subjects received one dose of NNC0195-0092 (0.01-0.32 mg/kg) (n = 6) or placebo (n = 2). Sixteen subjects (equal numbers of Japanese and non-Asian) received once-weekly doses of NNC0195-0092 (0.02-0.24 mg/kg; n=12) or placebo (n=4) for 4 weeks. Blood samples were drawn for assessment of safety, PK, IGF-1, and IGF binding protein 3 profiles and anti-drug antibodies. SD and MD of NNC0195-0092 were well tolerated at all dose levels. No safety concerns or local tolerability issues were identified. A dose-dependent IGF-1 response was observed. IGF-1 profiles suggest that NNC0195-0092 may be suitable for once-weekly dosing, with a clinically relevant dose ≤0.08 mg/kg/week. No differences in PK and PD were observed between Japanese and non-Asian subjects. SD and MD of NNC0195-0092 administered to healthy Japanese and non-Asian male subjects were well tolerated at all doses. The present trial suggests that NNC0195-0092 has the potential for an efficacious, well-tolerated, once-weekly GH treatment.

  6. Impact of Dose to the Bladder Trigone on Long-Term Urinary Function After High-Dose Intensity Modulated Radiation Therapy for Localized Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ghadjar, Pirus; Zelefsky, Michael J.; Spratt, Daniel E. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Munck af Rosenschöld, Per; Oh, Jung Hun; Hunt, Margie [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Kollmeier, Marisa [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Happersett, Laura; Yorke, Ellen; Deasy, Joseph O. [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Jackson, Andrew, E-mail: jacksona@mskcc.org [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2014-02-01

    Purpose: To determine the potential association between genitourinary (GU) toxicity and planning dose–volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients. Methods and Materials: A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose–volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analyses were done by the Kaplan-Meier method and Cox proportional hazard models, respectively. Results: Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19). Conclusions: The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the

  7. A fixed-dose approach to conducting emamectin benzoate tolerance assessments on field-collected sea lice, Lepeophtheirus salmonis.

    Science.gov (United States)

    Whyte, S K; Westcott, J D; Elmoslemany, A; Hammell, K L; Revie, C W

    2013-03-01

    In New Brunswick, Canada, the sea louse, Lepeophtheirus salmonis, poses an on-going management challenge to the health and productivity of commercially cultured Atlantic salmon, Salmo salar. While the in-feed medication, emamectin benzoate (SLICE® ; Merck), has been highly effective for many years, evidence of increased tolerance has been observed in the field since late 2008. Although bioassays on motile stages are a common tool to monitor sea lice sensitivity to emamectin benzoate in field-collected sea lice, they require the collection of large numbers of sea lice due to inherent natural variability in the gender and stage response to chemotherapeutants. In addition, sensitive instruments such as EC(50) analysis may be unnecessarily complex to characterize susceptibility subsequent to a significant observed decline in efficacy. This study proposes an adaptation of the traditional, dose-response format bioassay to a fixed-dose method. Analysis of 657 bioassays on preadult and adult stages of sea lice over the period 2008-2011 indicated a population of sea lice in New Brunswick with varying degrees of susceptibility to emamectin benzoate. A seasonal and spatial effect was observed in the robustness of genders and stages of sea lice, which suggest that mixing different genders and stages of lice within a single bioassay may result in pertinent information being overlooked. Poor survival of adult female lice in bioassays, particularly during May/June, indicates it may be prudent to consider excluding this stage from bioassays conducted at certain times of the year. This work demonstrates that fixed-dose bioassays can be a valuable technique in detecting reduced sensitivity in sea lice populations with varying degrees of susceptibility to emamectin benzoate treatments. © 2013 Blackwell Publishing Ltd.

  8. Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article.

    Science.gov (United States)

    Boockvar, John A; Tsiouris, Apostolos J; Hofstetter, Christoph P; Kovanlikaya, Ilhami; Fralin, Sherese; Kesavabhotla, Kartik; Seedial, Stephen M; Pannullo, Susan C; Schwartz, Theodore H; Stieg, Philip; Zimmerman, Robert D; Knopman, Jared; Scheff, Ronald J; Christos, Paul; Vallabhajosula, Shankar; Riina, Howard A

    2011-03-01

    The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. A total of 30 patients with recurrent malignant glioma were included in the current study. The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.

  9. Patient doses in interventional cardiology procedures

    International Nuclear Information System (INIS)

    Domienik, J.; Papierz, S.; Jankowski, J.; Peruga, J.Z.

    2008-01-01

    In most countries of European Union legislation requires the determination of the total skin dose to patient resulting from interventional procedures to assess the risk of deterministic effect. To this end, various dose indicators like dose area product (DAP), cumulative dose (CD) and entrance dose at the patient plane (EFD) are used in clinical practice. The study aims at relating those dose indicators with doses ascribe to the most irradiated areas of the patient skin usually expressed in terms of local maximal skin dose (MSD). For the study the local MSD and related to their areas are investigated and compared for coronary angiography CA and intervention (PCI). Two methods implying radiographic films Kodak EDR2 and matrixes of thermoluminescent dosimeters (TLDs) are applied for direct measurements of dose distribution for selected procedures. Both methods are compared. Additionally, for patient dosimetry the following data: MSD, CD, EFD, fluoroscopy time (FT), number of acquired images, total DAP, fluoro-DAP and record-DAP were collected for randomly selected procedure. The statistical quantities like: median, 3 rd quartile, mean and standard deviation for all dosimetric parameters are determined. Preliminary study showed that the values of data collected for coronary procedures are in the ranges 0,7 - 27,3 min for fluoroscopy time, 50 - 350 Gy cm 2 for total DAP, 300 - 2000 mGy for CD, 140 - 2000 mGy for EFD and 100 - 1500 mGy for local maximal skin dose. For interventions the ranges are, accordingly 3,0 - 43,6 min , 25 - 450 Gy cm 2 , 270 - 6600 mGy, 80 - 2600 mGy and 80 - 1500 mGy. As a result of the study the correlations between dose indicators and local MSD are analyzed. The concentration of dose on irradiated films are going to be investigated in some detail as well. (author)

  10. Maximizers versus satisficers

    OpenAIRE

    Andrew M. Parker; Wandi Bruine de Bruin; Baruch Fischhoff

    2007-01-01

    Our previous research suggests that people reporting a stronger desire to maximize obtain worse life outcomes (Bruine de Bruin et al., 2007). Here, we examine whether this finding may be explained by the decision-making styles of self-reported maximizers. Expanding on Schwartz et al. (2002), we find that self-reported maximizers are more likely to show problematic decision-making styles, as evidenced by self-reports of less behavioral coping, greater dependence on others when making decisions...

  11. Tissue tolerance under the combination treatment of maxillary cancer

    International Nuclear Information System (INIS)

    Egawa, Jun; Ono, Isamu; Suzuki, Kunio; Takeda, Chisato; Ebihara, Satoshi.

    1977-01-01

    The tissue tolerance doses of the maxillary sinus structures were estimated when they were subjected to treatment for maxillary cancer by the usual combination of surgery, radiotherapy and regional arterial infusion of 5-fluorouracil. Equivalent single dose calculation was applied with irreversible tissue damage as an indicator. The retardation of epithelialization of the maxillary sinus operated upon appeared to be correlated with the dose delivered. The study indicated that 2,200 rad expressed by equivalent single dose is a safe dose level for sufficient epithelialization. The safety dose level for the bony structure, exposed by surgery, seemed to be at 1,800 rad. (auth.)

  12. Hemodynamic mechanisms underlying the incomplete tolerance to caffeine's pressor effects.

    Science.gov (United States)

    Farag, Noha H; Vincent, Andrea S; McKey, Barbara S; Whitsett, Thomas L; Lovallo, William R

    2005-06-01

    Blood pressure (BP) and cardiovascular hemodynamics were assessed at baseline and after caffeine administration in a 4-week, placebo-controlled, double-blind, randomized, crossover trial of caffeine tolerance formation. Half of the subjects developed tolerance to the pressor effect of caffeine, whereas the other half continued to show increases in BP after caffeine ingestion (F = 16.7, p <0.0001). In the subjects who did not develop tolerance, peripheral resistance increased incrementally as the daily dose of caffeine increased (F = 2.8, p = 0.05).

  13. Fault tolerance based on serial communication of FPGA

    International Nuclear Information System (INIS)

    Peng Jing; Fang Zongliang; Xu Quanzhou; Hu Jiewei; Ma Guizhen

    2012-01-01

    There maybe appear mistake in serial communication. This paper was described the intellectual detector of γ dose ratemeter communication with FPGA. The software of FPGA designed the code about fault tolerance, prevented mistake effectively. (authors)

  14. Hypofractionation Regimens for Stereotactic Radiotherapy for Large Brain Tumors

    International Nuclear Information System (INIS)

    Yuan Jiankui; Wang, Jian Z.; Lo, Simon; Grecula, John C.; Ammirati, Mario; Montebello, Joseph F.; Zhang Hualin; Gupta, Nilendu; Yuh, William T.C.; Mayr, Nina A.

    2008-01-01

    Purpose: To investigate equivalent regimens for hypofractionated stereotactic radiotherapy (HSRT) for brain tumor treatment and to provide dose-escalation guidance to maximize the tumor control within the normal brain tolerance. Methods and Materials: The linear-quadratic model, including the effect of nonuniform dose distributions, was used to evaluate the HSRT regimens. The α/β ratio was estimated using the Gammaknife stereotactic radiosurgery (GKSRS) and whole-brain radiotherapy experience for large brain tumors. The HSRT regimens were derived using two methods: (1) an equivalent tumor control approach, which matches the whole-brain radiotherapy experience for many fractions and merges it with the GKSRS data for few fractions; and (2) a normal-tissue tolerance approach, which takes advantages of the dose conformity and fractionation of HSRT to approach the maximal dose tolerance of the normal brain. Results: A plausible α/β ratio of 12 Gy for brain tumor and a volume parameter n of 0.23 for normal brain were derived from the GKSRS and whole-brain radiotherapy data. The HSRT prescription regimens for the isoeffect of tumor irradiation were calculated. The normal-brain equivalent uniform dose decreased as the number of fractions increased, because of the advantage of fractionation. The regimens for potential dose escalation of HSRT within the limits of normal-brain tolerance were derived. Conclusions: The designed hypofractionated regimens could be used as a preliminary guide for HSRT dose prescription for large brain tumors to mimic the GKSRS experience and for dose escalation trials. Clinical studies are necessary to further tune the model parameters and validate these regimens

  15. The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients.

    Science.gov (United States)

    Massart, Annick; Pallier, Annaïck; Pascual, Julio; Viklicky, Ondrej; Budde, Klemens; Spasovski, Goce; Klinger, Marian; Sever, Mehmet Sukru; Sørensen, Søren Schwartz; Hadaya, Karine; Oberbauer, Rainer; Dudley, Christopher; De Fijter, Johan W; Yussim, Alexander; Hazzan, Marc; Wekerle, Thomas; Berglund, David; De Biase, Consuelo; Pérez-Sáez, María José; Mühlfeld, Anja; Orlando, Giuseppe; Clemente, Katia; Lai, Quirino; Pisani, Francesco; Kandus, Aljosa; Baas, Marije; Bemelman, Frederike; Ponikvar, Jadranka Buturovic; Mazouz, Hakim; Stratta, Piero; Subra, Jean-François; Villemain, Florence; Hoitsma, Andries; Braun, Laura; Cantarell, Maria Carmen; Colak, Hulya; Courtney, Aisling; Frasca, Giovanni Maria; Howse, Matthew; Naesens, Maarten; Reischig, Tomas; Serón, Daniel; Seyahi, Nurhan; Tugmen, Cem; Alonso Hernandez, Angel; Beňa, Luboslav; Biancone, Luigi; Cuna, Vania; Díaz-Corte, Carmen; Dufay, Alexandre; Gaasbeek, André; Garnier, Arnaud; Gatault, Philippe; Gentil Govantes, Miguel Angel; Glowacki, François; Gross, Oliver; Hurault de Ligny, Bruno; Huynh-Do, Uyen; Janbon, Bénédicte; Jiménez Del Cerro, Luis Antonio; Keller, Frieder; La Manna, Gaetano; Lauzurica, Ricardo; Le Monies De Sagazan, Hervé; Thaiss, Friedrich; Legendre, Christophe; Martin, Séverine; Moal, Marie-Christine; Noël, Christian; Pillebout, Evangeline; Piredda, Gian Benedetto; Puga, Ana Ramírez; Sulowicz, Wladyslaw; Tuglular, Serhan; Prokopova, Michaela; Chesneau, Mélanie; Le Moine, Alain; Guérif, Pierrick; Soulillou, Jean-Paul; Abramowicz, Marc; Giral, Magali; Racapé, Judith; Maggiore, Umberto; Brouard, Sophie; Abramowicz, Daniel

    2016-06-01

    Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  16. Low-dose oral tolerance due to antigen in the diet suppresses differentially the cholera toxin-adjuvantized IgE, IgA and IgG response

    DEFF Research Database (Denmark)

    Christensen, Hanne Risager; Kjær, Tanja; Frøkiær, Hanne

    2003-01-01

    Background: Cholera toxin (CT) is used as a mucosal adjuvant amongst other applications for studying food allergy because oral administration of antigen with CT induces an antigen-specific type 2 response, including IgE and IgA production. Priorly established oral tolerance due to antigen...... soy-trypsin inhibitor (KSTI) (F0 mice) and mice fed a soy-free diet (F2 mice) were orally immunized with KSTI and CT. KSTI-specific serum IgG1, IgG2a, IgA and IgE and fecal IgA were monitored. KSTI-stimulated cell proliferation and interleukin (IL)-6 production were determined. Results: The anti...... immunizations. However, cell proliferation and IL-6 production were clearly suppressed even after five immunizations. Conclusions: Priorly established low-dose oral tolerance considerably suppressed the CT-adjuvantized KSTI-specific IgE, IgA and cellular immune response but only weakly and transiently the Ig...

  17. Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations

    Directory of Open Access Journals (Sweden)

    John Sunyecz

    2008-12-01

    Full Text Available John SunyeczMenopauseRx, Inc., Hopwood, PA, USAAbstract: Postmenopausal osteoporosis is common and underrecognized among elderly women. Osteoporotic fractures cause disability and disfigurement and threaten patients’ mobility, independence, and survival. Care for incident fractures in this age group must go beyond orthopedic repair, to assessment and treatment of the underlying bone fragility. Fracture risk can be reduced by vitamin D and calcium supplementation along with antiresorptive drug treatment. First-line osteoporosis pharmacotherapy employs nitrogen-containing bisphosphonates. The inconvenience of daily oral treatment has motivated development of weekly, monthly, and intermittent oral regimens, as well as quarterly and yearly intravenous (iv regimens. Ibandronate is the first bisphosphonate to have shown direct anti-fracture efficacy with a non-daily regimen; it was approved for once-monthly oral dosing in 2005 and for quarterly iv dosing in 2006. Intermittent oral risedronate and yearly iv zoledronic acid were approved in 2007. Newly available regimens with extended dosing intervals reduce the inconvenience of bisphosphonate therapy and provide patients with a range of options from which to select a maximally sustainable course of treatment. This review discusses the development, efficacy, safety, and tolerability of extended-interval bisphosphonate regimens and examines their potential to improve patient acceptance and long-term success of osteoporosis treatment.Keywords: ibandronate, alendronate, risedronate, zoledronic acid, adherence, persistence

  18. 77 FR 25904 - Acequinocyl; Pesticide Tolerances

    Science.gov (United States)

    2012-05-02

    ... for parental males was 58.9/69.2 mg/kg/ day, based on hemorrhagic effects. The offspring systemic... effects because they were observed at very high doses and in the presence of more severe systemic effects... to enforce the tolerance expression. The methods may be requested from: Chief, Analytical Chemistry...

  19. Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial

    Energy Technology Data Exchange (ETDEWEB)

    Westover, Kenneth D. [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Loo, Billy W. [Department of Radiation Oncology, Stanford University, Stanford, California (United States); Gerber, David E. [Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Iyengar, Puneeth; Choy, Hak [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Diehn, Maximilian [Department of Radiation Oncology, Stanford University, Stanford, California (United States); Hughes, Randy; Schiller, Joan; Dowell, Jonathan [Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Wardak, Zabi [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Sher, David [Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois (United States); Christie, Alana; Xie, Xian-Jin [Department of Clinical Science, Southwestern Medical Center, Dallas, Texas (United States); Corona, Irma [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Sharma, Akanksha [School of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Wadsworth, Margaret E. [Radiation Oncology of Mississippi, Jackson, Mississippi (United States); Timmerman, Robert, E-mail: Robert.Timmerman@utsouthwestern.edu [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)

    2015-09-01

    Purpose: Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC. Methods and Materials: Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy. Results: Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59). Conclusions: Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long

  20. A theory of drug tolerance and dependence I: a conceptual analysis.

    Science.gov (United States)

    Peper, Abraham

    2004-08-21

    A mathematical model of drug tolerance and its underlying theory is presented. The model extends a first approach, published previously. The model is essentially more complex than the generally used model of homeostasis, which is demonstrated to fail in describing tolerance development to repeated drug administrations. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary only in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behavior to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes. In addition, it establishes a relation between the drug dose at any moment, and the resulting drug effect and relates the magnitude of the reactions following withdrawal to the rate of tolerance and other parameters involved in the tolerance process. The present paper analyses the concept behind the model. The next paper discusses the mathematical model.

  1. Mahalanobis distance and variable selection to optimize dose response

    International Nuclear Information System (INIS)

    Moore, D.H. II; Bennett, D.E.; Wyrobek, A.J.; Kranzler, D.

    1979-01-01

    A battery of statistical techniques are combined to improve detection of low-level dose response. First, Mahalanobis distances are used to classify objects as normal or abnormal. Then the proportion classified abnormal is regressed on dose. Finally, a subset of regressor variables is selected which maximizes the slope of the dose response line. Use of the techniques is illustrated by application to mouse sperm damaged by low doses of x-rays

  2. Kinetic and dose dependencies of the SOS-induction in E.coli K-12 (uvrA) cells exposed to different UV doses

    International Nuclear Information System (INIS)

    Komova, O.V.; Kandiano, E.S.; Malavina, G.; )

    2000-01-01

    Kinetic and dose dependencies of the SOS-induction in E. coli (uvrA) cells exposed to UV light were investigated. below 2 J/m 2 the rate of the SOS-induction increased with dose. Maximal level of the SOS-response was proportional to the UV dose. Pyrimidine dimers were necessary for the induction. In the dose range 2-10 J/m 2 the rate of SOS-induction decreased with dose. Dose-maximum response curve was non-linear. Pyrimidine dimers were not required for the induction. nature of the molecular events leading to the SOS-induction at low and high doses was discussed [ru

  3. External Beam Radiotherapy of Recurrent Glioma: Radiation Tolerance of the Human Brain

    Energy Technology Data Exchange (ETDEWEB)

    Sminia, Peter, E-mail: p.sminia@vumc.nl [Department of Radiation Oncology, Radiobiology Section, VU University Medical Center, De Boelelaan 1117, P.O. Box 7057, Amsterdam (Netherlands); Mayer, Ramona [EBG MedAustron GmbH., Viktor Kaplan-Strasse 2, A-2700, Wiener Neustadt (Austria)

    2012-04-05

    Malignant gliomas relapse in close proximity to the resection site, which is the postoperatively irradiated volume. Studies on re-irradiation of glioma were examined regarding radiation-induced late adverse effects (i.e., brain tissue necrosis), to obtain information on the tolerance dose and treatment volume of normal human brain tissue. The studies were analyzed using the linear-quadratic model to express the re-irradiation tolerance in cumulative equivalent total doses when applied in 2 Gy fractions (EQD2{sub cumulative}). Analysis shows that the EQD2{sub cumulative} increases from conventional re-irradiation series to fractionated stereotactic radiotherapy (FSRT) to LINAC-based stereotactic radiosurgery (SRS). The mean time interval between primary radiotherapy and the re-irradiation course was shortened from 30 months for conventional re-irradiation to 17 and 10 months for FSRT and SRS, respectively. Following conventional re-irradiation, radiation-induced normal brain tissue necrosis occurred beyond an EQD2{sub cumulative} around 100 Gy. With increasing conformality of therapy, the smaller the treatment volume is, the higher the radiation dose that can be tolerated. Despite the dose escalation, no increase in late normal tissue toxicity was reported. On basis of our analysis, the use of particle therapy in the treatment of recurrent gliomas, because of the optimized physical dose distribution in the tumour and surrounding healthy brain tissue, should be considered for future clinical trials.

  4. External Beam Radiotherapy of Recurrent Glioma: Radiation Tolerance of the Human Brain

    Directory of Open Access Journals (Sweden)

    Peter Sminia

    2012-04-01

    Full Text Available Malignant gliomas relapse in close proximity to the resection site, which is the postoperatively irradiated volume. Studies on re-irradiation of glioma were examined regarding radiation-induced late adverse effects (i.e., brain tissue necrosis, to obtain information on the tolerance dose and treatment volume of normal human brain tissue. The studies were analyzed using the linear-quadratic model to express the re-irradiation tolerance in cumulative equivalent total doses when applied in 2 Gy fractions (EQD2cumulative. Analysis shows that the EQD2cumulative increases from conventional re-irradiation series to fractionated stereotactic radiotherapy (FSRT to LINAC-based stereotactic radiosurgery (SRS. The mean time interval between primary radiotherapy and the re-irradiation course was shortened from 30 months for conventional re-irradiation to 17 and 10 months for FSRT and SRS, respectively. Following conventional re-irradiation, radiation-induced normal brain tissue necrosis occurred beyond an EQD2cumulative around 100 Gy. With increasing conformality of therapy, the smaller the treatment volume is, the higher the radiation dose that can be tolerated. Despite the dose escalation, no increase in late normal tissue toxicity was reported. On basis of our analysis, the use of particle therapy in the treatment of recurrent gliomas, because of the optimized physical dose distribution in the tumour and surrounding healthy brain tissue, should be considered for future clinical trials.

  5. Scheduling of Fault-Tolerant Embedded Systems with Soft and Hard Timing Constraints

    DEFF Research Database (Denmark)

    Izosimov, Viacheslav; Pop, Paul; Eles, Petru

    2008-01-01

    In this paper we present an approach to the synthesis of fault-tolerant schedules for embedded applications with soft and hard real-time constraints. We are interested to guarantee the deadlines for the hard processes even in the case of faults, while maximizing the overall utility. We use time....../utility functions to capture the utility of soft processes. Process re-execution is employed to recover from multiple faults. A single static schedule computed off-line is not fault tolerant and is pessimistic in terms of utility, while a purely online approach, which computes a new schedule every time a process...

  6. Long-term tolerance and outcomes for dose escalation in early salvage post-prostatectomy radiation therapy

    International Nuclear Information System (INIS)

    Safdieh, Joseph; Schwartz, David; Weiner, Joseph; Weiss, Jeffrey P.; Madeb, Isaac; Rotman, Marvin; Schreiber, David; Rineer, Justin

    2014-01-01

    To study the long-term outcomes and tolerance in our patients who received dose escalated radiotherapy in the early salvage post-prostatectomy setting. The medical records of 54 consecutive patients who underwent radical prostatectomy subsequently followed by salvage radiation therapy (SRT) to the prostate bed between 2003-2010 were analyzed. Patients included were required to have a pre-radiation prostate specific antigen level (PSA) of 2 ng/mL or less. The median SRT dose was 70.2 Gy. Biochemical failure after salvage radiation was defined as a PSA level >0.2 ng/mL. Biochemical control and survival endpoints were analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were used to identify the potential impact of confounding factors on outcomes. The median pre-SRT PSA was 0.45 ng/mL and the median follow-up time was 71 months. The 4- and 7-year actuarial biochemical control rates were 75.7% and 63.2%, respectively. The actuarial 4- and 7-year distant metastasis-free survival was 93.7% and 87.0%, respectively, and the actuarial 7-year prostate cancer specific survival was 94.9%. Grade 3 late genitourinary toxicity developed in 14 patients (25.9%), while grade 4 late genitourinary toxicity developed in 2 patients (3.7%). Grade 3 late gastrointestinal toxicity developed in 1 patient (1.9%), and grade 4 late gastrointestinal toxicity developed in 1 patient (1.9%). In this series with long-term follow-up, early SRT provided outcomes and toxicity profiles similar to those reported from the three major randomized trials studying adjuvant radiation therapy.

  7. Pump speed modulations and sub-maximal exercise tolerance in left ventricular assist device recipients

    DEFF Research Database (Denmark)

    Jung, Mette Holme; Houston, Brian; Russell, Stuart D

    2017-01-01

    of the 2 sub-maximal tests was determined by randomization. Both patient and physician were blinded to the sequence. Exercise duration, oxygen consumption (VO2) and rate of perceived exertion (RPE), using the Borg scale (score 6 to 20), were recorded. RESULTS: Nineteen patients (all with a HeartMate II...... ventricular assist device) completed 57 exercise tests. Baseline pump speed was 9,326 ± 378 rpm. At AT, workload was 63 ± 26 W (25 to 115 W) and VO2 was 79 ± 14% of maximum. Exercise duration improved by 106 ± 217 seconds (~13%) in Speedinc compared with Speedbase (837 ± 358 vs 942 ± 359 seconds; p = 0...

  8. A fixed-dose combination tablet of gemigliptin and metformin sustained release has comparable pharmacodynamic, pharmacokinetic, and tolerability profiles to separate tablets in healthy subjects

    Directory of Open Access Journals (Sweden)

    Park SI

    2015-02-01

    Full Text Available Sang-In Park,1,* Howard Lee,1,2,* Jaeseong Oh,1 Kyoung Soo Lim,3 In-Jin Jang,1 Jeong-Ae Kim,4 Jong Hyuk Jung,4 Kyung-Sang Yu1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 2Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Clinical Trials Center, Seoul National University Hospital, Seoul, 3Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, 4LG Life Sciences, Ltd, Seoul, Republic of Korea *These authors contributed equally to this work Background: In type 2 diabetes mellitus, fixed-dose combination (FDC can provide the complementary benefits of correction of multiple pathophysiologic defects such as dysfunctions in glycemic or metabolic control while improving compliance compared with separate tablets taken together. The objective of the study reported here was to compare the pharmacodynamic (PD, pharmacokinetic (PK, and tolerability profiles of gemigliptin and extended-release metformin (metformin XR between FDC and separate tablets.Methods: A randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 28 healthy male volunteers. Two FDC tablets of gemigliptin/metformin 25/500 mg or separate tablets of gemigliptin (50 mg ×1 and metformin XR (500 mg ×2 were orally administered in each period. Serial blood samples were collected up to 48 hours post-dose to determine dipeptidyl peptidase 4 (DPP-4 activity using spectrophotometric assay and concentrations of gemigliptin and metformin using tandem mass spectrometry. Geometric mean ratios (GMRs of FDC to separate tablet formulations and their 90% confidence intervals (CIs were calculated to compare the PD and PK parameters between the two formulations. Tolerability was assessed throughout the study.Results: The plasma DPP-4 activity

  9. Dose measurements in mammography

    International Nuclear Information System (INIS)

    Kainberger, F.; Kallinger, W.

    1977-01-01

    Dose measurements at the mamma during mammography were carried out in the form of direct measurement with thermoluminescent dosimetry. Measurement was done for the in- and outcoming doses at the mamma, the dose exposure of the sternal region and the scattered rays above the symphysis, the latter as parameter for the genetic radiation exposure. As expected, the dose of the smooth radiation used for mammography showed a strong decrease at the outcome point in comparison with the income point. Surprisingly high was the scattered radiation in the sternal region. A corresponding protection by lead plates could be taken into consideration. Extremely low is the scattered radiation above the symphysis. Even measurements with the very sensitive calcium fluoride dosimeters did not reveal any practically important dose in the symphysis region. Most measurement values remained below the determinable dose of 0.3mR. Some maximal values varied in the range of 3-1 mR. (orig.) [de

  10. Entropy maximization

    Indian Academy of Sciences (India)

    Abstract. It is shown that (i) every probability density is the unique maximizer of relative entropy in an appropriate class and (ii) in the class of all pdf f that satisfy. ∫ fhi dμ = λi for i = 1, 2,...,...k the maximizer of entropy is an f0 that is pro- portional to exp(. ∑ ci hi ) for some choice of ci . An extension of this to a continuum of.

  11. Bronchial mucosal tolerance following high dose rate endobronchial brachytherapy: clinical and laboratory correlates in late complication assessment of fatal hemoptysis

    International Nuclear Information System (INIS)

    Chen, Y.Y.; McDonald, S.; Nakamura, C.; Philips, A.; Ojomo, Karanita; Hernady, E.; Williams, J. P.; Smudzin, T.; Johnstone, D.; Feins, R.; Speiser, B.L.; Rubin, P.

    1996-01-01

    Purpose: This study reviews treatment related late complications following high dose rate endobronchial brachytherapy (HDR-EB) for primary lung cancers. Radiation dose contribution from HDR-EB treatment alone, or combined HDR-EB and external beam (EBRT) were analyzed in relation to the linear representation of the tracheobronchial anatomy. Results were presented in a dose volume histogram (DVH) analysis for the risk estimate of late complications from HDR-EB. Bronchial mucosal tolerance is estimated from the clinical experience study and histopathologic changes in laboratory animals treated with HDR-EB. Methods: 1.) There were forty one patients with primary lung cancer received HDR-EB as part of the radiation treatment between December 1990 and June 1994. Six of these developed late complications manifested as either fatal hemoptysis or endobronchial deposition of fibrinous material/bronchial stenosis. Treatment planning films were reviewed to map the volume treated with HDR-EB and EBRT along the tracheobronchial segments. DVH was constructed and compared for patients with and without late complications. Other clinical parameters of interest which were analyzed included: dose per fraction, EBRT total dose, HDR total dose, combined EBRT and HDR total dose, number of catheters per treatment, and points of prescriptions for HDR-EB. 2.) Forty four New Zealand White rabbits underwent HDR-EB of the major airway to a treatment length of 2 cm (1 cm above and below the carina) to a single fraction dose of 10 Gy, 30 Gy, or 50 Gy. Histopathologic changes were examined at 7, 14, 28, and 56 days post-treatment and compared with the control rabbits which received no irradiation. Results: 1.) The late complication rate is 14.5% with three patients developing fibrinous deposits/bronchial stenosis and four patients who experienced fatal hemoptysis in a total of six patients. There is a significant difference in DVH of HDR-EB treatment in the tracheobronchial high dose region

  12. Normal tissue tolerance to external beam radiation therapy: The stomach

    International Nuclear Information System (INIS)

    Oberdiac, P.; Mineur, L.

    2010-01-01

    In the following article, we will discuss general issues relating to acute and late gastric's radiation toxicities. The tolerance of the stomach to complete or partial organ irradiation is more un-appreciated than for most other organs. We consulted the Medline database via PubMed and used the key words gastric - radiotherapy - toxicity. Currently, 60 Gy or less is prescribed in gastric radiation therapy. Acute clinical toxicity symptoms are predominantly nausea and vomiting. Although there is a general agreement that the whole stomach tolerance is for doses of 40 to 45 Gy without unacceptable complication, it is well established that a stomach dose of 35 Gy increases the risk of ulcer complications. (authors)

  13. Real-life indications to ivabradine treatment for heart rate optimization in patients with chronic systolic heart failure.

    Science.gov (United States)

    Tondi, Lara; Fragasso, Gabriele; Spoladore, Roberto; Pinto, Giuseppe; Gemma, Marco; Slavich, Massimo; Godino, Cosmo; Salerno, Anna; Montanaro, Claudia; Margonato, Alberto

    2018-05-11

    : Ivabradine is a selective and specific inhibitor of If current. With its pure negative chronotropic action, it is recommended by European Society of Cardiology and American College of Cardiology/American Heart Association guidelines in symptomatic heart failure patients (NYHA ≥ 2) with ejection fraction 35% or less, sinus rhythm and heart rate (HR) at least 70 bpm, despite maximally titrated β-blocker therapy. Data supporting this indication mainly derive from the SHIFT study, in which ivabradine reduced the combined endpoint of mortality and hospitalization, despite the fact that only 26% of patients enrolled were on optimal β-blocker doses. The aim of the present analysis is to establish the real-life eligibility for ivabradine in a population of patients with systolic heart failure, regularly attending a single heart failure clinic and treated according to guideline-directed medical therapy (GDMT). The clinical cards of 308 patients with heart failure with reduced ejection fraction (HFrEF) through a 68-month period of observation were retrospectively analyzed. GDMT, including β-blocker up-titration to maximal tolerated dose, was implemented during consecutive visits at variable intervals. Demographic, clinical and echocardiographic data were collected at each visit, together with 12-leads ECG and N-terminal pro-B-type natriuretic peptide levels. Out of 308 analyzed HFrEF patients, 220 (71%) were on effective β-blocker therapy, up-titrated to effective/maximal tolerated dose (55 ± 28% of maximal dose) (HR 67 ± 10 bpm). Among the remaining 88 patients, 10 (3.2%) were on maximally tolerated β blocker and ivabradine; 21 patients (6.8%), despite being on maximal tolerated β-blocker dose, had still HR ≥70 bpm, ejection fraction 35% or less and were symptomatic NYHA ≥2, being therefore eligible for ivabradine treatment. The remaining 57 (18%) patients were not on β blocker due to either intolerance or major contraindications. Among

  14. Estimation of dependence between mean of fractionation of photons and neutrons dose and intensity of post-irradiation reaction of mouse large intestine; Ocena zaleznosci pomiedzy sposobem frakcjonowania dawki fotonow i neutronow a nasileniem popromiennego odczynu jelita grubego myszy

    Energy Technology Data Exchange (ETDEWEB)

    Gasinska, A. [Oncology Center, Cracow (Poland)

    1995-12-31

    The aim of the work was verification of mouse large intestine tolerance on fractionated 250 kV X-rays and 2.3 MeV neutrons doses. Two cm of large intestine of mouse CBA/HT strain were irradiated with various fraction doses: from 0.25 to 35 Gy of X-rays and 0.05-12 Gy of neutrons. The measure of injury was handicap of intestine function. Early post-irradiation reaction was measured by loss of body weight (2-3 weeks after irradiation) and mouse mortality (till 2 months after irradiation, LD50/2). The late reaction was measured on the base of maximal body weight in 1 year period after irradiation, deformation of excrements (after 10 months) and death of animals (till 12. month after irradiation, LD50/12). Fractionation of X-ray dose influenced on decrease of intensification of late irradiation effects. After fractionation of neutrons this effect has not been observed. {alpha}/{beta} coefficient for X-rays was 19.9 Gy [15.2; 27.0] for body weight nadir, 13.4 Gy [9.3; 19.5] for early mortality (LD50/2), 6.4 Gy [3.6;11.0] for maximal body weight and 6.9 [4.2; 10.8] for late mortality (LD50/12). Analysis of influence of low doses of photons 90.25-4 Gy) and neutrons (0.05-0.8 Gy) showed trend to reduction {alpha}/{beta} for photons only (LD50/2=5.4 Gy; LD50/12=4.6 Gy). {alpha}/{beta} coefficient for neutrons was defined by LQ model only for maximal body weight and was 19.9 Gy [9.5; 61.0]. In application of graphic method {alpha}/{beta} for neutrons was 230 Gy for early and 48 Gy for late effects. Lower values of {alpha}/{beta} coefficient for late irradiation effects for photon radiation demonstrate the big influence of fractionation of photons dose on large intestine tolerance (decrease intensity in all biological effects). Author did not observe increase of intestine tolerance in fractionation of neutrons dose. Effect of irradiation damages repair in interfraction pauses, measured by percent of regenerated dose (F{sub r}) was much bigger for photons. For X-rays it was 50

  15. Sensitization or tolerance to Mycobacterium leprae antigen by route of injection

    Energy Technology Data Exchange (ETDEWEB)

    Shepard, C.C.; Walker, L.L.; Van Landingham, R.M.; Ye, S.Z.

    1982-11-01

    Aqueous suspensions of heat-killed Mycobacterium leprae in a dose of 10(7) organisms were highly immunogenic when injected intradermally (i.d.). The same dose of bacteria did not sensitize when given intraperitoneally (i.p.) or intravenously (i.v.), and did so only minimally at best when given subcutaneously. The i.d. route was the most immunogenic for sheep erythrocytes also. M. leprae injected i.p. or i.v. stimulated immune tolerance to M. leprae challenge i.d. In older mice (greater than or equal to 8 weeks), the i.v. injections gave more complete tolerance. Mice that had been rendered tolerant by i.v. injections maintained their tolerance for at least 168 days. Prior UV irradiation of intact mice prevented sensitization by the i.d. route. In normal mice, living M. bovis BCG given i.d. produced good sensitization to M. leprae. Mice that had been made tolerant by i.v. injection of M. leprae could be partially sensitized to M. leprae by i.d. immunization with BCG; mixtures of living BCG and heat-killed M. leprae were no more effective than BCG alone. These findings appear to have relevance to the pathogenesis of lepromatous leprosy and its immunoprophylaxis.

  16. Sensitization or tolerance to Mycobacterium leprae antigen by route of injection

    International Nuclear Information System (INIS)

    Shepard, C.C.; Walker, L.L.; Van Landingham, R.M.; Ye, S.Z.

    1982-01-01

    Aqueous suspensions of heat-killed Mycobacterium leprae in a dose of 10(7) organisms were highly immunogenic when injected intradermally (i.d.). The same dose of bacteria did not sensitize when given intraperitoneally (i.p.) or intravenously (i.v.), and did so only minimally at best when given subcutaneously. The i.d. route was the most immunogenic for sheep erythrocytes also. M. leprae injected i.p. or i.v. stimulated immune tolerance to M. leprae challenge i.d. In older mice (greater than or equal to 8 weeks), the i.v. injections gave more complete tolerance. Mice that had been rendered tolerant by i.v. injections maintained their tolerance for at least 168 days. Prior UV irradiation of intact mice prevented sensitization by the i.d. route. In normal mice, living M. bovis BCG given i.d. produced good sensitization to M. leprae. Mice that had been made tolerant by i.v. injection of M. leprae could be partially sensitized to M. leprae by i.d. immunization with BCG; mixtures of living BCG and heat-killed M. leprae were no more effective than BCG alone. These findings appear to have relevance to the pathogenesis of lepromatous leprosy and its immunoprophylaxis

  17. An Efficient and Effective Design of InP Nanowires for Maximal Solar Energy Harvesting.

    Science.gov (United States)

    Wu, Dan; Tang, Xiaohong; Wang, Kai; He, Zhubing; Li, Xianqiang

    2017-11-25

    Solar cells based on subwavelength-dimensions semiconductor nanowire (NW) arrays promise a comparable or better performance than their planar counterparts by taking the advantages of strong light coupling and light trapping. In this paper, we present an accurate and time-saving analytical design for optimal geometrical parameters of vertically aligned InP NWs for maximal solar energy absorption. Short-circuit current densities are calculated for each NW array with different geometrical dimensions under solar illumination. Optimal geometrical dimensions are quantitatively presented for single, double, and multiple diameters of the NW arrays arranged both squarely and hexagonal achieving the maximal short-circuit current density of 33.13 mA/cm 2 . At the same time, intensive finite-difference time-domain numerical simulations are performed to investigate the same NW arrays for the highest light absorption. Compared with time-consuming simulations and experimental results, the predicted maximal short-circuit current densities have tolerances of below 2.2% for all cases. These results unambiguously demonstrate that this analytical method provides a fast and accurate route to guide high performance InP NW-based solar cell design.

  18. Entropy Maximization

    Indian Academy of Sciences (India)

    It is shown that (i) every probability density is the unique maximizer of relative entropy in an appropriate class and (ii) in the class of all pdf that satisfy ∫ f h i d = i for i = 1 , 2 , … , … k the maximizer of entropy is an f 0 that is proportional to exp ⁡ ( ∑ c i h i ) for some choice of c i . An extension of this to a continuum of ...

  19. Tolerance of edible flowers to gamma irradiation

    International Nuclear Information System (INIS)

    Koike, Amanda C.R.; Araujo, Michel M.; Costa, Helbert S.F.; Almeida, Mariana C.; Villavicencio, Anna Lucia C.H.

    2011-01-01

    People have been eating flowers and using them in culinary creations for hundreds of years. Edible flowers are increasingly being used in meals as an ingredient in salads or garnish, entrees, drinks and desserts. The irradiation process is an alternative method that can be used in disinfestation of food and flowers, using doses that do not damage the product. The sensitivity of flowers to irradiation varies from species to species. In the present research was irradiated with doses up to 1 kGy some edible flowers to examine their physical tolerance to gamma-rays. Furthermore, high doses gamma irradiation causes petal withering, browning process and injury in edible flowers. (author)

  20. Tolerance of edible flowers to gamma irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Koike, Amanda C.R.; Araujo, Michel M.; Costa, Helbert S.F.; Almeida, Mariana C.; Villavicencio, Anna Lucia C.H., E-mail: ackoike@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP) Sao Paulo, SP (Brazil)

    2011-07-01

    People have been eating flowers and using them in culinary creations for hundreds of years. Edible flowers are increasingly being used in meals as an ingredient in salads or garnish, entrees, drinks and desserts. The irradiation process is an alternative method that can be used in disinfestation of food and flowers, using doses that do not damage the product. The sensitivity of flowers to irradiation varies from species to species. In the present research was irradiated with doses up to 1 kGy some edible flowers to examine their physical tolerance to gamma-rays. Furthermore, high doses gamma irradiation causes petal withering, browning process and injury in edible flowers. (author)

  1. Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine

    Science.gov (United States)

    Hill, Rob; Lyndon, Abi; Withey, Sarah; Roberts, Joanne; Kershaw, Yvonne; MacLachlan, John; Lingford-Hughes, Anne; Kelly, Eamonn; Bailey, Chris; Hickman, Matthew; Henderson, Graeme

    2016-01-01

    Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths. PMID:26171718

  2. Maximally incompatible quantum observables

    Energy Technology Data Exchange (ETDEWEB)

    Heinosaari, Teiko, E-mail: teiko.heinosaari@utu.fi [Turku Centre for Quantum Physics, Department of Physics and Astronomy, University of Turku, FI-20014 Turku (Finland); Schultz, Jussi, E-mail: jussi.schultz@gmail.com [Dipartimento di Matematica, Politecnico di Milano, Piazza Leonardo da Vinci 32, I-20133 Milano (Italy); Toigo, Alessandro, E-mail: alessandro.toigo@polimi.it [Dipartimento di Matematica, Politecnico di Milano, Piazza Leonardo da Vinci 32, I-20133 Milano (Italy); Istituto Nazionale di Fisica Nucleare, Sezione di Milano, Via Celoria 16, I-20133 Milano (Italy); Ziman, Mario, E-mail: ziman@savba.sk [RCQI, Institute of Physics, Slovak Academy of Sciences, Dúbravská cesta 9, 84511 Bratislava (Slovakia); Faculty of Informatics, Masaryk University, Botanická 68a, 60200 Brno (Czech Republic)

    2014-05-01

    The existence of maximally incompatible quantum observables in the sense of a minimal joint measurability region is investigated. Employing the universal quantum cloning device it is argued that only infinite dimensional quantum systems can accommodate maximal incompatibility. It is then shown that two of the most common pairs of complementary observables (position and momentum; number and phase) are maximally incompatible.

  3. Maximally incompatible quantum observables

    International Nuclear Information System (INIS)

    Heinosaari, Teiko; Schultz, Jussi; Toigo, Alessandro; Ziman, Mario

    2014-01-01

    The existence of maximally incompatible quantum observables in the sense of a minimal joint measurability region is investigated. Employing the universal quantum cloning device it is argued that only infinite dimensional quantum systems can accommodate maximal incompatibility. It is then shown that two of the most common pairs of complementary observables (position and momentum; number and phase) are maximally incompatible.

  4. Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients.

    NARCIS (Netherlands)

    Ruslami, R.; Nijland, H.M.J.; Alisjahbana, B.; Parwati, I.; Crevel, R. van; Aarnoutse, R.E.

    2007-01-01

    Rifampin is a key drug for tuberculosis (TB) treatment. The available data suggest that the currently applied 10-mg/kg of body weight dose of rifampin may be too low and that increasing the dose may shorten the treatment duration. A double-blind randomized phase II clinical trial was performed to

  5. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects.

    Science.gov (United States)

    Anderson, Matt S; Gilmartin, Jocelyn; Cilissen, Caroline; De Lepeleire, Inge; Van Bortel, Luc; Dockendorf, Marissa F; Tetteh, Ernestina; Ancona, June K; Liu, Rachael; Guo, Ying; Wagner, John A; Butterton, Joan R

    2015-01-01

    Doravirine is a novel non-nucleoside inhibitor of HIV-1 reverse transcriptase with potent activity against wild-type virus (95% inhibitory concentration 19 nM, 50% human serum). Doravirine has low potential to cause drug-drug interactions since it is primarily eliminated by oxidative metabolism and does not inhibit or significantly induce drug-metabolizing enzymes. The pharmacokinetics and safety of doravirine were investigated in two double-blind, dose-escalation studies in healthy males. Thirty-two subjects received single doses of doravirine (6-1,200 mg) or matching placebo tablets; 40 subjects received doravirine (30-750 mg) or matching placebo tablets once daily for 10 days. In addition, the effect of doravirine (120 mg for 14 days) on single-dose pharmacokinetics of the CYP3A substrate midazolam was evaluated (10 subjects). The maximum plasma concentration (Cmax) of doravirine was achieved within 1-5 h with an apparent terminal half-life of 12-21 h. Consistent with single-dose pharmacokinetics, steady state was achieved after approximately 7 days of once daily administration, with accumulation ratios (day 10/day 1) of 1.1-1.5 in the area under the plasma concentration-time curve during the dosing interval (AUC0-24 h), Cmax and trough plasma concentration (C24 h). All dose levels produced C24 h>19 nM. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC time zero to infinity (AUC0-∞) and C24 h with no change in Cmax. Midazolam AUC0-∞ was slightly reduced by coadministration of doravirine (geometric mean ratio 0.82, 90% CI 0.70, 0.97). There was no apparent relationship between adverse event frequency or intensity and doravirine dose. No rash or significant central nervous system events other than headache were reported. Doravirine is generally well tolerated in single doses up to 1,200 mg and multiple doses up to 750 mg once daily for up to 10 days, with a pharmacokinetic profile supportive of once

  6. 78 FR 32146 - Triforine; Pesticide Tolerances

    Science.gov (United States)

    2013-05-29

    ... America Holding Corporation requested these tolerances under the Federal Food, Drug, and Cosmetic Act... in the liver and hematopoietic system following repeated oral dosing, and the dog is the most... UFA = 10x mg/kg/day. (dog) UFH = 10x cPAD = 0.22 mg/kg/ LOAEL = 120 mg/kg/day, based on FQPA SF = 1x...

  7. The time course of ethanol tolerance: associative learning

    Directory of Open Access Journals (Sweden)

    J.L.O. Bueno

    2007-11-01

    Full Text Available The effect of different contextual stimuli on different ethanol-induced internal states was investigated during the time course of both the hypothermic effect of the drug and of drug tolerance. Minimitters were surgically implanted in 16 Wistar rats to assess changes in their body temperature under the effect of ethanol. Rat groups were submitted to ethanol or saline trials every other day. The animals were divided into two groups, one receiving a constant dose (CD of ethanol injected intraperitoneally, and the other receiving increasing doses (ID during the 10 training sessions. During the ethanol training sessions, conditioned stimuli A (tone and B (buzzer were presented at "state +" (35 min after drug injection and "state -" (170 min after drug injection, respectively. Conditioned stimuli C (bip and D (white noise were presented at moments equivalent to stimuli A and B, respectively, but during the saline training sessions. All stimuli lasted 15 min. The CD group, but not the ID group, developed tolerance to the hypothermic effect of ethanol. Stimulus A (associated with drug "state +" induced hyperthermia with saline injection in the ID group. Stimulus B (associated with drug "state -" reduced ethanol tolerance in the CD group and modulated the hypothermic effect of the drug in the ID group. These results indicate that contextual stimuli acquire modulatory conditioned properties that are associated with the time course of both the action of the drug and the development of drug tolerance.

  8. Chronic ethanol or nicotine treatment results in partial cross-tolerance between these agents.

    Science.gov (United States)

    Burch, J B; de Fiebre, C M; Marks, M J; Collins, A C

    1988-01-01

    Female DBA/2Ibg mice were treated chronically (21 days) with ethanol- or dextrin-containing liquid diets or infused chronically with nicotine (8 mg/kg/h) or saline for 10 days. The responses of these animals to challenge doses of ethanol (2.5 g/kg) or nicotine (1 or 2 mg/kg) were measured using a test battery consisting of respiration rate, acoustic startle response, Y-maze crosses and rears, heart rate and body temperature. Chronic ethanol-treated animals were tolerant to the effects elicited by a challenge dose of ethanol on four of the six measures and were cross-tolerant to nicotine's effects on the acoustic startle test. Chronic nicotine-treated animals were tolerant to nicotine's effects on five of the six measures and cross-tolerant to ethanol's effects on heart rate and body temperature. Thus, partial cross-tolerance between ethanol and nicotine exists. Chronic nicotine treatment resulted in significant increases in L-[3H]-nicotine binding in six of seven brain regions and in alpha-[125I]-bungarotoxin binding in three of seven brain regions. Chronic ethanol treatment failed to alter the binding of either ligand. Therefore, the cross-tolerance that develops between ethanol and nicotine is not totally dependent on alterations in the number of brain nicotinic receptors.

  9. Tolerance to continuous intrathecal baclofen infusion can be reversed by pulsatile bolus infusion

    NARCIS (Netherlands)

    Heetla, H. W.; Staal, M. J.; van Laar, T.

    Study design: Pilot study. Objective: To study the effect of pulsatile bolus infusion of intrathecal baclofen (ITB) on daily ITB dose, in patients showing dose increases, probably due to tolerance. Setting: Department of neurology and neurosurgery, University Medical Center Groningen, the

  10. Phase I study of intraoperative radiotherapy with photon radiosurgery system in children with recurrent brain tumors: Preliminary report of first dose level (10 Gy)

    International Nuclear Information System (INIS)

    Kalapurakal, John A.; Goldman, Stewart; Stellpflug, Wendy; Curran, John; Sathiaseelan, Vythialingam; Marymont, Maryanne H.; Tomita, Tadanori

    2006-01-01

    Purpose: To describe the preliminary results after intraoperative radiotherapy (IORT) with the photon radiosurgery system in children with recurrent brain tumors treated at the first dose level (10 Gy) of a Phase I protocol. Methods and Materials: A Phase I IORT dose escalation protocol was initiated at Children's Memorial Hospital to determine the maximal tolerated IORT dose in children with recurrent brain tumors. Results: Fourteen children have received IORT thus far. Eight had been previously irradiated. Thirteen children had ependymoma. The median follow-up was 16 months. Three patients (21%) developed radiation necrosis on follow-up MRI scans 6 to 12 months after IORT. They had not been previously irradiated and had received 10 Gy to a depth of 5 mm. One required surgery and the other two had resolution of their lesions without treatment. All 3 patients were asymptomatic at the last follow-up. No other late toxicity was observed at the last follow-up visit. Eight patients (57%) had tumor control within the surgical bed after IORT. Conclusion: Our findings have demonstrated the safety and feasibility of IORT to a dose of 10 Gy to 2 mm in children with previously irradiated brain tumors. IORT to a dose of 10 Gy at 5 mm was associated with a greater complication rate

  11. Assessment of maximum tolerated dose of a new herbal drug, Semelil (ANGIPARSTM in patients with diabetic foot ulcer: A Phase I clinical trial

    Directory of Open Access Journals (Sweden)

    Heshmat R

    2008-04-01

    Full Text Available Background and the purpose of the study: In many cases of diabetic foot ulcer (DFU management, wound healing is incomplete, and wound closure and epithelial junctional integrity are rarely achieved. Our aim was to evaluate the maximum tolerated dose (MTD and dose-limiting toxicity (DLT of Semelil (ANGIPARSTM, a new herbal compound for wound treatment in a Phase I clinical trial.Methods: In this open label study, six male diabetic patients with a mean age of 57±7.6 years were treated with escalating intravenous doses of Semelil, which started at 2 cc/day to 13.5 cc/day for 28 days. Patients were assessed with a full physical exam; variables which analyzed included age, past history of diabetes and its duration, blood pressure, body temperature, weight, characteristics of DFU, Na, K, liver function test, Complete Blood Count and Differential(CBC & diff, serum amylase, HbA1c, PT, PTT, proteinuria, hematuria, and side effects were recorded. All the measurements were taken at the beginning of treatment, the end of week 2 and week 4. We also evaluated Semelil's side effects at the end of weeks 4 and 8 after ending therapy.Results and major conclusions: Up to the drug dose of 10 cc/day foot ulcer dramatically improved. We did not observe any clinical or laboratory side effects at this or lower dose levels in diabetic patients. With daily dose of 13.5 cc of Semelil we observed phlebitis at the infusion site, which was the only side effect. Therefore, in this study we determined the MTD of Semelil at 10 cc/day, and the only DLT was phlebitis in injection vein. The recommended dose of Semelil I.V. administration for Phase II studies was 4 cc/day.

  12. Maximal combustion temperature estimation

    International Nuclear Information System (INIS)

    Golodova, E; Shchepakina, E

    2006-01-01

    This work is concerned with the phenomenon of delayed loss of stability and the estimation of the maximal temperature of safe combustion. Using the qualitative theory of singular perturbations and canard techniques we determine the maximal temperature on the trajectories located in the transition region between the slow combustion regime and the explosive one. This approach is used to estimate the maximal temperature of safe combustion in multi-phase combustion models

  13. Developing maximal neuromuscular power: part 2 - training considerations for improving maximal power production.

    Science.gov (United States)

    Cormie, Prue; McGuigan, Michael R; Newton, Robert U

    2011-02-01

    This series of reviews focuses on the most important neuromuscular function in many sport performances: the ability to generate maximal muscular power. Part 1, published in an earlier issue of Sports Medicine, focused on the factors that affect maximal power production while part 2 explores the practical application of these findings by reviewing the scientific literature relevant to the development of training programmes that most effectively enhance maximal power production. The ability to generate maximal power during complex motor skills is of paramount importance to successful athletic performance across many sports. A crucial issue faced by scientists and coaches is the development of effective and efficient training programmes that improve maximal power production in dynamic, multi-joint movements. Such training is referred to as 'power training' for the purposes of this review. Although further research is required in order to gain a deeper understanding of the optimal training techniques for maximizing power in complex, sports-specific movements and the precise mechanisms underlying adaptation, several key conclusions can be drawn from this review. First, a fundamental relationship exists between strength and power, which dictates that an individual cannot possess a high level of power without first being relatively strong. Thus, enhancing and maintaining maximal strength is essential when considering the long-term development of power. Second, consideration of movement pattern, load and velocity specificity is essential when designing power training programmes. Ballistic, plyometric and weightlifting exercises can be used effectively as primary exercises within a power training programme that enhances maximal power. The loads applied to these exercises will depend on the specific requirements of each particular sport and the type of movement being trained. The use of ballistic exercises with loads ranging from 0% to 50% of one-repetition maximum (1RM) and

  14. Kinetic and dose dependences of the SOS-induction in E.coli K-12 (uvrA) cells exposed to the different UV doses

    International Nuclear Information System (INIS)

    Komova, O.V.; Kandiano, E.S.; Malavya, G.

    1999-01-01

    The kinetic and dose dependences of the SOS-induction in E.coli (uvrA) cells exposed to UV light were investigated. Below 2 J/m 2 the rate of the SOS-induction increased with dose. The maximal level of the SOS-response was proportional to the UV dose. Pyrimidine dimers were necessary for the induction. In the dose range 2-10 J/m 2 the rate of the SOS-induction decreased with dose. The dose-response curve was non-linear. Pyrimidine dimers were not required for the induction. The nature of the molecular events leading to the SOS-induction at low and high UV doses was discussed. (author)

  15. Impact of the lay-off length on +Gz tolerance.

    Science.gov (United States)

    Mikuliszyn, Romuald; Kowalski, Wieslaw; Kowalczuk, Krzysztof

    2002-07-01

    There are many factors affecting pilots' +Gz-tolerance. Recently, attention of the aviation community has been focused on lay-off and it's impact on +Gz-tolerance. Pilots of the Polish Air Force (PAF) have dealt with that problem for several years now. The aim of the study was to provide insight on how lay-off periods with different duration impact +Gz-tolerance. 95 male jet pilots from the PAF participated in the study. Every one had at least two weeks lay-off period (non-medical reasons). Subjects were divided into four groups according to the length of lay-off period (2-4 weeks; 5-13 weeks; 14-26 weeks; 27-154 weeks), All pilots were subjected to a centrifuge exposure in GOR (0.1 G/s) or ROR (1.0 G/s) profiles, depending on the pre-lay-off exposure. Post-lay-off exposures were carried out directly after lay-off. 18 jet pilots without any lay-off constituted the control group. The difference between pre- and post-lay-off G-tolerance limit (-0,93 +/- 0,53) was statistically significant (p<0.01) only for one group, where lay-off period ranged between two and four weeks. No statistically significant differences were found where influence of other factors like total and yearly flight hours, heart rate gain (AHR) or physical activity measured as maximal oxygen intake were considered. 2-4 weeks of lay-off period decreases +Gz tolerance is statistically significant manner. Subsequent increase of lay-off period does not result in mean tolerance changes for group, however in certain individuals critical decrement of +Gz tolerance occurs. Total and last year flying hours, physical fitness does not modify impact of lay-off period on +Gz tolerance.

  16. A study on mice exposure dose for low-dose gamma-irradiation using glass dosimeter

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Sung Jin; Kim, Hyo Jin; Kim, Hyun; Jeong, Dong Hyeok; Son, Tae Gen; Kim, Jung Ki; Yang, Kwang Mo; Kang, Yeong Rok [Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Nam, Sang Hee [Dept. of Biomedical Engineering, Inje University, Gimhae (Korea, Republic of)

    2015-12-15

    The low dose radiation is done for a long period, thus researchers have to know the exact dose distribution for the irradiated mouse. This research has been conducted in order to find out methods in transmitting an exact dose to mouse in a mouse irradiation experiment carried out using {sup 137}C{sub s} irradiation equipment installed in the DIRAMS (Dongnam Institution of Radiological and Medical Sciences) research center. We developed a single mouse housing cage and shelf with adjustable geometric factors such as distance and angle from collimator. The measurement of irradiated dose showed a maximal 42% difference of absorbed dose from the desired dose in the conventional irradiation system, whereas only 6% difference of the absorbed dose was measured in the self-developed mouse apartment system. In addition, multi mice housing showed much difference of the absorbed dose in between head and body, compared to single mouse housing in the conventional irradiation system. This research may allow further research about biological effect assessment for the low dose irradiation using the self-developed mouse apartment to provide more exact doses which it tries to transmit, and to have more reliability for the biological analysis results.

  17. Calculation methods for determining dose equivalent

    International Nuclear Information System (INIS)

    Endres, G.W.R.; Tanner, J.E.; Scherpelz, R.I.; Hadlock, D.E.

    1987-11-01

    A series of calculations of neutron fluence as a function of energy in an anthropomorphic phantom was performed to develop a system for determining effective dose equivalent for external radiation sources. Critical organ dose equivalents are calculated and effective dose equivalents are determined using ICRP-26 [1] methods. Quality factors based on both present definitions and ICRP-40 definitions are used in the analysis. The results of these calculations are presented and discussed. The effective dose equivalent determined using ICRP-26 methods is significantly smaller than the dose equivalent determined by traditional methods. No existing personnel dosimeter or health physics instrument can determine effective dose equivalent. At the present time, the conversion of dosimeter response to dose equivalent is based on calculations for maximal or ''cap'' values using homogeneous spherical or cylindrical phantoms. The evaluated dose equivalent is, therefore, a poor approximation of the effective dose equivalent as defined by ICRP Publication 26. 3 refs., 2 figs., 1 tab

  18. Approaching maximal performance of longitudinal beam compression in induction accelerator drivers

    International Nuclear Information System (INIS)

    Mark, J.W.K.; Ho, D.D.M.; Brandon, S.T.; Chang, C.L.; Drobot, A.T.; Faltens, A.; Lee, E.P.; Krafft, G.A.

    1986-01-01

    Longitudinal beam compression is an integral part of the US induction accelerator development effort for heavy ion fusion. Producing maximal performance for key accelerator components is an essential element of the effort to reduce driver costs. We outline here initial studies directed towards defining the limits of final beam compression including considerations such as: maximal available compression, effects of longitudinal dispersion and beam emittance, combining pulse-shaping with beam compression to reduce the total number of beam manipulations, etc. The use of higher ion charge state Z greater than or equal to 3 is likely to test the limits of the previously envisaged beam compression and final focus hardware. A more conservative approach is to use additional beamlets in final compression and focus. On the other end of the spectrum of choices, alternate approaches might consider new final focus with greater tolerances for systematic momentum and current variations. Development of such final focus concepts would also allow more compact (and hopefully cheaper) hardware packages where the previously separate processes of beam compression, pulse-shaping and final focus occur as partially combined and nearly concurrent beam manipulations

  19. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia

    Directory of Open Access Journals (Sweden)

    Balaji Ramachandran

    Full Text Available EGCG (Epigallocatechin-3-gallate is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal] and limited [p.o (oral] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment. Keywords: EGCG, Green tea, Serum lipids, Dose dependant toxicity, Route dependant toxicity, Liver toxicity, Dyslipidemia

  20. Hardness, function, emotional well-being, satisfaction and the overall sexual experience in men using 100-mg fixed-dose or flexible-dose sildenafil citrate.

    Science.gov (United States)

    Ströberg, P; Kaminetsky, J C; Park, N C; Goldfischer, E R; Creanga, D L; Stecher, V J

    2010-01-01

    The prescribing information for sildenafil citrate (VIAGRA, Pfizer, New York, NY, USA) recommends flexible dosing (50 mg initially, adjusted to 100 or 25 mg based on effectiveness and tolerability) in most men with erectile dysfunction (ED). In many men, however, 100 mg may be the most appropriate initial dose because it would reduce the need for titration and could prevent discouragement and treatment abandonment should 50 mg be insufficient. Results of two previously published double-blind, placebo-controlled sildenafil trials of similar design except for a fixed-dose vs flexible-dose regimen were analyzed. Relative to the flexible-dose, approximately one-third more men were satisfied with an initial and fixed dose of 100 mg. In addition, tolerability was similar, and improvements from baseline in outcomes on validated, ED-specific, patient-reported questionnaires were either similar (erectile function and the percentage of completely hard and fully rigid erections) or greater (emotional well-being and the overall sexual experience). The similarity in outcomes is not surprising given that almost 90% of the men in the flexible-dose trial titrated to 100 mg after 2 weeks. These data suggest prescription of an initial dose of 100 mg for men with ED, except in those for whom it is inappropriate.

  1. Brainstem tolerance to conformal radiotherapy of skull base tumors

    International Nuclear Information System (INIS)

    Debus, J.; Hug, E.B.; Liebsch, N.J.; O'Farrel, D.; Finkelstein, D.; Efird, J.; Munzenrider, J.E.

    1997-01-01

    Purpose: The aim of this study was to analyze the long-term incidence of brainstem toxicity in patients treated for skull base tumors with high dose conformal radiotherapy. Methods and Materials: Between 1974 and 1995, 367 patients with chordomas (n = 195) and chondrosarcomas (n = 172) of the base of skull have been treated with combined megavoltage photon and 160 MeV proton radiotherapy. Following 3D treatment planning with delineation of target volumes and critical nontarget structures dose distributions and dose-volume histograms were calculated. Radiotherapy was given an 1.8 Gy or CGE (=Cobalt Gray Equivalent) dose per fraction, with prescribed target doses ranging from 63 CGE to 79.2 CGE (mean = 67.8 CGE). Doses to the brainstem surface were limited to ≤64 CGE and to the brainstem center to ≤53 CGE. Results: Follow-up time ranged from 6 months to 21.4 years (mean = 42.5 months). Brainstem toxicity was observed in 17 of 367 patients attributable to treatment, resulting in death of three patients. Actuarial rates of 5 and 10-year high-grade toxicity-free survival were 94 and 88%, respectively. Increased risk of brainstem toxicity was significantly associated with maximum dose to brainstem, volume of brainstem receiving ≥50 CGE, ≥55 CGE, and ≥60 CGE, number of surgical procedures, and prevalence of diabetes or high blood pressure. Multivariate analysis identified three independent factors as important prognosticators: number of surgical procedures (p < 0.001), volume of the brainstem receiving 60 CGE (p < 0.001), and prevalence of diabetes (p < 0.01). Conclusions: Tolerance of brainstem to fractionated radiotherapy appears to be a steep function of tissue volume included in high dose regions rather than the maximum dose of brainstem alone. In addition, presence of predisposing factors as well as extent of surgical manipulation can significantly lower brainstem tolerance in the individual patient

  2. Relationship between sodium influx and salt tolerance of nitrogen-fixing cyanobacteria

    Energy Technology Data Exchange (ETDEWEB)

    Apte, S.K.; Reddy, B.R.; Thomas, J.

    1987-08-01

    The relationship between sodium uptake and cyanobacterial salt (NaCl) tolerance has been examined in two filamentous, heterocystous, nitrogen-fixing species of Anabaena. During diazotrophic growth at neutral pH of the growth medium, Anabaena sp. strain L-31, a freshwater strain, showed threefold higher uptake of Na+ than Anabaena torulosa, a brackish-water strain, and was considerably less salt tolerant (50% lethal dose of NaCl, 55 mM) than the latter (50% lethal dose of NaCl, 170 mM). Alkaline pH or excess K+ (more than 25 mM) in the medium causes membrane depolarization and inhibits Na+ influx in both cyanobacteria (S.K. Apte and J. Thomas, Eur. J. Biochem. 154:395-401, 1986). The presence of nitrate or ammonium in the medium caused inhibition of Na+ influx accompanied by membrane depolarization. These experimental manipulations affecting Na+ uptake demonstrated a good negative correlation between Na+ influx and salt tolerance. All treatments which inhibited Na+ influx (such as alkaline pH, K+ above 25 mM, NO3-, and NH4+), enhanced salt tolerance of not only the brackish-water but also the freshwater cyanobacterium. The results indicate that curtailment of Na+ influx, whether inherent or effected by certain environmental factors (e.g., combined nitrogen, alkaline pH), is a major mechanism of salt tolerance in cyanobacteria. (Refs. 27)

  3. Association Between Maximal Skin Dose and Breast Brachytherapy Outcome: A Proposal for More Rigorous Dosimetric Constraints

    International Nuclear Information System (INIS)

    Cuttino, Laurie W.; Heffernan, Jill; Vera, Robyn; Rosu, Mihaela; Ramakrishnan, V. Ramesh; Arthur, Douglas W.

    2011-01-01

    Purpose: Multiple investigations have used the skin distance as a surrogate for the skin dose and have shown that distances 4.05 Gy/fraction. Conclusion: The initial skin dose recommendations have been based on safe use and the avoidance of significant toxicity. The results from the present study have suggested that patients might further benefit if more rigorous constraints were applied and if the skin dose were limited to 120% of the prescription dose.

  4. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia.

    Science.gov (United States)

    Ramachandran, Balaji; Jayavelu, Subramani; Murhekar, Kanchan; Rajkumar, Thangarajan

    2016-01-01

    EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

  5. Exercise tolerance in children and adolescents with musculoskeletal pain in joint hypermobility and joint hypomobility syndrome

    NARCIS (Netherlands)

    Engelbert, Raoul H. H.; van Bergen, Monique; Henneken, Thamar; Helders, Paul J. M.; Takken, Tim

    2006-01-01

    Musculoskeletal pain is a common complaint in a pediatric health care practice, but exercise tolerance has never been described in detail in these children. Our objectives for this study were to evaluate the maximal exercise capacity, including peak heart rate and oxygen consumption, of children

  6. Exercise (effort) tolerance and factors affecting this tolerance for liquidators of consequences of the ChNPP accident

    International Nuclear Information System (INIS)

    Khomazyuk, I.N.

    1992-01-01

    Physical efficiency and factors affecting it for persons exposed to irradiation (the radiation dose being in the range up to 0.75 Gy) has been studied. 670 participants of liquidating the consequences of ChNPP accident have been examined. Depending on the radiation doses to which the people have been exposed the liquidators have been subdivided into 4 groups: for the 1st group the radiation doses ranging from 0.25 to 0.75 Gy; for the 2nd group the radiation doses ranging from 0.10 to 0.24 Gy; for the 3rd group the radiation doses ranging from 0.05 to 0.10 Gy; for the 4th group the radiation dose being up to 0.05 Gy. The physical load was ensured with veloergometer. The results have made it possible to estimate one of the basic health criterion for liquidators of consequences of ChNPP accident (i.e. exercise (effort) tolerance). No direct relationship of the exercise magnitude and the radiation dose within the range up to 0.75 Gy and the irradiation time have been observed. The correlation of the exercise magnitude with due account to age has been provided. 15 refs.; 2 tabs

  7. Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Parry, Gareth J; Rodrigues, Cecilia M P; Aranha, Marcia M; Hilbert, Sarah J; Davey, Cynthia; Kelkar, Praful; Low, Walter C; Steer, Clifford J

    2010-01-01

    Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration. Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly. Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner. These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.

  8. Brainstem tolerance to conformal radiotherapy of skull base tumors

    International Nuclear Information System (INIS)

    Debus, J.; Hug, E.B.; Munzenrider, J.E.; Liebsch, N.J.; O'Farrell, D.; Efird, J.; Daly, W.; Suit, H.D.

    1996-01-01

    Purpose/Objective: Brainstem tolerance to inhomogenous radiation doses applied by modern conformal radiotherapy has not yet been examined. The aim of this study was to analyse the incidence of brainstem toxicity in patients treated for skull base tumors with high dose conformal radiotherapy. Materials and Methods: Between 1974 and 1995, 367 patients with chordomas (n=195) and chondrosarcomas (n=172) of the base of skull have been treated with combined megavoltage photon and 160 MeV proton radiotherapy. All patients had previously undergone biopsy, subtotal or total tumor removal. 104 patients had two or more surgical procedures before radiotherapy. Following 3D treatment planning with delineation of target volumes and critical non-target structures, dose distributions and dose volume histograms were calculated [at the time of treatment delivery]. Radiotherapy was given once a day, 1.8 Gy or CGE (Cobalt Gy Equivalent: Proton Gy X 1.1) per fraction, 5 fractions per week, with prescribed target doses ranging from 63 CGE to 79.2 CGE (mean = 67.8 CGE). Doses to the brainstem surface were limited to ≤64 CGE and to the brainstem center to ≤53 CGE. Dose distributions were developed to limit dose to brainstem surface and center; current plans limit dose to surface and center to ≤64 CGE and ≤53 CGE, respectively. Brainstem toxicity was scored according to the RTOG grading system. Results: Follow-up ranged from 6 months to 21.4 years (mean = 42.5 months). Brainstem symptoms, attributable to the treatment, developed in 17 of 282 patients with local tumor control (6.0%), resulting in death of three patients. The mean time to onset of symptoms was 17 months (range: 4.5 to 177 months). These symptoms appeared in 89.5% within 3 years. Grading of the brainstem toxicity is listed in table 1. Actuarial rates of 5 and 10 year toxicity free survival were 87% and 82% respectively. Increased risk of brainstem toxicity was significantly associated with maximum brainstem dose

  9. On flaw tolerance of nacre: a theoretical study

    Science.gov (United States)

    Shao, Yue; Zhao, Hong-Ping; Feng, Xi-Qiao

    2014-01-01

    As a natural composite, nacre has an elegant staggered ‘brick-and-mortar’ microstructure consisting of mineral platelets glued by organic macromolecules, which endows the material with superior mechanical properties to achieve its biological functions. In this paper, a microstructure-based crack-bridging model is employed to investigate how the strength of nacre is affected by pre-existing structural defects. Our analysis demonstrates that owing to its special microstructure and the toughening effect of platelets, nacre has a superior flaw-tolerance feature. The maximal crack size that does not evidently reduce the tensile strength of nacre is up to tens of micrometres, about three orders higher than that of pure aragonite. Through dimensional analysis, a non-dimensional parameter is proposed to quantify the flaw-tolerance ability of nacreous materials in a wide range of structural parameters. This study provides us some inspirations for optimal design of advanced biomimetic composites. PMID:24402917

  10. Tolerance limits of X-ray image intensity

    International Nuclear Information System (INIS)

    Stargardt, A.; Juran, R.; Brandt, G.A.

    1985-01-01

    Evaluation of the tolerance limits of X-ray image density accepted by the radiologist shows that for different kinds of examinations, deviations of more than 50% from optimal density lead to images which cannot be used diagnostically. Within this range diagnostic accuracy shows a distinct maximum and diminishes to the limits by 20%. These figures are related to differences in the intensifying factor of screens, sensitivity of films, sensitometric parameters of film processing as well as the doses employed with automatic exposure control devices, measured in clinical conditions. Maximum permissible tolerance limits of the whole imaging system and of its constituents are discussed using the Gaussian law of error addition. (author)

  11. Realization of 3D evaluation algorithm in dose-guided radiotherapy

    International Nuclear Information System (INIS)

    Wang Yu; Li Gui; Wang Dong; Wu Yican; FDS Team

    2012-01-01

    3D evaluation algorithm instead of 2D evaluation method of clinical dose verification is highly needed for dose evaluation in Dose-guided Radiotherapy. 3D evaluation algorithm of three evaluation methods, including Dose Difference, Distance-To-Agreement and 7 Analysis, was realized by the tool of Visual C++ according to the formula. Two plans were designed to test the algorithm, plan 1 was radiation on equivalent water using square field for the verification of the algorithm's correctness; plan 2 was radiation on the emulation head phantom using conformal field for the verification of the algorithm's practicality. For plan 1, the dose difference, in the tolerance range has a pass rate of 100%, the Distance-To-Agreement and 7 analysis was of a pass rate of 100% in the tolerance range, and a pass rate of 99±1% at the boundary of range. For plan 2, the pass rate of algorithm were 88.35%, 100%, 95.07% for the three evaluation methods, respectively. It can be concluded that the 3D evaluation algorithm is feasible and could be used to evaluate 3D dose distributions in Dose-guided Radiotherapy. (authors)

  12. Dose titration to reduce dipyridamole-related headache.

    Science.gov (United States)

    Chang, Yeu-Jhy; Ryu, Shan-Jin; Lee, Tsong-Hai

    2006-01-01

    Combination of low-dose aspirin and modified-release dipyridamole (ASA+MR-DP) provides a significantly increased benefit in stroke prevention over aspirin alone. However, headaches were reported in more patients receiving dipyridamole-containing agents than in those receiving placebo. We undertook a randomized, double-blind, placebo-controlled trial to evaluate which dosing regimens of ASA+MR-DP have better tolerance. This trial randomized 146 patients with a history of ischemic cerebrovascular disease into three groups: placebo (days 1-28), reduced dose (placebo on days 1-4, ASA+MR-DP once daily before bed during days 5-14, and b.i.d. on days 15-28), and regular dose (placebo on days 1-4, and ASA+MR-DP b.i.d. on days 5-28). Using Chinese diary card, headache was assessed as mean cumulated headache (Sigma frequency x intensity/occurrence days x study days) over the study period, and was graded 0-4 according to Cancer Therapy Evaluation Program, Common Toxicity Criteria, Version 2.0. Intent-to-treat patients after randomization was 46 in placebo group, 45, reduced dose, and 49, regular dose. Among commonly reported adverse effects, headache of any grade occurred significantly more in the regular dose group (38.8%), as compared to the other two groups (p < 0.05). Mean cumulated headache was higher (p < 0.05) in the regular dose group than in the reduced group during days 5-14. Of 27 patients who dropped out, 15 (55.6%) were due to headache, which was substantially more in regular dose (8, 53.3%), though the difference was statistically insignificant. Initial reduced dose treatment with ASA+MR-DP may cause fewer headaches than regular dosing, and seems better tolerated by those susceptible to phosphodiesterase inhibitor-induced headache. Copyright 2006 S. Karger AG, Basel.

  13. AUC-Maximizing Ensembles through Metalearning.

    Science.gov (United States)

    LeDell, Erin; van der Laan, Mark J; Petersen, Maya

    2016-05-01

    Area Under the ROC Curve (AUC) is often used to measure the performance of an estimator in binary classification problems. An AUC-maximizing classifier can have significant advantages in cases where ranking correctness is valued or if the outcome is rare. In a Super Learner ensemble, maximization of the AUC can be achieved by the use of an AUC-maximining metalearning algorithm. We discuss an implementation of an AUC-maximization technique that is formulated as a nonlinear optimization problem. We also evaluate the effectiveness of a large number of different nonlinear optimization algorithms to maximize the cross-validated AUC of the ensemble fit. The results provide evidence that AUC-maximizing metalearners can, and often do, out-perform non-AUC-maximizing metalearning methods, with respect to ensemble AUC. The results also demonstrate that as the level of imbalance in the training data increases, the Super Learner ensemble outperforms the top base algorithm by a larger degree.

  14. Synthesis of Flexible Fault-Tolerant Schedules with Preemption for Mixed Soft and Hard Real-Time Systems

    DEFF Research Database (Denmark)

    Izosimov, Viacheslav; Pop, Paul; Eles, Petru

    2008-01-01

    In this paper we present an approach for scheduling with preemption for fault-tolerant embedded systems composed of soft and hard real-time processes. We are interested to maximize the overall utility for average, most likely to happen, scenarios and to guarantee the deadlines for the hard...

  15. A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days.

    Science.gov (United States)

    Bell, D; Duffin, A; Jacobs, A; Pediconi, C; Gruss, H J

    2014-03-01

    The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

  16. Tolerance and withdrawal from prolonged opioid use in critically ill children.

    Science.gov (United States)

    Anand, Kanwaljeet J S; Willson, Douglas F; Berger, John; Harrison, Rick; Meert, Kathleen L; Zimmerman, Jerry; Carcillo, Joseph; Newth, Christopher J L; Prodhan, Parthak; Dean, J Michael; Nicholson, Carol

    2010-05-01

    After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. Relevant manuscripts published in the English language were searched in Medline by using search terms "opioid," "opiate," "sedation," "analgesia," "child," "infant-newborn," "tolerance," "dependency," "withdrawal," "analgesic," "receptor," and "individual opioid drugs." Clinical and preclinical studies were reviewed for data synthesis. Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal.

  17. Bone and marrow dose modeling

    International Nuclear Information System (INIS)

    Stabin, Michael G.

    2004-01-01

    Nuclear medicine therapy is being used increasingly in the treatment of cancer (thyroid, leukemia/lymphoma with RIT, primary and secondary bone malignancies, and neuroblastomas). In all cases it is marrow toxicity that limits the amount of treatment that can be administered safely. Marrow dose calculations are more difficult than for many major organs because of the intricate association of bone and soft tissue elements. In RIT, there appears to be no consensus on how to calculate that dose accurately, or of individual patients ability to tolerate planned therapy. Available dose models are designed after an idealized average, healthy individual. Patient-specific methods are applied in evaluation of biokinetic data, and need to be developed for treatment of the physical data (dose conversion factors) as well: age, prior patient therapy, disease status. Contributors to marrow dose: electrons and photons

  18. Kaempferol Promotes Transplant Tolerance by Sustaining CD4+FoxP3+ Regulatory T Cells in the Presence of Calcineurin Inhibitor.

    Science.gov (United States)

    Zeng, Y Q; Liu, X S; Wu, S; Zou, C; Xie, Q; Xu, S M; Jin, X W; Li, W; Zhou, A; Dai, Z

    2015-07-01

    Calcineurin inhibitor cyclosporine is widely used as an immunosuppressant in clinic. However, mounting evidence has shown that cyclosporine hinders tolerance induction by dampening Tregs. Therefore, it is of paramount importance to overcome this pitfall. Kaempferol was reported to inhibit DC function. Here, we found that kaempferol delayed islet allograft rejection. Combination of kaempferol and low-dose, but not high-dose, of cyclosporine induced allograft tolerance in majority of recipient mice. Although kaempferol plus either dose of cyclosporine largely abrogated proliferation of graft-infiltrating T cells and their CTL activity, both proliferation and CTL activity in mice treated with kaempferol plus low-dose, but not high-dose, cyclosporine reemerged rapidly upon treatment withdrawal. Kaempferol increased CD4+FoxP3+ Tregs both in transplanted mice and in vitro, likely by suppressing DC maturation and their IL-6 expression. Reduction in Tregs by low dose of cyclosporine was reversed by kaempferol. Kaempferol-induced Tregs exhibited both allospecific and non-allospecific suppression. Administering IL-6 abrogated allograft tolerance induced by kaempferol and cyclosporine via diminishing CD4+FoxP3+ Tregs. Thus, for the first time, we demonstrated that kaempferol promotes transplant tolerance in the presence of low dose of cyclosporine, which allows for sufficient Treg generation while minimizing side effects, resulting in much-needed synergy between kaempferol and cyclosporine. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  19. Improving furfural tolerance of Zymomonas mobilis by rewiring a sigma factor RpoD protein.

    Science.gov (United States)

    Tan, Fu-Rong; Dai, Li-Chun; Wu, Bo; Qin, Han; Shui, Zong-Xia; Wang, Jing-Li; Zhu, Qi-Li; Hu, Qi-Chun; Ruan, Zhi-Yong; He, Ming-Xiong

    2015-06-01

    Furfural from lignocellulosic hydrolysates is the key inhibitor for bio-ethanol fermentation. In this study, we report a strategy of improving the furfural tolerance in Zymomonas mobilis on the transcriptional level by engineering its global transcription sigma factor (σ(70), RpoD) protein. Three furfural tolerance RpoD mutants (ZM4-MF1, ZM4-MF2, and ZM4-MF3) were identified from error-prone PCR libraries. The best furfural-tolerance strain ZM4-MF2 reached to the maximal cell density (OD600) about 2.0 after approximately 30 h, while control strain ZM4-rpoD reached its highest cell density of about 1.3 under the same conditions. ZM4-MF2 also consumed glucose faster and yield higher ethanol; expression levels and key Entner-Doudoroff (ED) pathway enzymatic activities were also compared to control strain under furfural stress condition. Our results suggest that global transcription machinery engineering could potentially be used to improve stress tolerance and ethanol production in Z. mobilis.

  20. Serum Tumor Necrosis Factor-alpha associates with Myocardial Oxygen Demand and Exercise Tolerance in Postmenopausal Women.

    Science.gov (United States)

    Carter, Stephen J; Bryan, David R; Neumeier, William H; Glasser, Stephen P; Hunter, Gary R

    2018-01-01

    The functional implications of serum tumor necrosis factor-alpha (TNF-α), a marker of oxidative stress, on hemodynamic parameters at rest and during physical exertion are unclear. The aims of this investigation were to examine the independent associations of TNF-α on myocardial oxygen demand at rest and during submaximal exercise, while also evaluating the association of TNF-α on exercise tolerance. Forty, postmenopausal women, provided blood samples and completed a modified-Balke protocol to measure maximal oxygen uptake (VO 2max ). Large artery compliance was measured by pulse contour analyses while rate-pressure product (RPP), an index of myocardial oxygen demand, was measured at rest and during two submaximal workloads (i.e., ≈55% and ≈75% VO 2max ). RPP was calculated by dividing the product of heart rate and systolic blood pressure (via auscultation) by 100. Exercise tolerance corresponded with the cessation of the graded exercise test. During higher-intensity exertion, ≈75% VO 2max , multiple linear regression revealed a positive association ( r = 0.43; p = 0.015) between TNF-α and RPP while adjusting for maximal heart rate, VO 2max , large artery compliance, and percent body fat. Path analyses revealed a significant indirect effect of large artery compliance on exercise tolerance through TNF-α, β = 0.13, CI [0.03, 0.35], indicating greater levels of TNF-α associated with poorer exercise tolerance. These data suggest TNF-α independently associates with myocardial oxygen demand during physical exertion, thus highlighting the utility of higher-intensity efforts to expose important phenomena not apparent at rest. TNF-α also appears to be indirectly associated with the link between large artery compliance and exercise tolerance.

  1. Tolerability and safety of antifungal drugs

    Directory of Open Access Journals (Sweden)

    Francesco Scaglione

    2013-08-01

    Full Text Available When treating critically ill patients, as those with fungal infections, attention should be focused on the appropriate use of drugs, especially in terms of dose, safety, and tolerability. The fungal infection itself and the concomitant physiological disorders concur to increase the risk of mortality in these patients, therefore the use of any antifungal agent should be carefully evaluated, considering both the direct action on the target fungus and the adverse effects eventually caused. Among antifungal drugs, echinocandins have the greatest tolerability. In fact, unlike amphotericin B, showing nephrotoxicity, and azoles, which are hepatotoxic, the use of echinocandins doesn’t result in major adverse events.http://dx.doi.org/10.7175/rhc.v4i2s.873

  2. Curcumin Attenuates Opioid Tolerance and Dependence by Inhibiting Ca2+/Calmodulin-Dependent Protein Kinase II α Activity

    Science.gov (United States)

    Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena

    2015-01-01

    Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA)-curcumin nanoparticles (nanocurcumin) to overcome the drug’s poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11- to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dose-dependent manner, with ED50 values of 3.9 and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED50 = 12.6 mg/kg p.o.) and dependence (ED50 = 3.1 mg/kg p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1–10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIα activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIα activity. PMID:25515789

  3. Is CP violation maximal

    International Nuclear Information System (INIS)

    Gronau, M.

    1984-01-01

    Two ambiguities are noted in the definition of the concept of maximal CP violation. The phase convention ambiguity is overcome by introducing a CP violating phase in the quark mixing matrix U which is invariant under rephasing transformations. The second ambiguity, related to the parametrization of U, is resolved by finding a single empirically viable definition of maximal CP violation when assuming that U does not single out one generation. Considerable improvement in the calculation of nonleptonic weak amplitudes is required to test the conjecture of maximal CP violation. 21 references

  4. A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma

    DEFF Research Database (Denmark)

    Hansson, Markus; Gimsing, Peter; Badros, Ashraf

    2015-01-01

    PURPOSE: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. EXPERIMENTAL DESIGN: BI-505 was given intravenously, every 2 weeks...... generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505's half-life increased with dose while clearance decreased, suggesting target-mediated clearance...

  5. Tolerance of canine portal vein anastomosis to intraoperative X-irradiation

    International Nuclear Information System (INIS)

    Ohara, K.; Takeshima, T.

    1987-01-01

    Tolerance of surgical portal vein anatomosis to intraoperative radiation therapy (IORT) was studied in dogs after single doses of zero, 10, 20 and 40 Gy (290 kVp X-rays). Portal venography was performed prior to IORT and before sacrificing. The dogs were sacrificed 3 and 12 months respectively after irradiation. Portal venography revealed no radiation induced anastomotic stenosis. Autopys disclosed macroscopic periportal fibrosis in all dogs, independent of radiation dose and observation periods. Microscopically, the three tunicas of the vein did not show any pathological changes after any dose level. (orig.)

  6. A Phase I Study of Pulse High-Dose Vorinostat (V) plus Rituximab (R), Ifosphamide, Carboplatin, and Etoposide (ICE) in Patients with Relapsed Lymphoma

    Science.gov (United States)

    Budde, Lihua E.; Zhang, Michelle M.; Shustov, Andrei R.; Pagel, John M.; Gooley, Ted A.; Oliveira, George R.; Chen, Tara L.; Knudsen, Nancy L.; Roden, Jennifer E.; Kammerer, Britt E.; Frayo, Shani L.; Warr, Thomas A.; Boyd, Thomas E.; Press, Oliver W.; Gopal, Ajay K.

    2013-01-01

    SUMMARY Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2.5 μM concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 days in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty-nine patients (median age 56 years, median 2 prior therapies, 14 chemoresistant [of 27 evaluable], 2 prior transplants) were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 days. Common dose limiting toxicities included infection (n=2), hypokalaemia (n=2), and transaminitis (n=2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4.5 μM (range 4.2–6.0 μM) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted. PMID:23356514

  7. Shareholder, stakeholder-owner or broad stakeholder maximization

    OpenAIRE

    Mygind, Niels

    2004-01-01

    With reference to the discussion about shareholder versus stakeholder maximization it is argued that the normal type of maximization is in fact stakeholder-owner maxi-mization. This means maximization of the sum of the value of the shares and stake-holder benefits belonging to the dominating stakeholder-owner. Maximization of shareholder value is a special case of owner-maximization, and only under quite re-strictive assumptions shareholder maximization is larger or equal to stakeholder-owner...

  8. Hardness, function, emotional well-being, satisfaction and the overall sexual experience in men using 100-mg fixed-dose or flexible-dose sildenafil citrate

    Science.gov (United States)

    Ströberg, P; Kaminetsky, J C; Park, N C; Goldfischer, E R; Creanga, D L; Stecher, V J

    2010-01-01

    The prescribing information for sildenafil citrate (VIAGRA, Pfizer, New York, NY, USA) recommends flexible dosing (50 mg initially, adjusted to 100 or 25 mg based on effectiveness and tolerability) in most men with erectile dysfunction (ED). In many men, however, 100 mg may be the most appropriate initial dose because it would reduce the need for titration and could prevent discouragement and treatment abandonment should 50 mg be insufficient. Results of two previously published double-blind, placebo-controlled sildenafil trials of similar design except for a fixed-dose vs flexible-dose regimen were analyzed. Relative to the flexible-dose, approximately one-third more men were satisfied with an initial and fixed dose of 100 mg. In addition, tolerability was similar, and improvements from baseline in outcomes on validated, ED-specific, patient-reported questionnaires were either similar (erectile function and the percentage of completely hard and fully rigid erections) or greater (emotional well-being and the overall sexual experience). The similarity in outcomes is not surprising given that almost 90% of the men in the flexible-dose trial titrated to 100 mg after 2 weeks. These data suggest prescription of an initial dose of 100 mg for men with ED, except in those for whom it is inappropriate. PMID:20596083

  9. Radiation tolerance of the pig kidney: a model for determining overall time and fraction factors for preserving renal function

    International Nuclear Information System (INIS)

    Hopewell, J.W.

    1975-01-01

    The Ellis Nominal Standard Dose system has attracted clinical interest for estimating irregular treatment schedules in radiotherapy. This study attempts to examine the system applied to renal tolerance in swine by looking for some regular relationship between time, dose, and fractionation. Also examined was renal function up to two years after treatment. These data indicate that renal tolerance may not be predictable by any simple mathematical expression

  10. Tolerance limits and methodologies for IMRT measurement-based verification QA: Recommendations of AAPM Task Group No. 218.

    Science.gov (United States)

    Miften, Moyed; Olch, Arthur; Mihailidis, Dimitris; Moran, Jean; Pawlicki, Todd; Molineu, Andrea; Li, Harold; Wijesooriya, Krishni; Shi, Jie; Xia, Ping; Papanikolaou, Nikos; Low, Daniel A

    2018-04-01

    Patient-specific IMRT QA measurements are important components of processes designed to identify discrepancies between calculated and delivered radiation doses. Discrepancy tolerance limits are neither well defined nor consistently applied across centers. The AAPM TG-218 report provides a comprehensive review aimed at improving the understanding and consistency of these processes as well as recommendations for methodologies and tolerance limits in patient-specific IMRT QA. The performance of the dose difference/distance-to-agreement (DTA) and γ dose distribution comparison metrics are investigated. Measurement methods are reviewed and followed by a discussion of the pros and cons of each. Methodologies for absolute dose verification are discussed and new IMRT QA verification tools are presented. Literature on the expected or achievable agreement between measurements and calculations for different types of planning and delivery systems are reviewed and analyzed. Tests of vendor implementations of the γ verification algorithm employing benchmark cases are presented. Operational shortcomings that can reduce the γ tool accuracy and subsequent effectiveness for IMRT QA are described. Practical considerations including spatial resolution, normalization, dose threshold, and data interpretation are discussed. Published data on IMRT QA and the clinical experience of the group members are used to develop guidelines and recommendations on tolerance and action limits for IMRT QA. Steps to check failed IMRT QA plans are outlined. Recommendations on delivery methods, data interpretation, dose normalization, the use of γ analysis routines and choice of tolerance limits for IMRT QA are made with focus on detecting differences between calculated and measured doses via the use of robust analysis methods and an in-depth understanding of IMRT verification metrics. The recommendations are intended to improve the IMRT QA process and establish consistent, and comparable IMRT QA

  11. Comparative bioavailability and tolerability of a single 20-mg dose of two fluoxetine hydrochloride dispersible tablet formulations in fasting, healthy Chinese male volunteers: an open-label, randomized-sequence, two-period crossover study.

    Science.gov (United States)

    Shi, Shaojun; Liu, Yani; Wu, Jianhong; Li, Zhongfang; Zhao, Yan; Zhong, Dafang; Zeng, Fandian

    2010-10-01

    The proprietary formulation of fluoxetine hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. Pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed to market generic fluoxetine in China. The aim of this study was to compare the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of fluoxetine hydrochloride 20 mg in a fasting, healthy Chinese male population. This 10-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 20-mg dose of the test or reference formulation, followed by a 35-day washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties (including C(max), T(max), AUC(0-t), AUC(0-∞), and t(½)), blood samples were obtained over a 672-hour period after dosing. Plasma concentrations of fluoxetine and its active metabolite, norfluoxetine, were analyzed using a validated LC-MS/MS method. The formulations were to be considered bioequivalent if the ln-transformed ratios (test/ reference) of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125%, as established by the US Food and Drug Administration, and if the P values were fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated. Copyright © 2010 Excerpta Medica Inc. All rights reserved.

  12. Hyperfractionated abdominal radiotherapy in children. Efficacy and tolerance in 13 cases

    International Nuclear Information System (INIS)

    Lagrange, J.L.; Roullet, B.; Cosset, J.M.; Sarrazin, D.; Lemerle, J.

    1984-01-01

    The experience at IGR has shown that hyperfractionation, especially abdominal has been well tolerated in adult patients. This finding led to employ this technic in the pediatric population who had failed standard treatment. An experience with hyperfractionated radiotherapy of the abdomen and liver in children, is reported. The children were treated 4 days per week, receiving 5 fractions daily of 0.7 Gy, with a 2 hours interval between each treatment. A total dose of 28 Gy was delivered in 40 fractions over 12 days. A second course of irradiation was delivered in 5 patients, 3 with abdominal treatment and 2 with liver irradiation. The vital organs were shielded with blocks at normal dose tolerance levels. The results are encouraging since an immediate efficacy was observed in 8 of 13 patients. Long term survivals were observed in 4 patients with nephroblastomas and 1 patient with a hepatoblastoma. On the other hand acute gastrointestinal tolerance seemed less good in the children than previously observed in the adults. Five radiation hepatitis appeared, immediately after the irradiation, whom four children irradiated to the entire abdomen [fr

  13. Tolerance and withdrawal to anticonvulsant action of clonazepam: role of nitric oxide.

    Science.gov (United States)

    Gupta, N; Bhargava, V K; Pandhi, P

    2000-05-01

    The use of clonazepam in the long-term treatment of epilepsy is greatly inhibited by its capacity to induce tolerance and dependence. A means of preventing or minimizing the tolerance and dependence inducing properties is required. Here the role of nitric oxide in preventing the development of tolerance and withdrawal hyperexcitability was studied. In Wistar rats, clonazepam at a dose of 0.25 mg/kg i.p. twice daily produced tolerance to its anticonvulsant action in 28 days. After sudden cessation of therapy it produced hyperexcitability. Tolerance was shown by a decrease in seizure threshold to near control value while withdrawal hyperexcitability was evidenced by a significant decrease in seizure threshold below the control value. L-Arginine (a donor of nitric oxide) and N omega-nitro-L-arginine (an inhibitor of nitric oxide synthase) were given in doses of 150 mg/kg and 8 mg/kg, respectively on day 1, 3, 7, 14, 21 and 28 with clonazepam. Withdrawal hyperexcitability was seen on day 1, 2 and 4 after cessation of drug therapy. Electroshock was used as a model of epilepsy and seizure thresholds were determined by an up and down method of Kimball et al. L-Arginine was found to inhibit the development tolerance as well as withdrawal hyperexcitability when administered with clonazepam while N omega-L-arginine did not prevent either the development of tolerance or withdrawal hyperexcitability in the electroshock model. In the PTZ model, however, L-arginine had no effect on the anticonvulsant action and withdrawal hyperexcitability while inhibition of nitric oxide synthesis prevented withdrawal hyperexcitability in PTZ-induced seizures.

  14. Late effects of radiation on the lumbar spinal cord of guinea pigs: Re-treatment tolerance

    International Nuclear Information System (INIS)

    Mason, K.A.; Withers, H.R.; Chiang, Chi-Shiun

    1993-01-01

    Using a guinea pig model of lumbar myelopathy, various factors affecting the tolerance of spinal cord to irradiation were assessed: (a) extent of initial injury; (b) time interval between priming and test doses; and (c) animal age at the time of initial radiation treatment. A 3 cm section of lumbar spinal cord of guinea pigs was irradiated with fractionated doses of 4.5 Gy gamma rays given as 9 fractions per week. Guinea pigs were primed with 9 x 4.5 Gy in 7 days which is 60% of the ED 50 for a continuous course of treatment. After 28 or 40 weeks, animal were retreated with 6-14 fractions of 4.5 Gy. Animals were observed for 2 years following the priming dose and both the incidence and latency of myelopathy recorded. Young adult guinea pigs (8 wk old) showed both a decreased radiation tolerance and latency compared to old individuals (40 wk old). At 28 or 40 wk after 9 x 4.5 Gy, only about 8% of the initial injury was remembered in young adult guinea pigs. The amount of residual injury was dependent on the initial damage as a proportion of the tolerance dose. The spinal cord shows a greater capacity for long-term recovery than generally appreciated and re-treatment doses clinically prescribed may be lower than necessary. 8 refs., 3 figs., 2 tabs

  15. Task-oriented maximally entangled states

    International Nuclear Information System (INIS)

    Agrawal, Pankaj; Pradhan, B

    2010-01-01

    We introduce the notion of a task-oriented maximally entangled state (TMES). This notion depends on the task for which a quantum state is used as the resource. TMESs are the states that can be used to carry out the task maximally. This concept may be more useful than that of a general maximally entangled state in the case of a multipartite system. We illustrate this idea by giving an operational definition of maximally entangled states on the basis of communication tasks of teleportation and superdense coding. We also give examples and a procedure to obtain such TMESs for n-qubit systems.

  16. A Phase 1, Single-center, Double-blind, Placebo-controlled Study in Healthy Subjects to Assess the Safety, Tolerability, Clinical Effects, and Pharmacokinetics-Pharmacodynamics of Intravenous Cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a Single Ascending Bolus Dose.

    Science.gov (United States)

    Struys, Michel M R F; Valk, Beatrijs I; Eleveld, Douglas J; Absalom, Anthony R; Meyer, Peter; Meier, Sascha; den Daas, Izaak; Chou, Thomas; van Amsterdam, Kai; Campagna, Jason A; Sweeney, Steven P

    2017-07-01

    Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new "soft" etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose-response and pharmacokinetic/pharmacodynamic relationships. Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer's assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated. Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration-effect relationship was described for the modified observer's assessment of alertness/sedation and Bispectral Index. This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.

  17. Dose sculpting with generalized equivalent uniform dose

    International Nuclear Information System (INIS)

    Wu Qiuwen; Djajaputra, David; Liu, Helen H.; Dong Lei; Mohan, Radhe; Wu, Yan

    2005-01-01

    With intensity-modulated radiotherapy (IMRT), a variety of user-defined dose distribution can be produced using inverse planning. The generalized equivalent uniform dose (gEUD) has been used in IMRT optimization as an alternative objective function to the conventional dose-volume-based criteria. The purpose of this study was to investigate the effectiveness of gEUD optimization to fine tune the dose distributions of IMRT plans. We analyzed the effect of gEUD-based optimization parameters on plan quality. The objective was to determine whether dose distribution to selected structures could be improved using gEUD optimization without adversely altering the doses delivered to other structures, as in sculpting. We hypothesized that by carefully defining gEUD parameters (EUD 0 and n) based on the current dose distributions, the optimization system could be instructed to search for alternative solutions in the neighborhood, and we could maintain the dose distributions for structures already satisfactory and improve dose for structures that need enhancement. We started with an already acceptable IMRT plan optimized with any objective function. The dose distribution was analyzed first. For structures that dose should not be changed, a higher value of n was used and EUD 0 was set slightly higher/lower than the EUD value at the current dose distribution for critical structures/targets. For structures that needed improvement in dose, a higher to medium value of n was used, and EUD 0 was set to the EUD value or slightly lower/higher for the critical structure/target at the current dose distribution. We evaluated this method in one clinical case each of head and neck, lung and prostate cancer. Dose volume histograms, isodose distributions, and relevant tolerance doses for critical structures were used for the assessment. We found that by adjusting gEUD optimization parameters, the dose distribution could be improved with only a few iterations. A larger value of n could lead to

  18. Robot-borne fault tolerant calculators for nuclear use

    International Nuclear Information System (INIS)

    Giraud, A.; Robiolle, M.

    1995-01-01

    The use of robots has become a necessity in civil nuclear industry. Electronic systems of such robots must tolerate cumulative ionizing radiation dose effects. Today's objective is to reach a 3 kGy dose resistance. Difficulties and costs involved during on-site maintenance imply to warrant at least one functioning mode in the case of system failure. To improve the behaviour of robot-borne systems, the CEA Department for Nuclear Engineering Studies (DEIN) has developed a method for the selection of industrial electronic components and has built computer architectures which allows to break free from some cumulative dose sensitive parameters. This paper presents the MICADO and CADMOS architectures developed at the DEIN. (J.S.). 15 refs., 5 figs

  19. SPECIAL CONSIDERATIONS REGARDING WARFARIN DOSE TITRATION IN PATIENTS WITH ATRIAL FIBRILLATION DEPENDING ON CLINICAL FACTORS

    Directory of Open Access Journals (Sweden)

    E. L. Artanova

    2011-01-01

    Full Text Available Aim. To study the relations of clinical characteristics and individual warfarin dose titration in patients with atrial fibrillation. Material and methods. Period of warfarin dose titration was analyzed in 68 patients with atrial fibrillation due to ischemic heart disease. Adjusted warfarin dose in milligram, duration of dose titration in days and maximal international normalized ratio (INR were taken into account. Sex, age, history of myocardial infarction and stroke, concomitant diseases, amiodarone therapy were considered among clinical characteristics. Results. Adjusted warfarin dose was significantly higher in obesity , and it was lower in case of experienced myocardial infarction. The INR highest levels and maximal amplitudes of its fluctuations were observed in patients with thyroid gland nodes and smokers. Period of warfarin dose titration was longer in patients treated with amiodarone. Conclusion. Warfarin dose titration in patients with atrial fibrillation depends on the presence of myocardial infarction, obesity , thyroid nodular changes, smoking and amiodarone treatment.

  20. Super-low dose endotoxin pre-conditioning exacerbates sepsis mortality.

    Science.gov (United States)

    Chen, Keqiang; Geng, Shuo; Yuan, Ruoxi; Diao, Na; Upchurch, Zachary; Li, Liwu

    2015-04-01

    Sepsis mortality varies dramatically in individuals of variable immune conditions, with poorly defined mechanisms. This phenomenon complements the hypothesis that innate immunity may adopt rudimentary memory, as demonstrated in vitro with endotoxin priming and tolerance in cultured monocytes. However, previous in vivo studies only examined the protective effect of endotoxin tolerance in the context of sepsis. In sharp contrast, we report herein that pre-conditionings with super-low or low dose endotoxin lipopolysaccharide (LPS) cause strikingly opposite survival outcomes. Mice pre-conditioned with super-low dose LPS experienced severe tissue damage, inflammation, increased bacterial load in circulation, and elevated mortality when they were subjected to cecal-ligation and puncture (CLP). This is in opposite to the well-reported protective phenomenon with CLP mice pre-conditioned with low dose LPS. Mechanistically, we demonstrated that super-low and low dose LPS differentially modulate the formation of neutrophil extracellular trap (NET) in neutrophils. Instead of increased ERK activation and NET formation in neutrophils pre-conditioned with low dose LPS, we observed significantly reduced ERK activation and compromised NET generation in neutrophils pre-conditioned with super-low dose LPS. Collectively, our findings reveal a novel mechanism potentially responsible for the dynamic programming of innate immunity in vivo as it relates to sepsis risks.

  1. Super-low Dose Endotoxin Pre-conditioning Exacerbates Sepsis Mortality

    Directory of Open Access Journals (Sweden)

    Keqiang Chen

    2015-04-01

    Full Text Available Sepsis mortality varies dramatically in individuals of variable immune conditions, with poorly defined mechanisms. This phenomenon complements the hypothesis that innate immunity may adopt rudimentary memory, as demonstrated in vitro with endotoxin priming and tolerance in cultured monocytes. However, previous in vivo studies only examined the protective effect of endotoxin tolerance in the context of sepsis. In sharp contrast, we report herein that pre-conditioning with super-low or low dose endotoxin lipopolysaccharide (LPS cause strikingly opposite survival outcomes. Mice pre-conditioned with super-low dose LPS experienced severe tissue damage, inflammation, increased bacterial load in circulation, and elevated mortality when they were subjected to cecal-ligation and puncture (CLP. This is in contrast to the well-reported protective phenomenon with CLP mice pre-conditioned with low dose LPS. Mechanistically, we demonstrated that super-low and low dose LPS differentially modulate the formation of neutrophil extracellular trap (NET in neutrophils. Instead of increased ERK activation and NET formation in neutrophils pre-conditioned with low dose LPS, we observed significantly reduced ERK activation and compromised NET generation in neutrophils pre-conditioned with super-low dose LPS. Collectively, our findings reveal a mechanism potentially responsible for the dynamic programming of innate immunity in vivo as it relates to sepsis risks.

  2. Radiation dose to the lens and cataract formation

    International Nuclear Information System (INIS)

    Henk, J.M.; Whitelocke, R.A.F.; Warrington, A.P.; Bessell, E.M.

    1993-01-01

    The purpose of this work was to determine the radiation tolerance of the lens of the eye and the incidence of radiation-induced lens changes in patients treated by fractionated supervoltage radiation therapy for orbital tumors. Forty patients treated for orbital lymphoma and pseudotumor with tumor doses of 20--40 Gy were studied. The lens was partly shielded using lead cylinders in most cases. The dose to the germinative zone of the lens was estimated by measurements in a tissue equivalent phantom using both film densitometry and thermoluminescent dosimetry. Opthalmological examination was performed at 6 monthly intervals after treatment. The lead shield was found to reduce the dose to the germinative zone of the lens to between 36--50% of the tumor dose for Cobalt beam therapy, and to between 11--18% for 5 MeV x-rays. Consequently, the lens doses were in the range 4.5--30 Gy in 10--20 fractions. Lens opacities first appeared from between 3 and 9 years after irradiation. Impairment of visual acuity ensued in 74% of the patients who developed lens opacities. The incidence of lens changes was strongly dose-related. None was seen after doses of 5 Gy or lower, whereas doses of 16.5 Gy or higher were all followed by lens opacities which impaired visual acuity. The largest number of patients received a maximum lens dose of 15 Gy; in this group the actuarial incidence of lens opacities at 8 years was 57% with visual impairment in 38%. The adult lens can tolerate a total dose of 5 Gy during a fractionated course of supervoltage radiation therapy without showing any changes. Doses of 16.5 Gy or higher will almost invariably lead to visual impairment. The dose which causes a 50% probability of visual impairment is approximately 15 Gy. 10 refs., 4 figs., 1 tab

  3. Is Drought Tolerance in Maize (Zea Mays L.) Cultivars at the Juvenile Stage Maintained at the Reproductive Stage

    International Nuclear Information System (INIS)

    Bashir, N.; Mahmood, S.; Zafar, Z. U.; Athar, H. R.; Manzoor, H.; Rasul, S.

    2016-01-01

    ), number of kernel number/cob, kernel weight/cob (g) was maximally reduced in water stress sensitive cv. 6621 whereas it was maximal in drought tolerant cv DTC. Drought stress at the reproductive stage hindered the floral development and/or fertilization process and thus yield reduction occurs. Overall, selection procedure for selecting drought tolerant maize cultivars was efficient at the germination and seedling growth stages. (author)

  4. FLOUTING MAXIMS IN INDONESIA LAWAK KLUB CONVERSATION

    Directory of Open Access Journals (Sweden)

    Rahmawati Sukmaningrum

    2017-04-01

    Full Text Available This study aims to identify the types of maxims flouted in the conversation in famous comedy show, Indonesia Lawak Club. Likewise, it also tries to reveal the speakers‘ intention of flouting the maxim in the conversation during the show. The writers use descriptive qualitative method in conducting this research. The data is taken from the dialogue of Indonesia Lawak club and then analyzed based on Grice‘s cooperative principles. The researchers read the dialogue‘s transcripts, identify the maxims, and interpret the data to find the speakers‘ intention for flouting the maxims in the communication. The results show that there are four types of maxims flouted in the dialogue. Those are maxim of quality (23%, maxim of quantity (11%, maxim of manner (31%, and maxim of relevance (35. Flouting the maxims in the conversations is intended to make the speakers feel uncomfortable with the conversation, show arrogances, show disagreement or agreement, and ridicule other speakers.

  5. Study of dose distribution in high energy photon beam used in radiotherapy

    International Nuclear Information System (INIS)

    Rafaravavy, R.; Raoelina Andriambololona; Bridier, A.

    2007-01-01

    The dose distribution in a medium traversed by a photon beam depends on beam energy, field size and medium nature. Percent depth dose (PDD), Dose Profile (DP) and Opening Collimator Factor (OCF) curves will be established to study this distribution. So, the PDD curves are composed by tree parts: the build-up region, the maximal dose and the quasi-equilibrium region. The maximum dose depth and the dose in depth increase with increasing photon beam energy but the dose surface decreases. The PDD increases with increasing field size.

  6. Response of human lymphocytes to low gamma ray doses

    International Nuclear Information System (INIS)

    Vega Carrillo, HR; Banuelos Valenzuela, R; Manzanares Acuna, E; Sanchez-Rodriguez, S.H

    2001-01-01

    Radiation and non-radiation workers lymphocytes were exposed to a low strength gamma-ray field to determine heat shock protein expression in function of radiation dose. Protein identification was carried out using mAb raised against Hsp25, Hsp60, Hsp70 and Hsp90; from these, only Hsp70 protein was detected before and after lymphocyte irradiation. In all cases, an increasing trend of relative amounts of Hsp70 in function to irradiation time was observed. After 70.5 mGy gamma-ray dose, radiation worker's lymphocytes expressed more Hsp70 protein, than non-radiation workers' lymphocytes, indicating a larger tolerance to gamma rays (gamma tolerance), due to an adaptation process developed by their labor condition (Au)

  7. VIOLATION OF CONVERSATION MAXIM ON TV ADVERTISEMENTS

    Directory of Open Access Journals (Sweden)

    Desak Putu Eka Pratiwi

    2015-07-01

    Full Text Available Maxim is a principle that must be obeyed by all participants textually and interpersonally in order to have a smooth communication process. Conversation maxim is divided into four namely maxim of quality, maxim of quantity, maxim of relevance, and maxim of manner of speaking. Violation of the maxim may occur in a conversation in which the information the speaker has is not delivered well to his speaking partner. Violation of the maxim in a conversation will result in an awkward impression. The example of violation is the given information that is redundant, untrue, irrelevant, or convoluted. Advertisers often deliberately violate the maxim to create unique and controversial advertisements. This study aims to examine the violation of maxims in conversations of TV ads. The source of data in this research is food advertisements aired on TV media. Documentation and observation methods are applied to obtain qualitative data. The theory used in this study is a maxim theory proposed by Grice (1975. The results of the data analysis are presented with informal method. The results of this study show an interesting fact that the violation of maxim in a conversation found in the advertisement exactly makes the advertisements very attractive and have a high value.

  8. Finding Maximal Quasiperiodicities in Strings

    DEFF Research Database (Denmark)

    Brodal, Gerth Stølting; Pedersen, Christian N. S.

    2000-01-01

    of length n in time O(n log n) and space O(n). Our algorithm uses the suffix tree as the fundamental data structure combined with efficient methods for merging and performing multiple searches in search trees. Besides finding all maximal quasiperiodic substrings, our algorithm also marks the nodes......Apostolico and Ehrenfeucht defined the notion of a maximal quasiperiodic substring and gave an algorithm that finds all maximal quasiperiodic substrings in a string of length n in time O(n log2 n). In this paper we give an algorithm that finds all maximal quasiperiodic substrings in a string...... in the suffix tree that have a superprimitive path-label....

  9. Radiation tolerant design - theory and practice for proximity sensing

    International Nuclear Information System (INIS)

    Sharp, R.E.; Pater, S.L.; Cook, J.

    1999-01-01

    This paper provides a description of the radiation tolerant design process used to develop a range of proximity detectors with guaranteed total dose lifetime. It also describes some of the applications in which the detectors are being used and the benefits gained by plant operators. (authors)

  10. ZD0473 pharmacokinetics in Japanese patients: a Phase I dose-escalation study.

    Science.gov (United States)

    Murakami, H; Tamura, T; Yamada, Y; Yamamoto, N; Ueda, Y; Shimoyama, T; Saijo, N

    2002-12-01

    ZD0473 is new platinum agent that was rationally designed to circumvent platinum resistance and reduce the potential for nephro-and neurotoxicity. This Phase I dose-escalating study investigated the pharmacokinetics, tolerability and efficacy of ZD0473 in Japanese patients with solid, refractory tumours. ZD0473 was administered as a 1-h intravenous infusion every 3 weeks. Nine patients received a total of 16 cycles of ZD0473 (median 1 cycle/patient), with 3 patients treated at each of 3 doses (60, 90, 120 mg/m2). The maximum plasma concentration (C(max)) and the area under the concentration-time curve to infinity (AUC(0-infinity)) increased with dose in a linear fashion for both total platinum and ZD0473 in plasma ultrafiltrate, suggesting that the pharmacokinetics of ZD0473 are linear. Haematological and non-haematological toxicities such as nausea and vomiting were mild (grade 1 or 2) and transient. No clinically significant nephro-, oto- or neurotoxicity was observed. Dose-limiting toxicity (DLT) was not observed and the maximum tolerated dose (MTD) was not identified. ZD0473 treatment showed evidence of disease stabilisation in 3 patients (33%). In conclusion, ZD0473 appears to have linear pharmacokinetics, and an acceptable tolerability profile at doses up to 120 mg/m2 in Japanese patients with refractory solid malignancies. Following evaluation of the data from all the Western trials, the ZD0473 development programme changed and this Japanese trial was stopped.

  11. Brachytherapy radiation doses to the neurovascular bundles

    International Nuclear Information System (INIS)

    Di Biase, Steven J.; Wallner, Kent; Tralins, Kevin; Sutlief, Steven

    2000-01-01

    Purpose: To investigate the role of radiation dose to the neurovascular bundles (NVB) in brachytherapy-related impotence. Methods and Materials: Fourteen Pd-103 or I-125 implant patients were studied. For patients treated with implant alone, the prostate and margin (clinical target volume [CTV]) received a prescription dose of 144 Gy for I-125 or 115 Gy for Pd-103. Two patients received Pd-103 (90 Gy) with 46 Gy supplemental external beam radiation (EBRT). Axial CT images were acquired 2 to 4 hours postoperatively for postimplant dosimetry. Because the NVBs cannot be visualized on CT, NVB calculation points were determined according to previously published anatomic descriptions. Bilateral NVB points were considered to lie posterior-laterally, approximately 2 mm from the prostatic capsule. NVB doses were recorded bilaterally, at 0.5-cm intervals from the prostatic base. Results: For Pd-103, the average NVB doses ranged from 150 Gy to 260 Gy, or 130% to 226% of the prescription dose. For I-125, the average NVB dose ranged from 200 Gy to 325 Gy, or 140% to 225% of the prescription dose. These was no consistent relationship between the NVB dose and the distance from the prostatic base. To examine the possible effect of minor deviations of our calculation points from the true NVB location, we performed NVB calculations at points 2 mm medial or lateral from the NVB calculation point in 8 patients. Doses at these alternate calculation points were comparable, although there was greater variability with small changes in the calculation point if sources were located outside the capsule, near the NVB calculation point. Three patients who developed early postimplant impotence had maximal NVB doses that far exceeded the average values. Conclusions: In the next few years, we hope to clarify the role of high NVB radiation doses on potency, by correlating NVB dose calculations with a large number of patients enrolled in an ongoing I-125 versus Pd-103 trial for early-stage patients

  12. Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera in healthy volunteers

    Directory of Open Access Journals (Sweden)

    Ashwinikumar A Raut

    2012-01-01

    Full Text Available Ashwagandha (Withania somnifera (WS, a "rasayana" drug, is recommended for balavardhan and mamsavardhan. The study was intended to evaluate dose-related tolerability, safety, and activity of WS formulation in normal individuals. The design was prospective, open-labeled, variable doses in volunteers. Eighteen apparently healthy volunteers (12M:6F, age:18-30 years, and BMI: 19-30 were enrolled. After baseline investigations, they received WS capsules (Rx (aqueous extract, 8:1 daily in two divided doses with increase in daily dosage every 10 days for 30 days (750 mg/day x10 days, 1 000 mg/day x 10 days, 1 250 mg/day x 10 days. Volunteers were assessed for symptoms/signs, vital functions, hematological and biochemical organ function tests. Muscle activity was measured by hand grip strength, quadriceps strength, and back extensor force. Exercise tolerance was determined using cycle ergometry. Lean body weight and fat% were computed from skin fold thickness measurement. Adverse events were recorded, as volunteered by the subjects. Repeated measures ANOVA, McNemar′s test, and paired t test were employed. All but one volunteer tolerated WS without any adverse event. One volunteer showed increased appetite, libido, and hallucinogenic effects with vertigo at the lowest dose and was withdrawn from study. In six subjects, improvement in quality of sleep was found. Organ function tests were in normal range before and after the intervention. Reduction in total- and LDL- cholesterol and increase of strength in muscle activity was significant. Total body fat percentage showed a reduction trend. WS, in escalated dose, was tolerated well. The formulation appeared safe and strengthened muscle activity. In view of its traditional Rasayana use, further studies are planned to evaluate potential of this drug in patients of sarcopenia.

  13. Oral glucose tolerance test performance in olanzapine-treated schizophrenia-spectrum patients is predicted by BMI and triglycerides but not olanzapine dose or duration.

    Science.gov (United States)

    Guina, Jeffrey; Roy, Sayon; Gupta, Ankur; Langleben, Daniel D; Elman, Igor

    2017-07-01

    Olanzapine, an atypical antipsychotic, is associated with glucoregulatory abnormalities, but the nature of this link is not fully elucidated. This is the first olanzapine oral glucose tolerance test (oGTT) study to consider treatment dose and duration, and to compare complementary indices respectively assessing insulin sensitivity (Matsuda index) and resistance (homeostasis model assessment). Body mass index (BMI), body composition, plasma lipids, and oGTT were measured in olanzapine-treated nondiabetic patients with DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder (n = 35). While only one previously undiagnosed participant met diabetes criteria based on fasting plasma glucose alone (≥126 mg/dL), seven were diagnosed with oGTT (2-hr plasma glucose ≥200 mg/dL). Multiple regression analyses revealed that the Matsuda index correlated with BMI (p triglycerides (p = 0.01), but not with age, olanzapine dose, olanzapine treatment duration, or plasma cholesterol. Homeostasis model assessment and fasting plasma glucose correlated with triglycerides only (p triglycerides may be implicated in olanzapine-related glucoregulatory abnormalities. The lack of correlation between glucoregulatory abnormalities and olanzapine dose or treatment duration suggests preexisting metabolic disturbances and/or disturbances arising early in the course of treatment. Clinicians prescribing antipsychotics should consider oGTT, especially in patients with obesity and/or hypertriglyceridemia. Copyright © 2017 John Wiley & Sons, Ltd.

  14. A cyclotron isotope production facility designed to maximize production and minimize radiation dose

    International Nuclear Information System (INIS)

    Dickie, W.J.; Stevenson, N.R.; Szlavik, F.F.

    1993-01-01

    Continuing increases in requirements from the nuclear medicine industry for cyclotron isotopes is increasing the demands being put on an aging stock of machines. In addition, with the 1990 recommendations of the ICRP publication in place, strict dose limits will be required and this will have an effect on the way these machines are being operated. Recent advances in cyclotron design combined with lessons learned from two decades of commercial production mean that new facilities can result in a substantial charge on target, low personnel dose, and minimal residual activation. An optimal facility would utilize a well engineered variable energy/high current H - cyclotron design, multiple beam extraction, and individual target caves. Materials would be selected to minimize activation and absorb neutrons. Equipment would be designed to minimize maintenance activities performed in high radiation fields. (orig.)

  15. 76 FR 5696 - Fluazifop-P-butyl; Pesticide Tolerances

    Science.gov (United States)

    2011-02-02

    ...: This regulation establishes tolerances for residues of fluazifop-P-butyl in or on multiple commodities... based on maternal body weight gain decrement during GD 7- 16. Incidental oral intermediate- NOAEL= 0.74....0 and 2% at 200 mg dose.) mg/kg/day based on fetal UFA = 10x weight decrement, UFH = 10x hydroureter...

  16. Radiation dose assessment in nuclear medicine

    International Nuclear Information System (INIS)

    Stabin, M.G.

    2002-01-01

    In any application involving the use of ionizing radiation in humans, risks and benefits must be properly evaluated and balanced. Radionuclides are used in nuclear medicine in a variety of diagnostic and therapeutic procedures. Recently, interest has grown in therapeutic agents for a number of applications in nuclear medicine, particularly in the treatment of hematologic and non-hematologic malignancies. This has heightened interest in the need for radiation dose calculations and challenged the scientific community to develop more patient-specific and relevant dose models. Consideration of radiation dose in such studies is central to efforts to maximize dose to tumor while sparing normal tissues. In many applications, a significant absorbed dose may be received by some radiosensitive organs, particularly the active marrow. This talk will review the methods and models used in internal dosimetry in nuclear medicine, and discuss some current trends and challenges in this field

  17. Boron neutron capture therapy using mixed epithermal and thermal neutron beams in patients with malignant glioma-correlation between radiation dose and radiation injury and clinical outcome

    International Nuclear Information System (INIS)

    Kageji, Teruyoshi; Nagahiro, Shinji; Matsuzaki, Kazuhito; Mizobuchi, Yoshifumi; Toi, Hiroyuki; Nakagawa, Yoshinobu; Kumada, Hiroaki

    2006-01-01

    Purpose: To clarify the correlation between the radiation dose and clinical outcome of sodium borocaptate-based intraoperative boron neutron capture therapy in patients with malignant glioma. Methods and Materials: The first protocol (P1998, n = 8) prescribed a maximal gross tumor volume (GTV) dose of 15 Gy. In 2001, a dose-escalated protocol was introduced (P2001, n 11), which prescribed a maximal vascular volume dose of 15 Gy or, alternatively, a clinical target volume (CTV) dose of 18 Gy. Results: The GTV and CTV doses in P2001 were 1.1-1.3 times greater than those in P1998. The maximal vascular volume dose of those with acute radiation injury was 15.8 Gy. The mean GTV and CTV dose in long-term survivors with glioblastoma was 26.4 and 16.5 Gy, respectively. A statistically significant correlation between the GTV dose and median survival time was found. In the 11 glioblastoma patients in P2001, the median survival time was 19.5 months and 1- and 2-year survival rate was 60.6% and 37.9%, respectively. Conclusion: Dose escalation contributed to the improvement in clinical outcome. To avoid radiation injury, the maximal vascular volume dose should be <12 Gy. For long-term survival in patients with glioblastoma after boron neutron capture therapy, the optimal mean dose of the GTV and CTV was 26 and 16 Gy, respectively

  18. Shareholder, stakeholder-owner or broad stakeholder maximization

    DEFF Research Database (Denmark)

    Mygind, Niels

    2004-01-01

    With reference to the discussion about shareholder versus stakeholder maximization it is argued that the normal type of maximization is in fact stakeholder-owner maxi-mization. This means maximization of the sum of the value of the shares and stake-holder benefits belonging to the dominating...... including the shareholders of a company. Although it may be the ultimate goal for Corporate Social Responsibility to achieve this kind of maximization, broad stakeholder maximization is quite difficult to give a precise definition. There is no one-dimensional measure to add different stakeholder benefits...... not traded on the mar-ket, and therefore there is no possibility for practical application. Broad stakeholder maximization instead in practical applications becomes satisfying certain stakeholder demands, so that the practical application will be stakeholder-owner maximization un-der constraints defined...

  19. A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

    Science.gov (United States)

    Sayed, Sehrish; Van Dam, Nicholas T; Horn, Sarah R; Kautz, Marin M; Parides, Michael; Costi, Sara; Collins, Katherine A; Iacoviello, Brian; Iosifescu, Dan V; Mathé, Aleksander A; Southwick, Steven M; Feder, Adriana; Charney, Dennis S; Murrough, James W

    2018-01-01

    Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519). © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

  20. On the maximal superalgebras of supersymmetric backgrounds

    International Nuclear Information System (INIS)

    Figueroa-O'Farrill, Jose; Hackett-Jones, Emily; Moutsopoulos, George; Simon, Joan

    2009-01-01

    In this paper we give a precise definition of the notion of a maximal superalgebra of certain types of supersymmetric supergravity backgrounds, including the Freund-Rubin backgrounds, and propose a geometric construction extending the well-known construction of its Killing superalgebra. We determine the structure of maximal Lie superalgebras and show that there is a finite number of isomorphism classes, all related via contractions from an orthosymplectic Lie superalgebra. We use the structure theory to show that maximally supersymmetric waves do not possess such a maximal superalgebra, but that the maximally supersymmetric Freund-Rubin backgrounds do. We perform the explicit geometric construction of the maximal superalgebra of AdS 4 X S 7 and find that it is isomorphic to osp(1|32). We propose an algebraic construction of the maximal superalgebra of any background asymptotic to AdS 4 X S 7 and we test this proposal by computing the maximal superalgebra of the M2-brane in its two maximally supersymmetric limits, finding agreement.

  1. Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog

    DEFF Research Database (Denmark)

    Gydesen, Sofie; Andreassen, Kim Vietz; Hjuler, Sara Toftegaard

    2017-01-01

    , and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance (P weight evenly with no significant...... second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time...... reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg...

  2. Tolerance to Gamma Radiation in the Tardigrade Hypsibius dujardini from Embryo to Adult Correlate Inversely with Cellular Proliferation.

    Directory of Open Access Journals (Sweden)

    Eliana Beltrán-Pardo

    Full Text Available Tardigrades are highly tolerant to desiccation and ionizing radiation but the mechanisms of this tolerance are not well understood. In this paper, we report studies on dose responses of adults and eggs of the tardigrade Hypsibius dujardini exposed to gamma radiation. In adults the LD50/48h for survival was estimated at ~ 4200 Gy, and doses higher than 100 Gy reduced both fertility and hatchability of laid eggs drastically. We also evaluated the effect of radiation (doses 50 Gy, 200 Gy, 500 Gy on eggs in the early and late embryonic stage of development, and observed a reduced hatchability in the early stage, while no effect was found in the late stage of development. Survival of juveniles from irradiated eggs was highly affected by a 500 Gy dose, both in the early and the late stage. Juveniles hatched from eggs irradiated at 50 Gy and 200 Gy developed into adults and produced offspring, but their fertility was reduced compared to the controls. Finally we measured the effect of low temperature during irradiation at 4000 Gy and 4500 Gy on survival in adult tardigrades, and observed a slight delay in the expressed mortality when tardigrades were irradiated on ice. Since H. dujardini is a freshwater tardigrade with lower tolerance to desiccation compared to limno-terrestrial tardigrades, the high radiation tolerance in adults, similar to limno-terrestrial tardigrades, is unexpected and seems to challenge the idea that desiccation and radiation tolerance rely on the same molecular mechanisms. We suggest that the higher radiation tolerance in adults and late stage embryos of H. dujardini (and in other studied tardigrades compared to early stage embryos may partly be due to limited mitotic activity, since tardigrades have a low degree of somatic cell division (eutely, and dividing cells are known to be more sensitive to radiation.

  3. Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study.

    Science.gov (United States)

    Zhou, Lin; He, Jiazhuo; Xiong, Weijie; Liu, Yongmei; Xiang, Jing; Yu, Qin; Liang, Maozhi; Zhou, Xiaojuan; Ding, Zhenyu; Huang, Meijuan; Ren, Li; Zhu, Jiang; Li, Lu; Hou, Mei; Ding, Lieming; Tan, Fenlai; Lu, You

    2016-06-01

    Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, Picotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Predicted allowable doses to normal organs for biologically targeted radiotherapy

    International Nuclear Information System (INIS)

    O'Donoghue, J.A.; Wheldon, T.E.; Western Regional Hospital Board, Glasgow

    1988-01-01

    The authors have used Dale's extension to the ''linear quadratic'' (LQ) model (Dale, 1985) to evaluate ''equivalent doses'' in cases involving exponentially decaying dose rates. This analysis indicates that the dose-rate effect will be a significant determinant of allowable doses to organs such as liver, kidney and lung. These organ tolerance doses constitute independent constraints on the therapeutic intensity of biologically targeted radiotherapy in exactly the same way as for conventional external beam radiotherapy. In the context of marrow rescue they will in all likelihood constitute the dose-limiting side-effects and thus be especially important. (author)

  5. The Cumulative Daily Tolerance Levels of Potentially Toxic Excipients Ethanol and Propylene Glycol Are Commonly Exceeded in Neonates and Infants

    DEFF Research Database (Denmark)

    Valeur, Kristine Svinning; Hertel, Steen Axel; Lundstrøm, Kaare Engell

    2018-01-01

    neonates and infants and compare these levels to the tolerance limits found in guidelines published by European Medicines Agency (EMA). As part of the SEEN study, all medicinal products administered to neonates and infants were recorded. All included neonates received ≥2 medicinal products/day and infants...... ≥3 medicinal products/day. Daily excipient levels were calculated based on quantities obtained from manufacturers or databases. Excipient levels were compared to tolerance limits proposed by the EMA. Altogether, 470 neonates and 160 infants were included, recording 4207 prescriptions and 316 products...... exceed tolerance limit of 6 mg/kg/day. Of the total number of prescriptions involving PG-containing medicinal products (n = 174), 70% would alone exceed a maximum tolerance limit of 50 mg/kg/day. Maximal daily exposure to ethanol (1563 mg/kg/day) or PG (954 mg/kg/day) exceeded the tolerance limits...

  6. A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang; Shentu, Jianzhong

    2016-11-01

    This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (T max ) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t 1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. This study demonstrated that higher-dose

  7. Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.

    Science.gov (United States)

    Kothare, Prajakti A; Linnebjerg, Helle; Isaka, Yoshitaka; Uenaka, Kazunori; Yamamura, Ayuko; Yeo, Kwee Poo; de la Peña, Amparo; Teng, Choo Hua; Mace, Kenneth; Fineman, Mark; Shigeta, Hirofumi; Sakata, Yukikuni; Irie, Shin

    2008-12-01

    In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

  8. A comprehensive analysis of the IMRT dose delivery process using statistical process control (SPC)

    Energy Technology Data Exchange (ETDEWEB)

    Gerard, Karine; Grandhaye, Jean-Pierre; Marchesi, Vincent; Kafrouni, Hanna; Husson, Francois; Aletti, Pierre [Research Center for Automatic Control (CRAN), Nancy University, CNRS, 54516 Vandoeuvre-les-Nancy (France); Department of Medical Physics, Alexis Vautrin Cancer Center, 54511 Vandoeuvre-les-Nancy Cedex (France) and DOSIsoft SA, 94230 Cachan (France); Research Laboratory for Innovative Processes (ERPI), Nancy University, EA 3767, 5400 Nancy Cedex (France); Department of Medical Physics, Alexis Vautrin Cancer Center, 54511 Vandoeuvre-les-Nancy Cedex (France); DOSIsoft SA, 94230 Cachan (France); Research Center for Automatic Control (CRAN), Nancy University, CNRS, 54516 Vandoeuvre-les-Nancy, France and Department of Medical Physics, Alexis Vautrin Cancer Center, 54511 Vandoeuvre-les-Nancy Cedex (France)

    2009-04-15

    The aim of this study is to introduce tools to improve the security of each IMRT patient treatment by determining action levels for the dose delivery process. To achieve this, the patient-specific quality control results performed with an ionization chamber--and which characterize the dose delivery process--have been retrospectively analyzed using a method borrowed from industry: Statistical process control (SPC). The latter consisted in fulfilling four principal well-structured steps. The authors first quantified the short term variability of ionization chamber measurements regarding the clinical tolerances used in the cancer center ({+-}4% of deviation between the calculated and measured doses) by calculating a control process capability (C{sub pc}) index. The C{sub pc} index was found superior to 4, which implies that the observed variability of the dose delivery process is not biased by the short term variability of the measurement. Then, the authors demonstrated using a normality test that the quality control results could be approximated by a normal distribution with two parameters (mean and standard deviation). Finally, the authors used two complementary tools--control charts and performance indices--to thoroughly analyze the IMRT dose delivery process. Control charts aim at monitoring the process over time using statistical control limits to distinguish random (natural) variations from significant changes in the process, whereas performance indices aim at quantifying the ability of the process to produce data that are within the clinical tolerances, at a precise moment. The authors retrospectively showed that the analysis of three selected control charts (individual value, moving-range, and EWMA control charts) allowed efficient drift detection of the dose delivery process for prostate and head-and-neck treatments before the quality controls were outside the clinical tolerances. Therefore, when analyzed in real time, during quality controls, they should

  9. A comprehensive analysis of the IMRT dose delivery process using statistical process control (SPC).

    Science.gov (United States)

    Gérard, Karine; Grandhaye, Jean-Pierre; Marchesi, Vincent; Kafrouni, Hanna; Husson, François; Aletti, Pierre

    2009-04-01

    The aim of this study is to introduce tools to improve the security of each IMRT patient treatment by determining action levels for the dose delivery process. To achieve this, the patient-specific quality control results performed with an ionization chamber--and which characterize the dose delivery process--have been retrospectively analyzed using a method borrowed from industry: Statistical process control (SPC). The latter consisted in fulfilling four principal well-structured steps. The authors first quantified the short-term variability of ionization chamber measurements regarding the clinical tolerances used in the cancer center (+/- 4% of deviation between the calculated and measured doses) by calculating a control process capability (C(pc)) index. The C(pc) index was found superior to 4, which implies that the observed variability of the dose delivery process is not biased by the short-term variability of the measurement. Then, the authors demonstrated using a normality test that the quality control results could be approximated by a normal distribution with two parameters (mean and standard deviation). Finally, the authors used two complementary tools--control charts and performance indices--to thoroughly analyze the IMRT dose delivery process. Control charts aim at monitoring the process over time using statistical control limits to distinguish random (natural) variations from significant changes in the process, whereas performance indices aim at quantifying the ability of the process to produce data that are within the clinical tolerances, at a precise moment. The authors retrospectively showed that the analysis of three selected control charts (individual value, moving-range, and EWMA control charts) allowed efficient drift detection of the dose delivery process for prostate and head-and-neck treatments before the quality controls were outside the clinical tolerances. Therefore, when analyzed in real time, during quality controls, they should improve the

  10. Gamma irradiation facilities for radiation tolerance assessment of components and systems at SCK.CEN

    International Nuclear Information System (INIS)

    Coenen, S.; Decreton, M.

    1999-01-01

    This paper presents the different gamma irradiation facilities available at SCK-CEN (Mol, Belgium). With gamma dose rates ranging from 1 Gy/h up to 50 kGy/h, extensive environmental control and on-line instrumentation possibilities, they offer ideal test environments for the radiation tolerance assessment of components and systems for many applications where radiation tolerance is a concern. (authors)

  11. Maximally multipartite entangled states

    Science.gov (United States)

    Facchi, Paolo; Florio, Giuseppe; Parisi, Giorgio; Pascazio, Saverio

    2008-06-01

    We introduce the notion of maximally multipartite entangled states of n qubits as a generalization of the bipartite case. These pure states have a bipartite entanglement that does not depend on the bipartition and is maximal for all possible bipartitions. They are solutions of a minimization problem. Examples for small n are investigated, both analytically and numerically.

  12. Maximally Symmetric Composite Higgs Models.

    Science.gov (United States)

    Csáki, Csaba; Ma, Teng; Shu, Jing

    2017-09-29

    Maximal symmetry is a novel tool for composite pseudo Goldstone boson Higgs models: it is a remnant of an enhanced global symmetry of the composite fermion sector involving a twisting with the Higgs field. Maximal symmetry has far-reaching consequences: it ensures that the Higgs potential is finite and fully calculable, and also minimizes the tuning. We present a detailed analysis of the maximally symmetric SO(5)/SO(4) model and comment on its observational consequences.

  13. Applications of maximally concentrating optics for solar energy collection

    Science.gov (United States)

    O'Gallagher, J.; Winston, R.

    1985-11-01

    A new family of optical concentrators based on a general nonimaging design principle for maximizing the geometric concentration, C, for radiation within a given acceptance half angle ±θα has been developed. The maximum limit exceeds by factors of 2 to 10 that attainable by systems using focusing optics. The wide acceptance angles permitted using these techniques have several unique advantages for solar concentrators including the elimination of the diurnal tracking requirement at intermediate concentrations (up to ˜10x), collection of circumsolar and some diffuse radiation, and relaxed tolerances. Because of these advantages, these types of concentrators have applications in solar energy wherever concentration is desired, e.g. for a wide variety of both thermal and photovoltaic uses. The basic principles of nonimaging optical design are reviewed. Selected configurations for thermal collector applications are discussed and the use of nonimaging elements as secondary concentrators is illustrated in the context of higher concentration applications.

  14. Modulation of morphine antinociceptive tolerance and physical dependence by co-administration of simvastatin.

    Science.gov (United States)

    Mansouri, Mohammad Taghi; Khodayar, Mohammad Javad; Tabatabaee, Amirhossein; Ghorbanzadeh, Behnam; Naghizadeh, Bahareh

    2015-10-01

    Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, are widely used in the management of different diseases beyond their primary indication for lowering cholesterol. Previous studies have demonstrated the neuroprotective effects of simvastatin in different animal models. In the present study, we examined the effects of simvastatin (30, 60, 100 and 300mg/kg, p.o.) on the development and expression of morphine-induced tolerance and dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10mg/kg, s.c.) for 5 consecutive days. Tolerance was evaluated by the hot-plate test and physical dependence by naloxone challenge, on the sixth day. The results showed that oral administration of simvastatin produced antinociceptive activity in a dose-dependent way. Co-administration of simvastatin with morphine did not affect the acute morphine-induced analgesia (10mg/kg, s.c.). However, repeated co-administration of simvastatin with morphine significantly attenuated the development of tolerance to the analgesic effect of morphine and inhibited the naloxone (5mg/kg, s.c.)-precipitated withdrawal signs (jumping and body weight loss). Also, simvastatin at doses of 100 and 300mg/kg attenuated the expression of morphine-induced tolerance and dependence. These data indicated that, while simvastatin can alleviate both development and expression of morphine-induced tolerance, it cannot enhance morphine-induced antinociception. Taken together, simvastatin may be used as an adjutant therapeutic agent in combination with morphine and or other opioids in patients with severe chronic pain. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Improved metabolic control in tetrahydrobiopterin (BH4), responsive phenylketonuria with sapropterin administered in two divided doses vs. a single daily dose.

    Science.gov (United States)

    Kör, Deniz; Yılmaz, Berna Şeker; Bulut, Fatma Derya; Ceylaner, Serdar; Mungan, Neslihan Önenli

    2017-07-26

    Phenylketonuria (PKU) often requires a lifelong phenylalanine (Phe)-restricted diet. Introduction of 6R-tetrahydrobiopterin (BH4) has made a huge difference in the diets of patients with PKU. BH4 is the co-factor of the enzyme phenylalanine hydroxylase (PAH) and improves PAH activity and, thus, Phe tolerance in the diet. A limited number of published studies suggest a pharmacodynamic profile of BH4 more suitable to be administered in divided daily doses. After a 72-h BH4 loading test, sapropterin was initiated in 50 responsive patients. This case-control study was conducted by administering the same daily dose of sapropterin in group 1 (n=24) as a customary single dose or in two divided doses in group 2 (n=26) over 1 year. Mean daily consumption of Phe increased significantly after the first year of BH4 treatment in group 2 compared to group 1 (p<0.05). At the end of the first year of treatment with BH4, another dramatic difference observed between the two groups was the ability to transition to a Phe-free diet. Eight patients from group 2 and two from group 1 could quit dietary restriction. When given in two divided daily doses, BH4 was more efficacious than a single daily dose in increasing daily Phe consumption, Phe tolerance and the ability to transition to a Phe-unrestricted diet at the end of the first year of treatment.

  16. Characterization and optimization of the RA-3 experimental dosimetry for normal sheep lung radio-tolerance study

    International Nuclear Information System (INIS)

    Soto, M.S.; Gonzalez, S.J.; Thorp, Silvia I.; Pozzi, Emiliano; Gadan, M.; Miller, Marcelo; Farias, R.

    2009-01-01

    In the spirit of the novel technique proposed by the University of Pavia group (Italy) to irradiate an isolated organ using BNCT, the Comision Nacional de Energia Atomica (CNEA) in collaboration with the Fundacion Favaloro has initiated a project that aims to investigate the feasibility of BNCT for ex-situ treatment of diffuse metastatic disease in the lungs. The present work was carried out in the framework of the undergoing experimental study of the radio tolerance of normal sheep lung. With the purpose of characterizing and optimizing the resulting experimental dosimetry in normal lung subjected to neutron irradiation in the BNCT facility of the RA-3 reactor (CNEA), we have performed a series of experiments to find the optimum configuration of the container-lung system deriving a dose distribution preferentially uniform throughout the organ. Once the optimal set-up was established, we measured the total gamma dose rate and estimated the irradiation time compatible with the maximum tolerable dose of normal lung resulting from previous studies in rats. This estimation was performed using RBE, CBE and tolerance dose values derived from radiobiological studies with BNCT. In parallel with the experimental characterization, we built two different computational models of the container-lung system to perform Monte Carlo simulation with MCNP and Treatment Planning System NCTPlan. (author)

  17. Integral dose and evaluation of irradiated tissue volume

    International Nuclear Information System (INIS)

    Sivachenko, T.P.; Kalina, V.K.; Belous, A.K.; Gaevskij, V.I.

    1984-01-01

    Two parameters having potentialities of radiotherapy planning improvement are under consideration. One of these two parameters in an integral dose. An efficiency of application of special tables for integral dose estimation is noted. These tables were developed by the Kiev Physician Improvement Institute and the Cybernetics Institute of the Ukrainian SSR Academy of Science. The meaning of the term of ''irradiated tissue volume'' is specified, and the method of calculation of the irradiated tissue effective mass is considered. It is possible to evaluate with higher accuracy tolerance doses taking into account the irradiated mass

  18. Dose dense cyclophosphamide, methotrexate, fluorouracil is feasible at 14-day intervals: a pilot study of every-14-day dosing as adjuvant therapy for breast cancer.

    Science.gov (United States)

    Drullinsky, Pamela; Sugarman, Steven M; Fornier, Monica N; D'Andrea, Gabriella; Gilewski, Teresa; Lake, Diana; Traina, Tiffany; Wasserheit-Lieblich, Carolyn; Sklarin, Nancy; Atieh-Graham, Deena; Mills, Nancy; Troso-Sandoval, Tiffany; Seidman, Andrew D; Yuan, Jeffrey; Patel, Hamangi; Patil, Sujata; Norton, Larry; Hudis, Clifford

    2010-12-01

    Cyclophosphamide/methotrexate/fluorouracil (CMF) is a proven adjuvant option for patients with early-stage breast cancer. Randomized trials with other regimens demonstrate that dose-dense (DD) scheduling can offer greater efficacy. We investigated the feasibility of administering CMF using a DD schedule. Thirty-eight patients with early-stage breast cancer were accrued from March 2008 through June 2008. They were treated every 14 days with C 600, M 40, F 600 (all mg/m2) with PEG-filgrastim (Neulasta®) support on day 2 of each cycle. The primary endpoint was tolerability using a Simon's 2-stage optimal design. The design would effectively discriminate between true tolerability (as protocol-defined) rates of ≤ 60% and ≥ 80%. The median age was 52-years-old (range, 38-78 years of age). Twenty-nine of the 38 patients completed 8 cycles of CMF at 14-day intervals. Dose-dense adjuvant CMF is tolerable and feasible at 14-day intervals with PEG-filgrastim support.

  19. Maximal quantum Fisher information matrix

    International Nuclear Information System (INIS)

    Chen, Yu; Yuan, Haidong

    2017-01-01

    We study the existence of the maximal quantum Fisher information matrix in the multi-parameter quantum estimation, which bounds the ultimate precision limit. We show that when the maximal quantum Fisher information matrix exists, it can be directly obtained from the underlying dynamics. Examples are then provided to demonstrate the usefulness of the maximal quantum Fisher information matrix by deriving various trade-off relations in multi-parameter quantum estimation and obtaining the bounds for the scalings of the precision limit. (paper)

  20. Correlation of patient maximum skin doses in cardiac procedures with various dose indicators

    International Nuclear Information System (INIS)

    Domienik, J.; Papierz, S.; Jankowski, J.; Peruga, J.Z.; Werduch, A.; Religa, W.

    2008-01-01

    In most countries of European Union, legislation requires the determination of the total skin dose received by patients during interventional procedures in order to prevent deterministic damages. Various dose indicators like dose-area product (DAP), cumulative dose (CD) and entrance dose at the patient plane (EFD) are used for patient dosimetry purposes in clinical practice. This study aimed at relating those dose indicators with doses ascribed to the most irradiated areas of the patient skin usually expressed in terms of local maximal skin dose (MSD). The study was performed in two different facilities for two most common cardiac procedures coronary angiography (CA) and percutaneous coronary interventions (PCI). For CA procedures, the registered values of fluoroscopy time, total DAP and MSD were in the range (0.7-27.3) min, (16-317) Gy cm 2 and (43-1507) mGy, respectively, and for interventions, accordingly (2.1-43.6) min, (17-425) Gy cm 2 , (71-1555) mGy. Moreover, for CA procedures, CD and EFD were in the ranges (295-4689) mGy and (121-1768) mGy and for PCI (267-6524) mGy and (68-2279) mGy, respectively. No general and satisfactory correlation was found for safe estimation of MSD. However, results show that the best dose indicator which might serve for rough, preliminary estimation is DAP value. In the study, the appropriate trigger levels were proposed for both facilities. (authors)

  1. Understanding Violations of Gricean Maxims in Preschoolers and Adults

    Directory of Open Access Journals (Sweden)

    Mako eOkanda

    2015-07-01

    Full Text Available This study used a revised Conversational Violations Test to examine Gricean maxim violations in 4- to 6-year-old Japanese children and adults. Participants’ understanding of the following maxims was assessed: be informative (first maxim of quantity, avoid redundancy (second maxim of quantity, be truthful (maxim of quality, be relevant (maxim of relation, avoid ambiguity (second maxim of manner, and be polite (maxim of politeness. Sensitivity to violations of Gricean maxims increased with age: 4-year-olds’ understanding of maxims was near chance, 5-year-olds understood some maxims (first maxim of quantity and maxims of quality, relation, and manner, and 6-year-olds and adults understood all maxims. Preschoolers acquired the maxim of relation first and had the greatest difficulty understanding the second maxim of quantity. Children and adults differed in their comprehension of the maxim of politeness. The development of the pragmatic understanding of Gricean maxims and implications for the construction of developmental tasks from early childhood to adulthood are discussed.

  2. Efficacy, safety and tolerability of ongoing statin plus ezetimibe versus doubling the ongoing statin dose in hypercholesterolemic Taiwanese patients: an open-label, randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Yu Chih-Chieh

    2012-05-01

    Full Text Available Abstract Background Reducing low-density lipoprotein cholesterol (LDL-C is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia. Methods This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83 to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks. Results At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026 and total cholesterol (20.8% vs 12.2%, p = 0.0003. Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6% vs doubling statin (41.2%, but the difference was not statistically significant (p = 0.1675. The safety and tolerability profiles were similar between treatments. Conclusion Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing. Trial registration Registered at ClinicalTrials.gov: NCT00652327

  3. Mid-ventilation position planning: Optimal model for dose distribution in lung tumour

    International Nuclear Information System (INIS)

    Benchalal, M.; Leseur, J.; Chajon, E.; Cazoulat, G.; Haigron, P.; Simon, A.; Bellec, J.; Lena, H.; Crevoisier, R. de

    2012-01-01

    Purpose. - The dose distribution for lung tumour is estimated using a 3D-CT scan, and since a person breathes while the images are captured, the dose distribution doesn't reflect the reality. A 4D-CT scan integrates the motion of the tumour during breathing and, therefore, provides us with important information regarding tumour's motion in all directions, the motion volume (ITV) and the time-weighted average position (MVP). Patient and methods. - Based on these two concepts, we have estimated, for a lung carcinoma case a 3D dose distribution from a 3D-CT scan, and a 4D dose distribution from a 4-D CT scan. To this, we have applied a non-rigid registration to estimate the cumulative dose. Results. - Our study shows that the 4D dose estimation of the GTV is almost the same when made using MVP and ITV concepts, but sparring of the healthy lung is better done using the MPV model (MVP), as compared to the ITV model. This improvement of the therapeutic index allows, from a projection on the theoretical maximal dose to PTV (strictly restricted to doses for the lungs and the spinal cord), for an increase of about 11% on the total dose (maximal dose of 86 Gy for the ITV and 96 Gy for the MVP). Conclusion. - Further studies with more patients are needed to confirm our data. (authors)

  4. SU-E-T-348: Effect of Treatment Table and Immobilization Devices On Surface Dose When Using a GRID Technique

    Energy Technology Data Exchange (ETDEWEB)

    Gajdos, S; Donaghue, J [Akron General Medical Center, Akron, OH (United States)

    2015-06-15

    Purpose: To determine the increase of surface dose of MLC-designed GRID therapy in the presence of immobilization devices and treatment table. Methods: To create a GRID field, our facility utilizes an MLC consisting of four millimeter wide leaves. The field is designed to have aperture sizes of 0.8 cm X 0.8 cm with inter-aperture distance of 3.2 cm. Gafchromic EBT3 film was placed between the surface of a solid water phantom and the immobilization device. The treatment table was also present within the beam path. The devices consist of carbon fiber exterior shell. A piece of film was also placed at maximal depth for the photon energy of 10 MV. Image files were converted to dose per a calibration curve based on the selected red channel. The surface dose to maximum dose was established by comparing the ratio of seven centrally located aperture regions-of-interest and four adjacent inter-aperture regions-of-interest were measured with the available software tools. Results: With no devices present in beam path, the ratio of surface dose to maximum dose was 11.5% ± 0.3% for aperture region and 7.0% ± 0.1% for inter-aperture region. When devices are present, the ratio of surface dose to maximum dose was 45.2% ± 0.5% and 33.8% ± 1.1%, respectively. Due to the presence of devices, the surface dose increases in aperture region by 3.8 times or in the inter-aperture region by 4.7 times. Conclusion: The purpose of using GRID technique is to deliver a single fractional dose in range of 15–20 Gy to a bulky lesion while also preserving skin tolerance. The increase of surface dose due to devices placed in beam path may increase the chance of skin toxicity in GRID therapy. Care should be used to determine best manageable patient immobilization while considering skin dose especially for posteriorly located lesions.

  5. Maximizing therapeutic gain with gemcitabine and fractionated radiation

    International Nuclear Information System (INIS)

    Mason, Kathy A.; Milas, Luka; Hunter, Nancy R.; Elshaikh, Mohamed; Buchmiller, Lara; Kishi, Kazushi; Hittelman, K. Walter; Ang, K. Kian

    1999-01-01

    Purpose/Objective: The nucleoside analogue gemcitabine inhibits cellular repair and repopulation, induces apoptosis, causes tumor growth delay, and enhances radiation-induced growth delay. After single doses of drug and radiation, maximum enhancement of tumor response was obtained when gemcitabine preceded radiation by at least 24 h. Conversely, the cellular radioresponse of the normal gastrointestinal epithelium was slightly protected when gemcitabine and radiation were separated by 24 h. This differential response created a time frame within which therapeutic gain could be maximized. In our present investigation, we sought to define the most therapeutically beneficial scheme of gemcitabine administration when combined with fractionated radiotherapy. Methods and Materials: C3Hf/Kam mice were given identical drug and radiation schedules of administration, and both normal tissue (jejunal mucosa) and tumor (Sa-NH) responses were measured. Irradiation was given once per day for 5 days in normal tissue and tumor growth delay studies and twice per day for the tumor cure endpoint. A total dose of 25 mg/kg gemcitabine was given i.p. in 1 of 3 schedules: a single dose of 25 mg/kg 24 h before the start of fractionated irradiation, 12.5 mg/kg 24 h before the first and third radiation doses, or 24 h before each of 5 radiation doses. Groups of mice bearing 7- or 8-mm diameter tumors were treated with gemcitabine alone or in combination with fractionated irradiation under ambient or hypoxic conditions. The survival response of the jejunal mucosa was quantified by the microcolony assay and histologically by quantifying apoptosis, mitosis, S-phase fraction, and crypt cellularity. Results: For tumor growth delay, dose-modifying factors (DMFs) were similar (1.34-1.46) for all 3 schedules of drug administration. In contrast, the response of the jejunum was strongly dependent on the schedule of gemcitabine administration. A single dose of gemcitabine before the start of fractionated

  6. Tolerance

    DEFF Research Database (Denmark)

    Tønder, Lars

    is linked to a different set of circumstances than the ones suggested by existing models in contemporary democratic theory. Reorienting the discussion of tolerance, the book raises the question of how to disclose new possibilities within our given context of affect and perception. Once we move away from......Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated...... by the desire to experiment and to become otherwise. The objective is to discuss what gets lost, conceptually as well as politically, when we neglect the subsistence of active tolerance within other practices of tolerance, and to develop a theory of active tolerance in which tolerance's mobilizing character...

  7. Tolerância ao alumínio em cultivares de aveia branca sob cultivo hidropônico Tolerance to the aluminum in oat cultivars under hydroponic culture

    Directory of Open Access Journals (Sweden)

    José Antonio Gonzalez da Silva

    2007-01-01

    Full Text Available O emprego do cultivo hidropônico para avaliar a tolerância à toxicidade pelo alumínio em genótipos de aveia pode ser feito por meio da medida da retomada do crescimento de raiz. Avaliaram-se 12 cultivares de aveia branca indicadas para o cultivo no Sul do Brasil com o intuito de caracterizar a tolerância ao alumínio, de maneira a ser estrategicamente recomendadas e/ou incluídas em blocos de cruzamento na obtenção de constituições genéticas de elevado potencial produtivo e tolerante ao íon metálico. Foram utilizadas doses de 10, 15 e 20 mg L-1 de alumínio na solução hidropônica e o delineamento experimental adotado foi o completamente casualizado, com três repetições, seguindo o esquema fatorial (12 x 3. As doses empregadas são altamente eficientes na identificação de genótipos de aveia tolerantes e sensíveis ao alumínio tóxico. As cultivares UPF 16, URS 21, UFRGS 14, UPF 19 e UFRGS 17 expressam tolerância.The use of hidroponic culture to evaluate tolerance to aluminum toxicity in oat genotypes can be performed by measuring root regrowth, allowing phenotypically to discriminate tolerant genetic constitutions sensitivity. Twelve white oat cultivars indicated for cultivation in Southern Brazil were evaluated aiming at to characterize their aluminum tolerance, in order to use them as parents in crosses or to recommend them for in cultivation regions. Aluminum concentration of 10, 15 and 20 mg L-1 were used in the hydroponic solution arranged in complete randomized blocks with three replications in 12 x 3 factorial designs. Concentrations of 10, 15 and 20 mg L-1 were highly efficient for the identification of tolerant and sensitive oat genotypes. Cultivars UPF 16, URS 21, UFRGS 14, UPF 19 and UFRGS 17 showed aluminum.

  8. The Radiation Dose-Response of the Human Spinal Cord

    International Nuclear Information System (INIS)

    Schultheiss, Timothy E.

    2008-01-01

    Purpose: To characterize the radiation dose-response of the human spinal cord. Methods and Materials: Because no single institution has sufficient data to establish a dose-response function for the human spinal cord, published reports were combined. Requisite data were dose and fractionation, number of patients at risk, number of myelopathy cases, and survival experience of the population. Eight data points for cervical myelopathy were obtained from five reports. Using maximum likelihood estimation correcting for the survival experience of the population, estimates were obtained for the median tolerance dose, slope parameter, and α/β ratio in a logistic dose-response function. An adequate fit to thoracic data was not possible. Hyperbaric oxygen treatments involving the cervical cord were also analyzed. Results: The estimate of the median tolerance dose (cervical cord) was 69.4 Gy (95% confidence interval, 66.4-72.6). The α/β = 0.87 Gy. At 45 Gy, the (extrapolated) probability of myelopathy is 0.03%; and at 50 Gy, 0.2%. The dose for a 5% myelopathy rate is 59.3 Gy. Graphical analysis indicates that the sensitivity of the thoracic cord is less than that of the cervical cord. There appears to be a sensitizing effect from hyperbaric oxygen treatment. Conclusions: The estimate of α/β is smaller than usually quoted, but values this small were found in some studies. Using α/β = 0.87 Gy, one would expect a considerable advantage by decreasing the dose/fraction to less than 2 Gy. These results were obtained from only single fractions/day and should not be applied uncritically to hyperfractionation

  9. 131I-BSP liver function test by BSP tolerance

    International Nuclear Information System (INIS)

    Kanda, Koichi

    1974-01-01

    131 I-BSP liver function test after BSP intravenous tolerance was discussed, assuming that the reason why measurements of 131 I-BSP retention rate at 30 minutes and 131 I-BSP disappearance rate in blood showed respectable overlapping between normal group and group with slight liver disorders as compared with BSP test and the reason why differential diagnosis was difficult were due to underestimate of tolerance volume of 131 I-BSP. 131 I-BSP was observed with time as to 70 persons with normal liver function and 257 cases of liver diseases, using 5, 3 and 2 mg of non-radioactive BSP tolerance volume per kilogram of body weight. 131 I-BSP retention rate at 30 minutes and 131 I-BSP disappearance rate in blood are possible to separate overlapping over control in each measurement value at 3-5 mg/kg of tolerance, and in comparison of 3 mg and 5 mg, the latter showed a little excellent result. So, it was decided that tolerance of 3 mg/kg was a proper dose, considering tolerance to liver cells. 131 I-BSP retention rate at 30 minutes was a little excellent in accuracy and disappearance rate in blood after BSP tolerance is simple and profitable for practical use because collection of blood was only one time and measurement could be made with whole blood. As mentioned above, this method is seemed to be useful to practice of liver function test. (Kanao, N.)

  10. Soil bacteria show different tolerance ranges to an unprecedented disturbance

    DEFF Research Database (Denmark)

    Nunes, Ines Marques; Jurburg, Stephanie; Jacquiod, Samuel Jehan Auguste

    2018-01-01

    stress doses. FRG1, the most sensitive group, was dominated by Actinobacteria. FRG2 and FRG3, with intermediate tolerance, displayed prevalence of Proteobacteria, while FRG4, the most resistant group, was driven by Firmicutes. While the most sensitive FRGs showed predictable responses linked to changes...

  11. Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children.

    Science.gov (United States)

    Gastine, Silke; Lehrnbecher, Thomas; Müller, Carsten; Farowski, Fedja; Bader, Peter; Ullmann-Moskovits, Judith; Cornely, Oliver A; Groll, Andreas H; Hempel, Georg

    2018-01-01

    The pharmacokinetic variability of voriconazole (VCZ) in immunocompromised children is high, and adequate exposure, particularly in the first days of therapy, is uncertain. A population pharmacokinetic model was developed to explore VCZ exposure in plasma after alternative dosing regimens. Concentration data were obtained from a pediatric phase II study. Nonlinear mixed effects modeling was used to develop the model. Monte Carlo simulations were performed to test an array of three-times-daily (TID) intravenous dosing regimens in children 2 to 12 years of age. A two-compartment model with first-order absorption, nonlinear Michaelis-Menten elimination, and allometric scaling best described the data (maximal kinetic velocity for nonlinear Michaelis-Menten clearance [ V max ] = 51.5 mg/h/70 kg, central volume of distribution [ V 1 ] = 228 liters/70 kg, intercompartmental clearance [ Q ] = 21.9 liters/h/70 kg, peripheral volume of distribution [ V 2 ] = 1,430 liters/70 kg, bioavailability [ F ] = 59.4%, K m = fixed value of 1.15 mg/liter, absorption rate constant = fixed value of 1.19 h -1 ). Interindividual variabilities for V max , V 1 , Q , and F were 63.6%, 45.4%, 67%, and 1.34% on a logit scale, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/liter (additive error). Monte Carlo simulations of a regimen of 9 mg/kg of body weight TID simulated for 24, 48, and 72 h followed by 8 mg/kg two times daily (BID) resulted in improved early target attainment relative to that with the currently recommended BID dosing regimen but no increased rate of accumulation thereafter. Pharmacokinetic modeling suggests that intravenous TID dosing at 9 mg/kg per dose for up to 3 days may result in a substantially higher percentage of children 2 to 12 years of age with adequate exposure to VCZ early during treatment. Before implementation of this regimen in patients, however, validation of exposure, safety, and tolerability in a carefully designed

  12. A tolerant lactic acid bacteria, Lactobacillus paracasei, and its immunoregulatory function.

    Science.gov (United States)

    Kou, Xiaohong; Chen, Qiong; Ju, Xiaoying; Liu, Huiping; Chen, Wenrong; Xue, Zhaohui

    2014-11-01

    The aim of the present investigation was to isolate a probiotic strain from 23 samples of yurts cheese and 21 samples of kumiss (collected from scattered households in Xinjiang and Inner Mongolia), and from eN-Lac Capsules, a health-promoting product. The isolates were subjected to biochemical characterization analysis and were tested for tolerance to low pH, sodium salt, bile salt, pepsin, and trypsin. 16S DNA sequence analysis was conducted to identify the strain. The possible dose-dependent role of strain LP2 in immunomodulation was investigated using the ICR mouse model (from the Institute of Cancer Research). Daily, we conducted clinical observations, a carbon clearance test, a spleen lymphocyte proliferation test, and measurements of body mass and lymphoid organ index. Natural killer cell activity and delayed-type hypersensitivity reaction were determined. The results showed that 3 selected strains (LP2, LP4, and LP9) had high tolerance to low pH, sodium chloride, and bile salt and were not significantly different from Lactobacillus paracasei in terms of morphology, colony, and biochemistry characterizations. A further tolerance test showed that LP2 had the highest survival rate (90%) under the conditions of pH 3.0, 0.3% bile salt, 10 mg/mL pepsin, and 10 mg/mL trypsin for 24 h. The sequence heterogeneities within the 16S rDNA genes molecularly elucidated that the LP2 belongs to the L. paracasei family, on the basis of a homology of 99.6%. A significant enhanced footpad swelling reaction and natural killer cell activity in the middle-dose (10(8) cfu/mL) and the high-dose (10(9) cfu/mL) groups were observed but without obvious dose dependence (P < 0.05). Lymphocyte proliferation was also increased significantly in a dose-dependent manner (P < 0.01) compared with that of the control group, indicating a positive immunoregulatory effect.

  13. Radiation effects after low dose chronic long-term exposure

    International Nuclear Information System (INIS)

    Fliedner, T.M.; Friesecke, I.

    1997-01-01

    This document approaches the radiation effects after low dose chronic long-term exposure, presenting examples occurred, the pathophysiologic mechanisms for cell system tolerance in elevated radiation fields, and the diagnostic and therapeutic possibilities

  14. Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability

    Energy Technology Data Exchange (ETDEWEB)

    Poon, Kirsten Achilles, E-mail: achilles.kirsten@gene.com [Genentech, Inc., South San Francisco, CA (United States); Flagella, Kelly; Beyer, Joseph [Genentech, Inc., South San Francisco, CA (United States); Tibbitts, Jay [UCB, Brussels (Belgium); Kaur, Surinder; Saad, Ola; Yi, Joo-Hee; Girish, Sandhya; Dybdal, Noel; Reynolds, Theresa [Genentech, Inc., South San Francisco, CA (United States)

    2013-12-01

    Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (∼ 4400 μg DM1/m{sup 2}) and 30 mg/kg (∼ 6000 μg DM1/m{sup 2}) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μg DM1/m{sup 2}). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. - Highlights: • T-DM1 was well tolerated in preclinical studies in rats and cynomolgus monkeys. • T-DM1 is associated with bone marrow/hematologic, hepatic, and neuronal toxicities. • T-DM1 toxicities are related to DM1 mechanisms of action and pharmacologic

  15. Effectiveness and gastrointestinal tolerability during conversion and titration with once-daily OROS® hydromorphone extended release in opioid-tolerant patients with chronic low back pain

    Science.gov (United States)

    Hale, Martin E; Nalamachu, Srinivas R; Khan, Arif; Kutch, Michael

    2013-01-01

    Purpose To describe the efficacy and safety of hydromorphone extended-release tablets (OROS hydromorphone ER) during dose conversion and titration. Patients and methods A total of 459 opioid-tolerant adults with chronic moderate to severe low back pain participated in an open-label, 2- to 4-week conversion/titration phase of a double-blind, placebo-controlled, randomized withdrawal trial, conducted at 70 centers in the United States. Patients were converted to once-daily OROS hydromorphone ER at 75% of the equianalgesic dose of their prior total daily opioid dose (5:1 conversion ratio), and titrated as frequently as every 3 days to a maximum dose of 64 mg/day. The primary outcome measure was change in pain intensity numeric rating scale; additional assessments included the Patient Global Assessment and the Roland–Morris Disability Questionnaire scores. Safety assessments were performed at each visit and consisted of recording and monitoring all adverse events (AEs) and serious AEs. Results Mean (standard deviation) final daily dose of OROS hydromorphone ER was 37.5 (17.8) mg. Mean (standard error of the mean [SEM]) numeric rating scale scores decreased from 6.6 (0.1) at screening to 4.3 (0.1) at the final titration visit (mean [SEM] change, −2.3 [0.1], representing a 34.8% reduction). Mean (SEM) change in Patient Global Assessment was −0.6 (0.1), and mean change (SEM) in the Roland–Morris Disability Questionnaire was −2.8 (0.3). Patients achieving a stable dose showed greater improvement than patients who discontinued during titration for each of these measures (P < 0.001). Almost 80% of patients achieving a stable dose (213/268) had a ≥30% reduction in pain. Commonly reported AEs were constipation (15.4%), nausea (11.9%), somnolence (8.7%), headache (7.8%), and vomiting (6.5%); 13.0% discontinued from the study due to AEs. Conclusion The majority of opioid-tolerant patients with chronic low back pain were successfully converted to effective doses of

  16. Dose-volume based ranking of incident beam direction and its utility in facilitating IMRT beam placement

    International Nuclear Information System (INIS)

    Schreibmann, Eduard; Xing Lei

    2005-01-01

    Purpose: Beam orientation optimization in intensity-modulated radiation therapy (IMRT) is computationally intensive, and various single beam ranking techniques have been proposed to reduce the search space. Up to this point, none of the existing ranking techniques considers the clinically important dose-volume effects of the involved structures, which may lead to clinically irrelevant angular ranking. The purpose of this work is to develop a clinically sensible angular ranking model with incorporation of dose-volume effects and to show its utility for IMRT beam placement. Methods and Materials: The general consideration in constructing this angular ranking function is that a beamlet/beam is preferable if it can deliver a higher dose to the target without exceeding the tolerance of the sensitive structures located on the path of the beamlet/beam. In the previously proposed dose-based approach, the beamlets are treated independently and, to compute the maximally deliverable dose to the target volume, the intensity of each beamlet is pushed to its maximum intensity without considering the values of other beamlets. When volumetric structures are involved, the complication arises from the fact that there are numerous dose distributions corresponding to the same dose-volume tolerance. In this situation, the beamlets are not independent and an optimization algorithm is required to find the intensity profile that delivers the maximum target dose while satisfying the volumetric constraints. In this study, the behavior of a volumetric organ was modeled by using the equivalent uniform dose (EUD). A constrained sequential quadratic programming algorithm (CFSQP) was used to find the beam profile that delivers the maximum dose to the target volume without violating the EUD constraint or constraints. To assess the utility of the proposed technique, we planned a head-and-neck and abdominal case with and without the guidance of the angular ranking information. The qualities of the

  17. Planning and delivering high doses to targets surrounding the spinal cord at the lower neck and upper mediastinal levels: static beam-segmentation technique executed by a multileaf collimator

    Energy Technology Data Exchange (ETDEWEB)

    Schelfhout, J; Derycke, S; Fortan, L; Van Duyse, B; Colle, C; De Wagter, C; De Neve, W [Ghent Rijksuniversiteit (Belgium). Kliniek voor Radiotherapie en Kerngeneeskunde

    1995-12-01

    The possibility to plan and deliver beam intensity modulated radiotherapy using a general purpose 3D-planning system (Sherouse`s GRATISTM) and a linear accelerator equipped with a standard multileaf collimator (MLC) was investigated in view of limiting the dose at the spinal cord below tolerance. During the planning process, dose homogenization at the target is obtained by the calculation of the weights, given to beam segments of a specific predetermined geometry. This specific geometry maximizes the area of each segment and thus reduces the number of segments. With a virtual patient in supine position, a first planning using a single isocenter, with gantry positions of -60, -30, 0, 30 and 60 degrees was performed. Medial edges of all segments were located tangential to the spinal cord. The resulting dose distribution allowed to encompass the target by an isodose surface of 66-70 Gy without exceeding spinal cord tolerance but required 42 segments distributed over 5 gantry angles. Therefore, dose-volume histogram analysis were performed for those cases where: (1) for some gantry positions, all beam segments could be omitted; (2) at the remaining gantry angles, segments could be omitted; (3) at least 2 segments could be traded off against 1 additional gantry angle. This procedure resulted in a final plan containing 22 segments spread over 8 gantry angles. Preliminary dosimetric results on a RANDO phantom support the robustness of the method. The first clinical applications have been planned. Although up to 99 beam segments can be programmed on the Philips SL25 linear accelerator, it remained impossible to use these segments synchronized with the MLC. From a clinical viewpoint, the proposed treatment for irradiating lower neck and upper mediastinal targets could be used as a standard against which other solutions might be tested.

  18. Planning and delivering high doses to targets surrounding the spinal cord at the lower neck and upper mediastinal levels: static beam-segmentation technique executed by a multileaf collimator

    International Nuclear Information System (INIS)

    Schelfhout, J.; Derycke, S.; Fortan, L.; Van Duyse, B.; Colle, C.; De Wagter, C.; De Neve, W.

    1995-01-01

    The possibility to plan and deliver beam intensity modulated radiotherapy using a general purpose 3D-planning system (Sherouse's GRATISTM) and a linear accelerator equipped with a standard multileaf collimator (MLC) was investigated in view of limiting the dose at the spinal cord below tolerance. During the planning process, dose homogenization at the target is obtained by the calculation of the weights, given to beam segments of a specific predetermined geometry. This specific geometry maximizes the area of each segment and thus reduces the number of segments. With a virtual patient in supine position, a first planning using a single isocenter, with gantry positions of -60, -30, 0, 30 and 60 degrees was performed. Medial edges of all segments were located tangential to the spinal cord. The resulting dose distribution allowed to encompass the target by an isodose surface of 66-70 Gy without exceeding spinal cord tolerance but required 42 segments distributed over 5 gantry angles. Therefore, dose-volume histogram analysis were performed for those cases where: 1) for some gantry positions, all beam segments could be omitted; 2) at the remaining gantry angles, segments could be omitted; 3) at least 2 segments could be traded off against 1 additional gantry angle. This procedure resulted in a final plan containing 22 segments spread over 8 gantry angles. Preliminary dosimetric results on a RANDO phantom support the robustness of the method. The first clinical applications have been planned. Although up to 99 beam segments can be programmed on the Philips SL25 linear accelerator, it remained impossible to use these segments synchronized with the MLC. From a clinical viewpoint, the proposed treatment for irradiating lower neck and upper mediastinal targets could be used as a standard against which other solutions might be tested

  19. Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies.

    Science.gov (United States)

    Tobinai, Kensei; Ogura, Michinori; Ishizawa, Kenichi; Suzuki, Tatsuya; Munakata, Wataru; Uchida, Toshiki; Aoki, Tomohiro; Morishita, Takanobu; Ushijima, Yoko; Takahara, Satoko

    2016-01-01

    In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. NCT01704963.

  20. Mechanistic Insight into Salt Tolerance of Acacia auriculiformis: The Importance of Ion Selectivity, Osmoprotection, Tissue Tolerance, and Na+ Exclusion

    Science.gov (United States)

    Rahman, Md. M.; Rahman, Md. A.; Miah, Md. G.; Saha, Satya R.; Karim, M. A.; Mostofa, Mohammad G.

    2017-01-01

    Salinity, one of the major environmental constraints, threatens soil health and consequently agricultural productivity worldwide. Acacia auriculiformis, being a halophyte, offers diverse benefits against soil salinity; however, the defense mechanisms underlying salt-tolerant capacity in A. auriculiformis are still elusive. In this study, we aimed to elucidate mechanisms regulating the adaptability of the multi-purpose perennial species A. auriculiformis to salt stress. The growth, ion homeostasis, osmoprotection, tissue tolerance and Na+ exclusion, and anatomical adjustments of A. auriculiformis grown in varied doses of seawater for 90 and 150 days were assessed. Results showed that diluted seawater caused notable reductions in the level of growth-related parameters, relative water content, stomatal conductance, photosynthetic pigments, proteins, and carbohydrates in dose- and time-dependent manners. However, the percent reduction of these parameters did not exceed 50% of those of control plants. Na+ contents in phyllodes and roots increased with increasing levels of salinity, whereas K+ contents and K+/Na+ ratio decreased significantly in comparison with control plants. A. auriculiformis retained more Na+ in the roots and maintained higher levels of K+, Ca2+ and Mg2+, and K+/Na+ ratio in phyllodes than roots through ion selective capacity. The contents of proline, total free amino acids, total sugars and reducing sugars significantly accumulated together with the levels of malondialdehyde and electrolyte leakage in the phyllodes, particularly at day 150th of salt treatment. Anatomical investigations revealed various anatomical changes in the tissues of phyllodes, stems and roots by salt stress, such as increase in the size of spongy parenchyma of phyllodes, endodermal thickness of stems and roots, and the diameter of root vascular bundle, relative to control counterparts. Furthermore, the estimated values for Na+ exclusion and tissue tolerance index suggested that

  1. Intercomparison programme of dose calibration used in nuclear medicine center in Malaysia

    International Nuclear Information System (INIS)

    Norhayati Abdullah; Abdul Aziz Mohd Ramli; Muhammad Jamal Md Isa; Siti Sara Deraman; Shahrul Azlan Azizan; Nor Azlin Azraai; Md Khairusalih Md Zin

    2010-01-01

    Calibration of dose calibrator is significant in order to ensure that the equipment operates optimally and provides accurate and reliable measurements of the total activity of radiopharmaceuticals before being administered into the patients. Through this work, the response between the secondary standard dose calibrator and users radioactivity measurement are obtained by using standard sources such as 57 Co, 133 Ba, 1 '3 7 Cs and 60 Co. The calibration procedure is in accordance with the NPLs (National Physical Laboratory, United Kingdom) document; Guide No. 93[1] and the IAEA (International Atomic Energy Agency) Technical Report Series No. 454 [2] is used as a reference for maintaining secondary standard dose calibrator. A total of 21 units of dose calibrator from eight nuclear medicine departments comprising five hospitals, two medical centres and one production laboratory were calibrated. The measurement results were inter compared with the national standard equipment and a baseline data was established for future comparison as well as dose optimization purposes. Results showed that the overall response of all dose calibrators are within NPLs tolerance limit of ±10 % except for 5 units which exceed the tolerance limit for radionuclide 133 Ba and 57 Co.(author)

  2. Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.

    Science.gov (United States)

    Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

    2013-05-01

    The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. © 2012 Abbott Laboratories. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  3. On maximal massive 3D supergravity

    OpenAIRE

    Bergshoeff , Eric A; Hohm , Olaf; Rosseel , Jan; Townsend , Paul K

    2010-01-01

    ABSTRACT We construct, at the linearized level, the three-dimensional (3D) N = 4 supersymmetric " general massive supergravity " and the maximally supersymmetric N = 8 " new massive supergravity ". We also construct the maximally supersymmetric linearized N = 7 topologically massive supergravity, although we expect N = 6 to be maximal at the non-linear level. (Bergshoeff, Eric A) (Hohm, Olaf) (Rosseel, Jan) P.K.Townsend@da...

  4. Clinical applicability of biologically effective dose calculation for spinal cord in fractionated spine stereotactic body radiation therapy

    International Nuclear Information System (INIS)

    Lee, Seung Heon; Lee, Kyu Chan; Choi, Jinho; Ahn, So Hyun; Lee, Seok Ho; Sung, Ki Hoon; Kil, Se Hee

    2015-01-01

    The aim of the study was to investigate whether biologically effective dose (BED) based on linear-quadratic model can be used to estimate spinal cord tolerance dose in spine stereotactic body radiation therapy (SBRT) delivered in 4 or more fractions. Sixty-three metastatic spinal lesions in 47 patients were retrospectively evaluated. The most frequently prescribed dose was 36 Gy in 4 fractions. In planning, we tried to limit the maximum dose to the spinal cord or cauda equina less than 50% of prescription or 45 Gy 2/2 . BED was calculated using maximum point dose of spinal cord. Maximum spinal cord dose per fraction ranged from 2.6 to 6.0 Gy (median 4.3 Gy). Except 4 patients with 52.7, 56.4, 62.4, and 67.9 Gy 2/2 , equivalent total dose in 2-Gy fraction of the patients was not more than 50 Gy 2/2 (12.1–67.9, median 32.0). The ratio of maximum spinal cord dose to prescription dose increased up to 82.2% of prescription dose as epidural spinal cord compression grade increased. No patient developed grade 2 or higher radiation-induced spinal cord toxicity during follow-up period of 0.5 to 53.9 months. In fractionated spine SBRT, BED can be used to estimate spinal cord tolerance dose, provided that the dose per fraction to the spinal cord is moderate, e.g. < 6.0 Gy. It appears that a maximum dose of up to 45–50 Gy 2/2 to the spinal cord is tolerable in 4 or more fractionation regimen

  5. High dose rate (HDR) and low dose rate (LDR) interstitial irradiation (IRT) of the rat spinal cord

    International Nuclear Information System (INIS)

    Pop, Lucas A.M.; Plas, Mirjam van der; Skwarchuk, Mark W.; Hanssen, Alex E.J.; Kogel, Albert J. van der

    1997-01-01

    Purpose: To describe a newly developed technique to study radiation tolerance of rat spinal cord to continuous interstitial irradiation (IRT) at different dose rates. Material and methods: Two parallel catheters are inserted just laterally on each side of the vertebral bodies from the level of Th 10 to L 4 . These catheters are afterloaded with two 192 Ir wires of 4 cm length each (activity 1-2.3 mCi/cm) for the low dose rate (LDR) IRT or connected to the HDR micro-Selectron for the high dose rate (HDR) IRT. Spinal cord target volume is located at the level of Th 12 -L 2 . Due to the rapid dose fall-off around the implanted sources, a dose inhomogeneity across the spinal cord thickness is obtained in the dorso-ventral direction. Using the 100% reference dose (rate) at the ventral side of the spinal cord to prescribe the dose, experiments have been carried out to obtain complete dose response curves at average dose rates of 0.49, 0.96 and 120 Gy/h. Paralysis of the hind-legs after 5-6 months and histopathological examination of the spinal cord of each irradiated rat are used as experimental endpoints. Results: The histopathological damage seen after irradiation is clearly reflected the inhomogeneous dose distribution around the implanted catheters, with the damage predominantly located in the dorsal tract of the cord or dorsal roots. With each reduction in average dose rate, spinal cord radiation tolerance is significantly increased. When the dose is prescribed at the 100% reference dose rate, the ED 50 (induction of paresis in 50% of the animals) for the HDR-IRT is 17.3 Gy. If the average dose rate is reduced from 120 Gy/h to 0.96 or 0.49 Gy/h, a 2.9- or 4.7-fold increase in the ED 50 values to 50.3 Gy and 80.9 Gy is observed; for the dose prescribed at the 150% reference dose rate (dorsal side of cord) ED 50 values are 26.0, 75.5 and 121.4 Gy, respectively. Using different types of analysis and in dependence of the dose prescription and reference dose rate, the

  6. Efficacy and tolerability of concurrent weekly low dose cisplatin during radiation treatment of localised muscle invasive bladder transitional cell carcinoma: A report of two sequential Phase II studies from the Trans Tasman Radiation Oncology Group

    International Nuclear Information System (INIS)

    Gogna, Nirdosh Kumar; Matthews, John H.L.; Turner, Sandra L.; Mameghan, Heidi; Duchesne, Gillian M.; Spry, Nigel; Berry, Martin P.; Keller, Jacqui; Tripcony, Lee

    2006-01-01

    Background and purpose: To determine the feasibility, toxicity, and clinical effectiveness of concurrent weekly cisplatin chemotherapy in conjunction with definitive radiation in the treatment of localised muscle invasive bladder cancer. Patients and methods: In January 1997 the Trans Tasman Radiation Oncology Group embarked on a Phase II study (TROG 97.01) of weekly cisplatin (35 mg/m 2 x 7 doses) plus radiation to a dose of 63 Gy over 7 weeks. Following an interim toxicity analysis, the dose intensity of cisplatin was reduced to 6 cycles and the radiation schedule changed to 64 Gy over 6.5 weeks leading to the second study (TROG 99.06). A total of 113 patients were enrolled. Results: Acute grade 3 urinary toxicity occurred in 23% of the patients. Acute grade 4 pelvic toxicity was not seen. Thirty-eight patients (33%) experienced grade 3 or 4 cisplatin related toxicities with 15 patients (12%) requiring significant dose modification. The reduced dose intensity in Study 99.06 improved tolerability. Incidence of significant late morbidity was low (6%). Seventy-nine patients (70%) achieved complete remission at the 6 month cystoscopic assessment. Local invasive recurrence was seen in 11 of the 79 patients (14%). In 18 patients (16%) isolated superficial TCC/CIS were detected (6 months and beyond).The local control rate was 45% with a functional bladder being retained in 69 of the 113 patients (61%). RFS and DSS at 5 years were 33% and 50%, respectively. Conclusion: Our two sequential Phase II studies have shown that concurrent chemoradiation using weekly cisplatin in the management of localised invasive bladder TCC is feasible and reasonably well tolerated. This approach is currently being investigated further in a randomised study

  7. Inclusive fitness maximization: An axiomatic approach.

    Science.gov (United States)

    Okasha, Samir; Weymark, John A; Bossert, Walter

    2014-06-07

    Kin selection theorists argue that evolution in social contexts will lead organisms to behave as if maximizing their inclusive, as opposed to personal, fitness. The inclusive fitness concept allows biologists to treat organisms as akin to rational agents seeking to maximize a utility function. Here we develop this idea and place it on a firm footing by employing a standard decision-theoretic methodology. We show how the principle of inclusive fitness maximization and a related principle of quasi-inclusive fitness maximization can be derived from axioms on an individual׳s 'as if preferences' (binary choices) for the case in which phenotypic effects are additive. Our results help integrate evolutionary theory and rational choice theory, help draw out the behavioural implications of inclusive fitness maximization, and point to a possible way in which evolution could lead organisms to implement it. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Optimized total body irradiation for induction of renal allograft tolerance through mixed chimerism in cynomolgus monkeys

    International Nuclear Information System (INIS)

    Kimikawa, Masaaki; Kawai, Tatsuo; Ota, Kazuo

    1996-01-01

    We previously demonstrated that a nonmyeloablative preparative regimen can induce mixed chimerism and renal allograft tolerance between MHC-disparate non-human primates. The basic regimen includes anti-thymocyte globulin (ATG), total body irradiation (TBI, 300 cGy), thymic irradiation (TI, 700 cGy), splenectomy, donor bone marrow (DBM) infusion, and posttransplant cyclosporine therapy (CYA, discontinued after 4 weeks). To evaluate the importance and to minimize the toxicity of irradiation, kidney allografts were transplanted with various manipulations of the irradiation protocol. Monkeys treated with the basic protocol without TBI and TI did not develop chimerism or long-term allograft survival. In monkeys treated with the full protocol, all six monkeys treated with two fractionated dose of 150 cGy developed chimerism and five monkeys appeared tolerant. In contrast, only two of the four monkeys treated with fractionated doses of 125 cGy developed chimerism and only one monkey survived long term. The degree of lymphocyte depletion in all recipients was proportional to the TBI dose. The fractionated TBI regimen of 150 cGy appears to be the most consistently effective regimen for establishing donor bone marrow cell engraftment and allograft tolerance. (author)

  9. Optimized total body irradiation for induction of renal allograft tolerance through mixed chimerism in cynomolgus monkeys

    Energy Technology Data Exchange (ETDEWEB)

    Kimikawa, Masaaki; Kawai, Tatsuo; Ota, Kazuo [Tokyo Women`s Medical Coll. (Japan)

    1996-12-01

    We previously demonstrated that a nonmyeloablative preparative regimen can induce mixed chimerism and renal allograft tolerance between MHC-disparate non-human primates. The basic regimen includes anti-thymocyte globulin (ATG), total body irradiation (TBI, 300 cGy), thymic irradiation (TI, 700 cGy), splenectomy, donor bone marrow (DBM) infusion, and posttransplant cyclosporine therapy (CYA, discontinued after 4 weeks). To evaluate the importance and to minimize the toxicity of irradiation, kidney allografts were transplanted with various manipulations of the irradiation protocol. Monkeys treated with the basic protocol without TBI and TI did not develop chimerism or long-term allograft survival. In monkeys treated with the full protocol, all six monkeys treated with two fractionated dose of 150 cGy developed chimerism and five monkeys appeared tolerant. In contrast, only two of the four monkeys treated with fractionated doses of 125 cGy developed chimerism and only one monkey survived long term. The degree of lymphocyte depletion in all recipients was proportional to the TBI dose. The fractionated TBI regimen of 150 cGy appears to be the most consistently effective regimen for establishing donor bone marrow cell engraftment and allograft tolerance. (author)

  10. Study in radiation tolerance of damaged liver induced by dimethylaminoazobenzene. Histological study using Wistar rats

    International Nuclear Information System (INIS)

    Izumiyama, Kazutaka; Kodama, Akihisa; Kono, Michio

    1997-01-01

    We studied to determine the tolerable dose of radiation in damaged liver using Wistar male rats aged 4 weeks. A damaged liver group fed on low-protein animal chow containing 0.07% dimethylaminoazobenzene (DAB) ad libitum. Rats feeding on the chow without DAB served as the normal liver group. In both groups, two rats each underwent irradiation of the right half of the liver with doses of 5 Gy, 10 Gy, 15 Gy, or 20 Gy using a 15 MeV electron beam. The animals were sacrificed 2 or 4 weeks after irradiation, and the irradiated and non-irradiated parts of the liver were compared histologically with respect to hepatocellular necrosis, the extent of degeneration, and the degree of inflammatory cell infiltration, as well as the degree of inflammatory cell infiltration and fibrosis in Glisson's capsule. Secondly, in the normal liver group, 6 rats were irradiated with dose of 20 Gy, and in the damaged liver group, 6 rats each were irradiated with doses of 10 Gy, 12 Gy, 15 Gy or 20 Gy, and the same study was performed. In the normal liver group, no histological differences were seen between the irradiated and non-irradiated parts of the liver even when irradiated with 20 Gy dose. In the damaged liver group, there were no differences between the irradiated and non-irradiated parts of the liver in animals given 15 Gy or 10 Gy. In the 12 Gy group, however, one out of three rats each showed more severe changes in the irradiated part at 2 and 4 weeks after irradiation. One out of six rats in the 15 Gy group and four out of six rats in the 20 Gy group died in the first week after irradiation. In the damaged liver group, a single irradiation of up to 10 Gy delivered to one half of the liver was tolerable. At doses of 12 Gy or higher, however, irreversible changes occurred in some animals, and deaths occurred at 15 Gy or 20 Gy. Since even 20 Gy was tolerated in the normal liver group, damaged liver showed a lower tolerance than normal liver. (author)

  11. Impact of electromechanical parameter variations in treatment volume doses and adjacent structures; Impacto da variacao dos parametros eletro-mecanicos nas doses do volume de tratamento e nas estruturas adjacentes

    Energy Technology Data Exchange (ETDEWEB)

    Morais, M.E.; Campos, A.M. [Instituto Nacional do Cancer (INCa), Rio de Janeiro, RJ (Brazil). Programa de Qualidade em Radioterapia]. E-mails: memorais@yahoo.com.br; amcampos@inca.gov.br; Goncalves, J. F. [Instituto de Oncologia e Radioterapia GV, Governador Valadares, MG (Brazil)]. E-mail: joelfgoncalves@yahoo.com.br; Ferreira, M.L. [Centro Radioterapico Gavea, Rio de Janeiro, RJ (Brazil)]. E-mail: mluciaf@yahoo.com

    2003-07-01

    ICRU Report 62 recommends that radiotherapy treatment dose should be prescribed in such a way that the dose to the target volume varies no more than 10%. In order to keep this goal, a very important role is played by the quality assurance (QA) of the treatment unit associated to the high level work of the personnel involved in planning and patient treatment. This paper shows the influence of the main electrical and mechanical linear accelerator parameters: field size, source-skin distance, gantry angle and light x radiation field coincidence in tumor volume and adjacent organ doses. We simulated a cubic tumor and a cubic adjacent critical organ in a cubic phantom and used a 3D Prowess system for planning. The treatment has been simulated for a 6 MV linear accelerator. We simulated two treatment planning: one using all the parameters inside their tolerance limits and another doubling these limits. The final results have show that, if the irradiation machine operates out of the tolerance limits, the dose variation in the planning target volume (PTV) can goes till {+-} 5,8% and in the critical adjacent organ till {+-} 7,7%. Therefore we concluded that, according to the complexity of the treatment, it can be necessary to reduce the tolerance levels advised by the IAEA/TECDOC - 1151. (author)

  12. Maximizing Benefits from Maintenance Pemetrexed with Stereotactic Ablative Radiotherapy in Oligoprogressive Non-Squamous Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Shao-Lun Lu

    2016-08-01

    Full Text Available Maintenance pemetrexed offers survival benefit with well-tolerated toxicities for advanced non-squamous non-small cell lung cancer (NSCLC. We present 3 consecutively enrolled patients with advanced non-squamous NSCLC, receiving stereotactic ablative radiotherapy (SABR for oligoprogressive disease during maintenance pemetrexed. All of them had sustained local control of thoracic oligoprogression after the SABR, while maintenance pemetrexed were kept for additionally long progression-free interval. SABR targeting oligoprogression with continued pemetrexed is an effective and safe approach to extend exposure of maintenance pemetrexed, thus maximizing the benefit from it.

  13. Feasibility, safety and tolerability of accelerated dobutamine stress echocardiography

    Directory of Open Access Journals (Sweden)

    Pavaci Herribert

    2007-11-01

    Full Text Available Abstract A continuous infusion of a single high dose of dobutamine has been, recently, suggested as a simple and effective protocol of stress echocardiography. The present study assesses the feasibility, safety, and tolerability of an accelerated dobutamine stress protocol performed in patients with suspected or known coronary artery disease. Two hundred sixty five consecutive patients underwent accelerated dobutamine stress echocardiography: the dobutamine was administered at a constant dose of 50 μg/kg/min for up to 10 minutes. The mean weight-adjusted cumulative dose of dobutamine used was 330 ± 105.24 μg/kg. Total duration of dobutamine infusion was 6.6 ± 2.1 min. Heart rate rose from 69.9 ± 12.1 to 123.1 ± 22.1 beats/min at peak with a concomitant change in systolic blood pressure (127.6 ± 18.1 vs. 167.6 ± 45.0 mmHg. Dobutamine administration produced a rapid increase in heart rate (9.4 ± 5.9 beats/min2. The side effects were similar to those described with the standard protocol; the most common were frequent premature ventricular complexes (21.5%, frequent premature atrial complexes (1.5% and non sustained ventricular tachycardia (1.5%; among non cardiac symptoms the most frequent were nausea (3.4%, headache (1.1% and symptomatic hypotension (1.1%. No major side effects were observed during the test. Our data demonstrate that a continous infusion of a single high dose of dobutamine is a safe and well tolerated method of performing stress echocardiography in patients with suspected or known coronary artery disease. This new protocol requires the administration of lower cumulative dobutamine dose than standard protocol and results in a significant reduction in test time.

  14. Maximal Entanglement in High Energy Physics

    Directory of Open Access Journals (Sweden)

    Alba Cervera-Lierta, José I. Latorre, Juan Rojo, Luca Rottoli

    2017-11-01

    Full Text Available We analyze how maximal entanglement is generated at the fundamental level in QED by studying correlations between helicity states in tree-level scattering processes at high energy. We demonstrate that two mechanisms for the generation of maximal entanglement are at work: i $s$-channel processes where the virtual photon carries equal overlaps of the helicities of the final state particles, and ii the indistinguishable superposition between $t$- and $u$-channels. We then study whether requiring maximal entanglement constrains the coupling structure of QED and the weak interactions. In the case of photon-electron interactions unconstrained by gauge symmetry, we show how this requirement allows reproducing QED. For $Z$-mediated weak scattering, the maximal entanglement principle leads to non-trivial predictions for the value of the weak mixing angle $\\theta_W$. Our results are a first step towards understanding the connections between maximal entanglement and the fundamental symmetries of high-energy physics.

  15. SPECIAL CONSIDERATIONS REGARDING WARFARIN DOSE TITRATION IN PATIENTS WITH ATRIAL FIBRILLATION DEPENDING ON CLINICAL FACTORS

    OpenAIRE

    E. L. Artanova; E. V. Saleeva; I. M. Sokolov; Y. G. Shvarts

    2011-01-01

    Aim. To study the relations of clinical characteristics and individual warfarin dose titration in patients with atrial fibrillation. Material and methods. Period of warfarin dose titration was analyzed in 68 patients with atrial fibrillation due to ischemic heart disease. Adjusted warfarin dose in milligram, duration of dose titration in days and maximal international normalized ratio (INR) were taken into account. Sex, age, history of myocardial infarction and stroke, concomitant diseases, a...

  16. Dose effect relationships in cervical and thoracic radiation myelopathies

    International Nuclear Information System (INIS)

    Holdorff, B.

    1980-01-01

    The course and prognosis of radiation myelopathies are determined by 3 factors: the segmental (vertical) location of the lesion, the extent of the transverse syndrome (complete or incomplete) and the radiation dose. The median spinal dose in cervical radiation myelopathies with fatal outcome was higher than in survivals with an incomplete transverse syndrome. In thoracic radiation myelopathies a dose difference between complete and incomplete transverse syndromes could be found as well. Incomplete transverse syndromes as submaximum radiation injuries are more suitable for the determination of the spinal tolerance dose than complete transverse syndromes. The lowest threshold could be stated for cases following high-volume irradiation of the lymphatic system. (Auth.)

  17. Absorbed Doses and Risk Estimates of (211)At-MX35 F(ab')2 in Intraperitoneal Therapy of Ovarian Cancer Patients

    DEFF Research Database (Denmark)

    Cederkrantz, Elin; Andersson, Håkan; Bernhardt, Peter

    2015-01-01

    dose associated with i.p. administration of (211)At-MX35 F(ab')2. METHODS AND MATERIALS: Patients in clinical remission after salvage chemotherapy for peritoneal recurrence of ovarian cancer underwent i.p. infusion of (211)At-MX35 F(ab')2. Potassium perchlorate was given to block unwanted accumulation...... 100 MBq/L, organ equivalent doses were less than 10% of the estimated tolerance dose. CONCLUSION: Intraperitoneal (211)At-MX35 F(ab')2 treatment is potentially a well-tolerated therapy for locally confined microscopic ovarian cancer. Absorbed doses to normal organs are low, but because the effective...

  18. Bio-herbicide effect of salt marsh tolerant Enterobacter sp. I-3 on weed seed germination and seedling growth

    International Nuclear Information System (INIS)

    Radhakrishan, R.; Lee, I.J.

    2017-01-01

    Weeds are major challenges in crop cultivation and cause yield loss. The bacteria based bio-herbicides are emerging against chemical herbicides. This study was aimed to explore the bio-herbicide effect of salt marsh tolerant Enterobacter sp. I-3 on various weed species. The efficacy of I-3 bacterial isolates against weed growth was compared with I-4-5 bacterial strain. The bacterial strains, I-3 and I-4-5 inhibited the seed germination of Cyperus microiria Maxim. Enterobacter sp. I-3 showed higher weed control activity than I-4-5. It was confirmed with growth reduction of C. microiria Maxim. The seed germination of Digitaria sanguinalis L. weed was accelerated during the interaction of I-4-5 and it was drastically declined by I-3 bacterial culture. However, Alopecurus aequalis Sobol. seeds treated with either I-3 or I-4-5 bacterial culture showed no significant germination inhibition. The results of this study suggested that salt marsh tolerant Enterobacter sp. I-3 can be applied as bacterial herbicides to control weeds in agricultural fields. (author)

  19. Biodistribution and tolerance of intravenous iodine-131-labelled hypericin in healthy dogs.

    Science.gov (United States)

    Abma, E; Peremans, K; De Vos, F; Bosmans, T; Kitshoff, A M; Daminet, S; Ni, Y; Dockx, R; de Rooster, H

    2018-01-04

    Hypericin (Hyp) is a necrosis-avid compound that can be efficiently labelled with radioiodine for both diagnostic and therapeutic purposes. Before 131 I-Hyp can be considered as a clinically useful drug in a combination therapy for canine cancer patients, evaluation of its toxicity is necessary. The aim of this study was to investigate the biodistribution and tolerance of a single dose administration of 131 I-Hyp. Three healthy dogs were included. 131 I-Hyp at a dose of 0.2 mg/kg and an activity of 185 MBq was intravenously injected. The effects on physical, haematological and biochemical parameters were characterized and the biodistribution and elimination pattern, the effective half-life and dose rate were assessed. Drug-related adverse events were limited to mild gastrointestinal signs, resolving within 48 hours. No significant differences were found in blood haematology and serum biochemistry before and after treatment. Following administration, highest percentage of injected dose (%ID ± SD) was found in the liver (5.5 ± 0.33), the lungs (4.17 ± 0.14) and the heart (3.11 ± 0.78). After 24 hours, highest %ID was found in colon (4.25 ± 1.45) and liver (3.45 ± 0.60). Clearance from all organs was effective within 7 days. Effective half-life was established at 80 hours, and the dose rate fell below <20 μSv/h at 1 m within 1 day. The current study reveals that single dose treatment with 131 I-Hyp at the described dose is well tolerated by healthy dogs and supports the use of radioiodinated hypericin in a combination therapy for canine cancer patients. © 2018 John Wiley & Sons Ltd.

  20. Maximal Inequalities for Dependent Random Variables

    DEFF Research Database (Denmark)

    Hoffmann-Jorgensen, Jorgen

    2016-01-01

    Maximal inequalities play a crucial role in many probabilistic limit theorem; for instance, the law of large numbers, the law of the iterated logarithm, the martingale limit theorem and the central limit theorem. Let X-1, X-2,... be random variables with partial sums S-k = X-1 + ... + X-k. Then a......Maximal inequalities play a crucial role in many probabilistic limit theorem; for instance, the law of large numbers, the law of the iterated logarithm, the martingale limit theorem and the central limit theorem. Let X-1, X-2,... be random variables with partial sums S-k = X-1 + ... + X......-k. Then a maximal inequality gives conditions ensuring that the maximal partial sum M-n = max(1) (...

  1. An ethical justification of profit maximization

    DEFF Research Database (Denmark)

    Koch, Carsten Allan

    2010-01-01

    In much of the literature on business ethics and corporate social responsibility, it is more or less taken for granted that attempts to maximize profits are inherently unethical. The purpose of this paper is to investigate whether an ethical argument can be given in support of profit maximizing...... behaviour. It is argued that some form of consequential ethics must be applied, and that both profit seeking and profit maximization can be defended from a rule-consequential point of view. It is noted, however, that the result does not apply unconditionally, but requires that certain form of profit (and...... utility) maximizing actions are ruled out, e.g., by behavioural norms or formal institutions....

  2. Phase I trial of Orzel (UFT plus leucovorin), cisplatin, and radiotherapy in the treatment of potentially resectable esophageal cancer

    International Nuclear Information System (INIS)

    Tedesco, Karen L.; Berlin, Jordan; Blanke, Charles D.; Teng Ming; Choy, Hak; Roberts, John; Beauchamp, R. Daniel; Leach, Steve; Wyman, Ken; Tarpley, John; Shyr, Yu; Caillouette, Carol; Chakravarthy, Bapsi

    2005-01-01

    Purpose: Fluorinated pyrimidines have been established as radiosensitizers in the combined modality therapy of esophageal cancer. UFT, an oral combination of a 5-fluorouracil pro-drug (uracil) and a dihydropyrimidine dehydrogenase inhibitor (ftorafur), may provide improvement in the ease of administration with equal efficacy. This Phase I study was designed to determine the maximal tolerated dose and dose-limiting toxicity of UFT, leucovorin, and cisplatin when given with radiotherapy in the neoadjuvant treatment of resectable esophageal cancer. Methods: Chemotherapy consisted of i.v. cisplatin 80 mg/m 2 (Days 1 and 22) and UFT with leucovorin orally on Days 1-35. UFT was escalated in 50-mg/m 2 increments, starting at 200 mg/m 2 /d. Radiotherapy consisted of 4500 cGy in 25 fractions. Patients underwent resection 4-6 weeks after chemoradiotherapy. Results: Ten patients with resectable esophageal cancer were enrolled. Of the 7 patients entered at dose level 1, 1 developed a dose-limiting toxicity of nausea. All 3 patients entered at dose level 2 developed dose-limiting toxicity. The maximal tolerated dose for UFT was the starting level, 200 mg/m 2 /d. Of the 10 patients enrolled, 8 underwent esophagectomy and 2 developed progressive disease and did not undergo surgery. The disease of 6 of the 8 patients was downstaged at surgery. Conclusion: The recommended UFT dose for Phase II studies is 200 mg/m 2 /d given orally in two divided doses when given with leucovorin, cisplatin, and radiotherapy

  3. Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age.

    Science.gov (United States)

    Hoover, Randall; Hunt, Thomas; Benedict, Michael; Paulson, Susan K; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

    2016-01-01

    The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. Delafloxacin Cmax and AUC0-∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0-∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0-∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in

  4. Spiral CT and radiation dose

    International Nuclear Information System (INIS)

    Imhof, H.; Schibany, N.; Ba-Ssalamah, A.; Czerny, C.; Hojreh, A.; Kainberger, F.; Krestan, C.; Kudler, H.; Noebauer, I.; Nowotny, R.

    2003-01-01

    Recent studies in the USA and Europe state that computed tomography (CT) scans compromise only 3-5% of all radiological exams, but they contribute 35-45% of total radiation dose to the patient population. These studies lead to concern by several public authorities. Basis of CT-dose measurements is the computed tomography dose index (CTDI), which was established 1981. Nowadays there are several modifications of the CTDI values, which may lead to confusion. It is suggested to use the standardized CTDI-100 w. value together with the dose length product in all CT-examinations. These values should be printed on all CT-images and allows an evaluation of the individualized patient dose. Nowadays, radiologist's aim must be to work at the lowest maximal diagnostic acceptable signal to noise ratio. To decrease radiation dose radiologist should use low kV and mA, but high pitches. Newly developed CT-dose-reduction soft-wares and filters should be installed in all CT-machines. We should critically compare the average dose used for a specific examination with the reference dose used in this country and/or Europe. Greater differences should caution the radiologist. Finally, we as radiologists must check very carefully all indications and recommend alternative imaging methods. But we have also to teach our customers--patients and medical doctors who are non-radiologists--that a 'good' image is not that which show all possible information, but that which visualize 'only' the diagnostic necessary information

  5. Stress for Stress Tolerance? A Fundamentally New Approach in Mammalian Embryology

    DEFF Research Database (Denmark)

    Pribenszky, Csaba; Vajta, Gabor; Molnár, Miklós

    2010-01-01

    tolerance to various in vitro procedures. The aim of this review is to summarize reports on the effects of stress on gametes and embryos of several species. Treatment with sublethal doses of high hydrostatic pressure (HHP), osmotic, heat, or oxidative stress resulted in increased morphological survival...

  6. Feasibility of extreme dose escalation for glioblastoma multiforme using 4π radiotherapy

    International Nuclear Information System (INIS)

    Nguyen, Dan; Rwigema, Jean-Claude M; Yu, Victoria Y; Kaprealian, Tania; Kupelian, Patrick; Selch, Michael; Lee, Percy; Low, Daniel A; Sheng, Ke

    2014-01-01

    Glioblastoma multiforme (GBM) frequently recurs at the same location after radiotherapy. Further dose escalation using conventional methods is limited by normal tissue tolerance. 4π non-coplanar radiotherapy has recently emerged as a new potential method to deliver highly conformal radiation dose using the C-arm linacs. We aim to study the feasibility of very substantial GBM dose escalation while maintaining normal tissue tolerance using 4π. 11 GBM patients previously treated with volumetric modulated arc therapy (VMAT/RapidArc) on the NovalisTx™ platform to a prescription dose of either 59.4 Gy or 60 Gy were included. All patients were replanned with 30 non-coplanar beams using a 4π radiotherapy platform, which inverse optimizes both beam angles and fluence maps. Four different prescriptions were used including original prescription dose and PTV (4πPTV PD ), 100 Gy to the PTV and GTV (4πPTV 100Gy ), 100 Gy to the GTV only while maintaining prescription dose to the rest of the PTV (4πGTV 100Gy ), and a 5 mm margin expansion plan (4πPTV PD+5mm ). OARs included in the study are the normal brain (brain – PTV), brainstem, chiasm, spinal cord, eyes, lenses, optical nerves, and cochleae. The 4π plans resulted in superior dose gradient indices, as indicated by >20% reduction in the R50, compared to the clinical plans. Among all of the 4π cases, when compared to the clinical plans, the maximum and mean doses were significantly reduced (p < 0.05) by a range of 47.01-98.82% and 51.87-99.47%, respectively, or unchanged (p > 0.05) for all of the non-brain OARs. Both the 4πPTV PD and 4π GTV 100GY plans reduced the mean normal brain mean doses. 4π non-coplanar radiotherapy substantially increases the dose gradient outside of the PTV and better spares critical organs. Dose escalation to 100 Gy to the GTV or additional margin expansion while meeting clinical critical organ dose constraints is feasible. 100 Gy to the PTV result in higher normal brain doses but may

  7. Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

    Science.gov (United States)

    Weisel, Katja C.; Dimopoulos, Meletios A.; Moreau, Philippe; Lacy, Martha Q.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Banos, Anne; Oriol, Albert; Alegre, Adrian; Chen, Christine; Cavo, Michele; Garderet, Laurent; Ivanova, Valentina; Martinez-Lopez, Joaquin; Knop, Stefan; Yu, Xin; Hong, Kevin; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Miguel, Jesus San

    2016-01-01

    Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 − < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 − < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30. PMID:27081177

  8. An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection.

    Science.gov (United States)

    Saber, Haleh; Del Valle, Pedro; Ricks, Tiffany K; Leighton, John K

    2017-11-01

    We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naïve patients to an MTD achieved with intra-patient dose escalation design may be unsafe. Published by Elsevier Inc.

  9. Pharmacokinetics and tolerability of the new second-generation nonnucleoside reverse- transcriptase inhibitor KM-023 in healthy subjects

    Directory of Open Access Journals (Sweden)

    Cha YJ

    2014-09-01

    Full Text Available Yu-Jung Cha,1,* Kyoung Soo Lim,2,* Min-Kyu Park,1 Stephen Schneider,3 Brian Bray,3 Myung-Chol Kang,3 Jae-Yong Chung,1 Seo Hyun Yoon,1 Joo-Youn Cho,1 Kyung-Sang Yu11Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea; 2Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, South Korea; 3Kainos Medicine USA Inc., Morrisville, NC, USA *These authors contributed equally to this workBackground: KM-023 is a new second-generation nonnucleoside reverse-transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus (HIV type 1 infection. Objective: This study determined KM-023 tolerability and pharmacokinetic characteristics in healthy subjects. Materials and methods: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 80 healthy South Korean male volunteers. The subjects were allocated to single- or multiple-dose (once daily for 7 days groups that received 75, 150, 300, or 600 mg drug or placebo in a 4:1 ratio. Safety and pharmacokinetic assessments were performed during the study. Plasma and urine concentrations were quantified using liquid chromatography–tandem mass spectrometry. Results: The average maximum concentration (Cmax and area under the concentration–time curve from time 0 to infinity (AUC∞ values of KM-023 for the 75–600 mg doses in the single-dose study ranged from 440.2 ng/mL to 1,245.4 ng/mL and 11,142.4 ng • h/mL to 33,705.6 ng • h/mL, respectively. Values of the mean Cmax at a steady state and AUC within the dosing interval ranged from 385.1 ng/mL to 1,096.7 ng/mL and 3,698.9 ng • h/mL to 10,232.6 ng • h/mL, respectively, following 75–600 mg doses in the multiple-dose study. Dose proportionality was not observed for KM-023. KM-023 showed a 0.6-fold accumulation after multiple doses in the 600

  10. Quantitative Trait Loci for Mercury Tolerance in Rice Seedlings

    Directory of Open Access Journals (Sweden)

    Chong-qing WANG

    2013-05-01

    Full Text Available Mercury (Hg is one of the most toxic heavy metals to living organisms and its conspicuous effect is the inhibition of root growth. However, little is known about the molecular genetic basis for root growth under excess Hg2+ stress. To map quantitative trait loci (QTLs in rice for Hg2+ tolerance, a population of 120 recombinant inbred lines derived from a cross between two japonica cultivars Yuefu and IRAT109 was grown in 0.5 mmol/L CaCl2 solution. Relative root length (RRL, percentage of the seminal root length in +HgCl2 to –HgCl2, was used for assessing Hg2+ tolerance. In a dose-response experiment, Yuefu had a higher RRL than IRAT109 and showed the most significant difference at the Hg2+ concentration of 1.5 μmol/L. Three putative QTLs for RRL were detected on chromosomes 1, 2 and 5, and totally explained about 35.7% of the phenotypic variance in Hg2+ tolerance. The identified QTLs for RRL might be useful for improving Hg2+ tolerance of rice by molecular marker-assisted selection.

  11. Peptide-Conjugated Nanoparticles Reduce Positive Co-stimulatory Expression and T Cell Activity to Induce Tolerance.

    Science.gov (United States)

    Kuo, Robert; Saito, Eiji; Miller, Stephen D; Shea, Lonnie D

    2017-07-05

    Targeted approaches to treat autoimmune diseases would improve upon current therapies that broadly suppress the immune system and lead to detrimental side effects. Antigen-specific tolerance was induced using poly(lactide-co-glycolide) nanoparticles conjugated with disease-relevant antigen to treat a model of multiple sclerosis. Increasing the nanoparticle dose and amount of conjugated antigen both resulted in more durable immune tolerance. To identify active tolerance mechanisms, we investigated downstream cellular and molecular events following nanoparticle internalization by antigen-presenting cells. The initial cell response to nanoparticles indicated suppression of inflammatory signaling pathways. Direct and functional measurement of surface MHC-restricted antigen showed positive correlation with both increasing particle dose from 1 to 100 μg/mL and increasing peptide conjugation by 2-fold. Co-stimulatory analysis of cells expressing MHC-restricted antigen revealed most significant decreases in positive co-stimulatory molecules (CD86, CD80, and CD40) following high doses of nanoparticles with higher peptide conjugation, whereas expression of a negative co-stimulatory molecule (PD-L1) remained high. T cells isolated from mice immunized against myelin proteolipid protein (PLP 139-151 ) were co-cultured with antigen-presenting cells administered PLP 139-151 -conjugated nanoparticles, which resulted in reduced T cell proliferation, increased T cell apoptosis, and a stronger anti-inflammatory response. These findings indicate several potential mechanisms used by peptide-conjugated nanoparticles to induce antigen-specific tolerance. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  12. TOLERANCE OF PEANUT GENOTYPES TO ACIDIC SOIL CONDITION

    Directory of Open Access Journals (Sweden)

    Astanto Kasno

    2013-06-01

    Full Text Available The acidic soil is generally less productive due to soil pH ranging from 3.1 to 5.0. However, it could be solved through soil amelioration, planting tolerant varieties to acidic soil condition, and a combination of both. Twenty peanut genotypes including two check varieties (Jerapah and Talam 1 were evaluated on dolomite-ameliorated and non ameliorated soil. In the greenhouse, the treatments were laid out in factorial design with four replications, while in the field using strip plot design with three replications. Assessment of tolerance was using Stressed Tolerance Index (STI according to Fernandez (1992. Results showed that dolomite application at dose equivalent to 0.5 x exchangeable Al was optimal in improving peanut growth, and peanut yield on acidic soil. Lines of GH3 (G/92088/92088-02-B-2-8-1 and GH 4 (G/92088/ 92088-02-B-2-8-2 genotypes had high STI with average yield of 2.47 tha-1 and 2.62 t ha-1 of dry pods and potential yield of 4.05 t ha-1 and 3.73 t ha-1 of dry pods, respectively as well as check varieties (Jerapah and Talam-1. It is concluded that peanut genotype of G/92088//92088-02-B-2-8-1 and G/92088//920 88- 02-B-2-8-2 were adaptable and tolerance to acidic, and tolerance of peanuts on acidic soil condition were probably controlled by the buffering mechanisms.

  13. Tolerances of microorganisms to extreme environmental conditions

    International Nuclear Information System (INIS)

    West, J.M.; Arme, S.C.

    1985-03-01

    Microbial isolates from sites relevant to the disposal of radioactive wastes have been subjected to extreme environmental conditions in order to ascertain their tolerance ability. Two groups were chosen, sulphate reducing bacteria and sulphur oxidising bacteria, because of their potential effects on waste containment. They have been subjected to high temperatures, pressures and radiation (delta-emissions) in optimal media conditions and their ability to tolerate the conditions has been ascertained by epifluorescence microscopy and adenosine tri-phosphate (ATP) analysis followed by 'culture-on' to assess post experimental viability. Results indicate that the sulphate reducers in general, are more tolerant to these conditions than the sulphur oxidisers, some proving to be thermophilic. The sulphate reducer showed increased growth rates, as determined by population numbers, at 50 0 C and survived at 80 0 C, 4,500 psig (310 bar) with no subsequent loss in viability. Gamma irradiation of this group and an isolate of 10 5 rad over 4 hours had no effect on population numbers or viability. Such resistances are not apparent with the sulphur oxidisers whose numbers decreased with increasing radiation dose and are destroyed with pressure. (author)

  14. Feasibility of TCP-based dose painting by numbers applied to a prostate case with 18F-choline PET imaging

    International Nuclear Information System (INIS)

    Dirscherl, Thomas; Bogner, Ludwig; Rickhey, Mark

    2012-01-01

    Introduction: A biologically adaptive radiation treatment method to maximize the TCP is shown. Functional imaging is used to acquire a heterogeneous dose prescription in terms of Dose Painting by Numbers and to create a patient-specific IMRT plan. Method and Materials: Adapted from a method for selective dose escalation under the guidance of spatial biology distribution, a model, which translates heterogeneously distributed radiobiological parameters into voxelwise dose prescriptions, was developed. At the example of a prostate case with 18 F-choline PET imaging, different sets of reported values for the parameters were examined concerning their resulting range of dose values. Furthermore, the influence of each parameter of the linear-quadratic model was investigated. A correlation between PET signal and proliferation as well as cell density was assumed. Using our in-house treatment planning software Direct Monte Carlo Optimization (DMCO), a treatment plan based on the obtained dose prescription was generated. Gafchromic EBT films were irradiated for evaluation. Results: When a TCP of 95% was aimed at, the maximal dose in a voxel of the prescription exceeded 100 Gy for most considered parameter sets. One of the parameter sets resulted in a dose range of 87.1 Gy to 99.3 Gy, yielding a TCP of 94.7%, and was investigated more closely. The TCP of the plan decreased to 73.5% after optimization based on that prescription. The dose difference histogram of optimized and prescribed dose revealed a mean of -1.64 Gy and a standard deviation of 4.02 Gy. Film verification showed a reasonable agreement of planned and delivered dose. Conclusion: If the distribution of radiobiological parameters within a tumor is known, this model can be used to create a dose-painting by numbers plan which maximizes the TCP. It could be shown, that such a heterogeneous dose distribution is technically feasible. (orig.)

  15. Therapeutic Drug Monitoring of Lacosamide in Norway: Focus on Pharmacokinetic Variability, Efficacy and Tolerability.

    Science.gov (United States)

    Svendsen, Torleiv; Brodtkorb, Eylert; Baftiu, Arton; Burns, Margrete Larsen; Johannessen, Svein I; Johannessen Landmark, Cecilie

    2017-07-01

    Lacosamide (LCM) is a new antiepileptic drug (AED). Experience from therapeutic drug monitoring (TDM) in clinical practice is limited. The purpose of this study is to evaluate the pharmacokinetic variability of LCM in relation to efficacy and tolerability in patients with refractory epilepsy in a real-life setting. Variables included age, gender, daily doses and serum concentrations of LCM and other AEDs from the TDM-database at the National Center for Epilepsy in Norway. Clinical data regarding efficacy and tolerability were collected from medical records. The Norwegian Prescription Database (NorPD) was used to include population-based numbers of users. TDM-data from 344 patients were included. The median dose, serum concentration, and concentration/dose (C/D)-ratio of LCM was 350 (range 25-700) mg/day, 19.7 (range 8.1-56.2) µmol/L, and 0.06 (0.02-0.82) µmol/L/mg, respectively. Serum concentrations were reduced by 28% by concomitant use of enzyme inducers and increased by 30% in patients aged >65 years. Efficacy and tolerability were assessed in 227 patients: 29% had >50% seizure reduction (eight seizure free), 30% had no effect, and 44% reported adverse effects. In Norway, there were on average 500 patients per year using LCM in this period based on NorPD. The study demonstrated pharmacokinetic variability and use of TDM of LCM in Norway. Data were collected from multiple sources for improved pharmacovigilance. Serum concentrations were influenced by enzyme inducers and ageing, indicating the usefulness of TDM. Effect and tolerability were favorable within a suggested reference range of 10-40 µmol/L given drug-fasting conditions.

  16. Inclusive Fitness Maximization:An Axiomatic Approach

    OpenAIRE

    Okasha, Samir; Weymark, John; Bossert, Walter

    2014-01-01

    Kin selection theorists argue that evolution in social contexts will lead organisms to behave as if maximizing their inclusive, as opposed to personal, fitness. The inclusive fitness concept allows biologists to treat organisms as akin to rational agents seeking to maximize a utility function. Here we develop this idea and place it on a firm footing by employing a standard decision-theoretic methodology. We show how the principle of inclusive fitness maximization and a related principle of qu...

  17. Does mental exertion alter maximal muscle activation?

    Directory of Open Access Journals (Sweden)

    Vianney eRozand

    2014-09-01

    Full Text Available Mental exertion is known to impair endurance performance, but its effects on neuromuscular function remain unclear. The purpose of this study was to test the hypothesis that mental exertion reduces torque and muscle activation during intermittent maximal voluntary contractions of the knee extensors. Ten subjects performed in a randomized order three separate mental exertion conditions lasting 27 minutes each: i high mental exertion (incongruent Stroop task, ii moderate mental exertion (congruent Stroop task, iii low mental exertion (watching a movie. In each condition, mental exertion was combined with ten intermittent maximal voluntary contractions of the knee extensor muscles (one maximal voluntary contraction every 3 minutes. Neuromuscular function was assessed using electrical nerve stimulation. Maximal voluntary torque, maximal muscle activation and other neuromuscular parameters were similar across mental exertion conditions and did not change over time. These findings suggest that mental exertion does not affect neuromuscular function during intermittent maximal voluntary contractions of the knee extensors.

  18. Attenuation of Morphine-Induced Tolerance and Dependence by Pretreatment with Cerebrolysin in Male rats.

    Science.gov (United States)

    Ghavimi, Hamed; Darvishi, Sara; Ghanbarzadeh, Saeed

    2018-01-01

    Dependence and tolerance to morphine are major problems which limit its chronic clinical application. This study was aimed to investigate the attenuation effect of Cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,), on the development of Morphine-induced dependence and tolerance. Male Wistar rats were selected randomly and divided into different groups (n=8) including: a control group, groups received additive doses of morphine (5-25 mg/kg, ip, at an interval of 12 h until tolerance completion), and groups pretreated with Cerebrolysin (40, 80 and 160 mg/kg, ip, before morphine administration). Development of tolerance was assessed by tail-flick test and the attenuation effect of Cerebrolysin on morphine-induced dependence was evaluated after injection of naloxone (4 mg/kg, ip, 12 h after the morning dose of morphine). Seven distinct withdrawal signs including: jumping, rearing, genital grooming, abdominal writhing, wet dog shake and teeth grinding were recorded for 45 min and total withdrawal score (TWS) was calculated. Results showed that administration of Cerebrolysin could prolonged development (10 and 14 days in administration of 80 mg/kg and 160 mg/kg Cerebrolysin) and completion (4, 10 and 14 days in administration of 40, 80 and 160 mg/kg Cerebrolysin, respectively) of tolerance. Results also indicated that administration of Cerebrolysin (40, 80 and 160 mg/kg) could significantly decreased the TWS value (62±2, 77±4 and 85±6%, respectively). In conclusion, it was found that pretreatment with Cerebrolysin could attenuated morphine-induced tolerance and dependence. © Georg Thieme Verlag KG Stuttgart · New York.

  19. Verification of absorbed dose calculation with XIO Radiotherapy Treatment Planning System

    International Nuclear Information System (INIS)

    Bokulic, T.; Budanec, M.; Frobe, A.; Gregov, M.; Kusic, Z.; Mlinaric, M.; Mrcela, I.

    2013-01-01

    Modern radiotherapy relies on computerized treatment planning systems (TPS) for absorbed dose calculation. Most TPS require a detailed model of a given machine and therapy beams. International Atomic Energy Agency (IAEA) recommends acceptance testing for the TPS (IAEA-TECDOC-1540). In this study we present customization of those tests for measurements with the purpose of verification of beam models intended for clinical use in our department. Elekta Synergy S linear accelerator installation and data acquisition for Elekta CMS XiO 4.62 TPS was finished in 2011. After the completion of beam modelling in TPS, tests were conducted in accordance with the IAEA protocol for TPS dose calculation verification. The deviations between the measured and calculated dose were recorded for 854 points and 11 groups of tests in a homogenous phantom. Most of the deviations were within tolerance. Similar to previously published results, results for irregular L shaped field and asymmetric wedged fields were out of tolerance for certain groups of points.(author)

  20. In vitro induction, isolation, and selection of potato mutants tolerant to salinity

    International Nuclear Information System (INIS)

    Al-Safadi, B.; Arabi, M. I. E.

    2008-01-01

    A mutation breeding program was conducted to improve potato (Solanum tuberosum) tolerance to salinity. In vitro cultured explants from potato cvs. Draga, Diamant, and Spunta were irradiated with gamma ray doses of 25, 30, and 35 Gy. Growing plantlets were subsequently propagated to obtain enough explants for in vitro selection of plants tolerant to salinity. Around 1300 MV 4 plantlets from the three cultivars were subjected to selection pressure. MV 4 explants were cultured on an MS medium supplemented with NaCl in varying concentrations ranging from 50 to 200 mM. Surviving plantlets were propagated and re-cultured on a similar medium to insure their tolerance to salinity. Salt tolerant plantlets were acclimatized and transferred to pots and grown under greenhouse conditions. Mutant and control plants were later subjected to a second selection pressure by irrigating them with water containing NaCl in concentrations ranging from 50 to 250 mM. Cultivar Spunta produced the highest number of tolerant plants. Four plants of Spunta appeared to be tolerant to salinity whereas only one plant from Diamant was tolerant and no plants from cultivar Draga were tolerant. The average number of produced minitubers per plant varied in the mutant plants from eight to 14. Also, weight of these minitubers varied from less than 1 to 31 grams. (author)

  1. An imidazopyridine anxiolytic alters glucose tolerance in patients: a pilot investigation.

    Science.gov (United States)

    Bottaï, T; Cartault, F; Pouget, R; Blayac, J P; Petit, P

    1995-02-01

    We have recently shown that compounds with high affinity for peripheral-type benzodiazepine receptors inhibited glucose-induced insulin secretion in vitro. We therefore performed an oral glucose tolerance test in anxious inpatients treated with the imidazopyridine derivative alpidem, which has been shown to display high affinity for these binding sites. The test was performed before and after 1 week of daily administration of the drug. As compared with pretreatment values, a significant alteration of the insulin response to glucose was observed. It is suggested that daily administration of alpidem, at therapeutically effective doses for the treatment of anxiety, may alter glucose tolerance.

  2. Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation.

    LENUS (Irish Health Repository)

    Li, Chong Hui

    2012-02-03

    Tolerance to bacterial cell-wall components may represent an essential regulatory mechanism during bacterial infection. We have demonstrated previously that the inhibition of nuclear factor (NF)-kappaB and mitogen-activated protein kinase activation was present in bacterial lipoprotein (BLP) self-tolerance and its cross-tolerance to lipopolysaccharide (LPS). In this study, the effect of BLP-induced tolerance on the myeloid differentiation factor 88 (MyD88)-dependent upstream signaling pathway for NF-kappaB activation in vitro was examined further. When compared with nontolerant human monocytic THP-1 cells, BLP-tolerant cells had a significant reduction in tumor necrosis factor alpha (TNF-alpha) production in response to a high-dose BLP (86+\\/-12 vs. 6042+\\/-245 ng\\/ml, P < 0.01) or LPS (341+\\/-36 vs. 7882+\\/-318 ng\\/ml, P < 0.01) stimulation. The expression of Toll-like receptor 2 (TLR2) protein was down-regulated in BLP-tolerant cells, whereas no significant differences in TLR4, MyD88, interleukin-1 receptor-associated kinase 4 (IRAK-4), and TNF receptor-associated factor 6 expression were observed between nontolerant and BLP-tolerant cells, as confirmed by Western blot analysis. The IRAK-1 protein was reduced markedly in BLP-tolerant cells, although IRAK-1 mRNA expression remained unchanged as revealed by real-time reverse transcriptase-polymerase chain reaction analysis. Furthermore, decreased MyD88-IRAK immunocomplex formation, as demonstrated by immunoprecipitation, was observed in BLP-tolerant cells following a second BLP or LPS stimulation. BLP pretreatment also resulted in a marked inhibition in total and phosphorylated inhibitor of kappaB-alpha (IkappaB-alpha) expression, which was not up-regulated by subsequent BLP or LPS stimulation. These results demonstrate that in addition to the down-regulation of TLR2 expression, BLP tolerance is associated with a reduction in IRAK-1 expression, MyD88-IRAK association, and IkappaB-alpha phosphorylation. These

  3. Effect of isopregnanolone on rapid tolerance to the anxiolytic effect of ethanol

    Directory of Open Access Journals (Sweden)

    Debatin Thaize

    2006-01-01

    Full Text Available OBJETIVE: It has been shown that neurosteroids can either block or stimulate the development of chronic and rapid tolerance to the incoordination and hypothermia caused by ethanol consumption. The aim of the present study was to investigate the influence of isopregnanolone on the development of rapid tolerance to the anxiolytic effect of ethanol in mice. METHOD: Male Swiss mice were pretreated with isopregnanolone (0.05, 0.10 or 0.20 mg/kg 30 min before administration of ethanol (1.5 g/kg. Twenty-four hours later, all animals we tested using the plus-maze apparatus. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to the anxiolytic effect of ethanol. In the second, the influence of pretreatment of mice with isopregnanolone (0.05, 0.10 or 0.20 mg/kg on rapid tolerance to ethanol (1.5 g/kg was studied. CONCLUSIONS: The results show that pretreatment with isopregnanolone interfered with the development of rapid tolerance to the anxiolytic effect of ethanol.

  4. Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects

    NARCIS (Netherlands)

    Ford, John; Lawson, Matt; Fowler, David; Maruyama, Nobuko; Mito, Seiji; Tomiyasu, Koichi; Kinoshita, Shuji; Suzuki, Chisa; Kawaguchi, Atsuhiro; Round, Patrick; Boyce, Malcolm; Warrington, Steve; Weber, Werner; van Deventer, Sander; Kastelein, John J. P.

    2014-01-01

    Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5,

  5. Comparison in muscle damage between maximal voluntary and electrically evoked isometric contractions of the elbow flexors.

    Science.gov (United States)

    Jubeau, Marc; Muthalib, Makii; Millet, Guillaume Y; Maffiuletti, Nicola A; Nosaka, Kazunori

    2012-02-01

    This study compared between maximal voluntary (VOL) and electrically stimulated (ES) isometric contractions of the elbow flexors for changes in indirect markers of muscle damage to investigate whether ES would induce greater muscle damage than VOL. Twelve non-resistance-trained men (23-39 years) performed VOL with one arm and ES with the contralateral arm separated by 2 weeks in a randomised, counterbalanced order. Both VOL and ES (frequency 75 Hz, pulse duration 250 μs, maximally tolerated intensity) exercises consisted of 50 maximal isometric contractions (4-s on, 15-s off) of the elbow flexors at a long muscle length (160°). Changes in maximal voluntary isometric contraction torque (MVC), range of motion, muscle soreness, pressure pain threshold and serum creatine kinase (CK) activity were measured before, immediately after and 1, 24, 48, 72 and 96 h following exercise. The average peak torque over the 50 isometric contractions was greater (P < 0.05) for VOL (32.9 ± 9.8 N m) than ES (16.9 ± 6.3 N m). MVC decreased greater and recovered slower (P < 0.05) after ES (15% lower than baseline at 96 h) than VOL (full recovery). Serum CK activity increased (P < 0.05) only after ES, and the muscles became more sore and tender after ES than VOL (P < 0.05). These results showed that ES induced greater muscle damage than VOL despite the lower torque output during ES. It seems likely that higher mechanical stress imposed on the activated muscle fibres, due to the specificity of motor unit recruitment in ES, resulted in greater muscle damage.

  6. Disinfestation of agricultural products with electron beams and their radiation tolerance

    International Nuclear Information System (INIS)

    Hayashi, Toru

    1996-01-01

    Some agricultural products contaminated with insect pests are fumigated with methyl bromide for quarantine purposes. However, the use of methyl bromide is preferably restricted because of its ozone depleting effect. Therefore, establishing alternative quarantine techniques is highly desirable; one such technique is exposure to ionizing radiation. Few data are available on the effects of radiation on insect pests other than fruit flies and stored-product insects and on the radiation tolerance of host commodities. Radiation technology as an alternative to methyl bromide fumigation will be used to inactivate not only insects but also mites, spider mites, thrips, nematodes, scales, mealybugs and thrips contaminating fruits, grains, cut flowers, vegetables, timbers, seedlings and seeds. In order to collect data on the effects of irradiation on pests and host commodities, IAEA and FAO have conducted an international project, 'FAO/IAEA Coordinated Research Programme on Irradiation as a Quarantine Treatment of Mites, Nematodes and Insects other than Fruit Fly' since 1992. The project determines the minimum doses necessary to inactivate pests and the maximum doses host commodities tolerate. All pests except nematodes can be inactivated at doses 400Gy or lower. Various varieties of cut flowers and herbs are tolerant to 400Gy of radiation, although some flowers and herbs such as chrysanthemum, rose, lily, calla, anthurium, sweet pea, iris, dill, basil and arugula are intolerant to 200Gy of radiation. Japanese research project on treatment of cut flowers with electron beams carried out mainly by Yokohama Plant Protection Station greatly contributes to these conclusions. Aqueous solution (2%) of sucrose, glucose, fructose or maltose prevents radiation-induced detrimental effects of radiation on chrysanthemums. Sugars reduce radiation-induced physiological deterioration of chrysanthemums. (author)

  7. Tolerance of rat spinal cord to continuous interstitial irradiation

    International Nuclear Information System (INIS)

    Pop, Lucas A.M.; Plas, Mirjam van der; Ruifrok, Arnout C.C.; Schalkwijk, Lia J.M.; Hanssen, Alex E.J.; Kogel, Albert J. van der

    1998-01-01

    Purpose: To study the kinetics of repair in rat spinal cord during continuous interstitial irradiation at different dose rates and to investigate the impact of a rapid dose fall off over the spinal cord thickness. Material and Methods: Two parallel catheters were inserted on each side of the vertebral bodies from the level of T 10 to L 4 . These catheters were afterloaded with two 192 Ir- wires of 4 cm length each (activity 1 - 10 mCi/cm) or connected to the HDR- microSelectron. Experiments have been carried out to obtain complete dose response curves at 7 different dose rates: 0.53, 0.90, 1.64, 2.56, 4.4, 9.9 and 120 Gy/h. Paralysis of the hindlegs after 5 - 6 months and histopathological examination of the spinal cord of each animal were used as experimental endpoints. Results: The distribution of the histological damage was a good reflection of the rapid dose fall - off over the spinal cord, with white matter necrosis or demyelination predominantly seen in the dorsal tracts of the spinal cord or dorsal roots. With each reduction of the dose rate, spinal cord tolerance was significantly increased, with a maximum dose rate factor of 4.3 if the dose rate was reduced from 120 Gy/h to 0.53 Gy/h (ED 50 of 17.3 Gy and 75.0 Gy, respectively). Estimates of the repair parameters using different types of analysis are presented. For the direct analysis the best fit of the data was obtained if a biexponential function for repair was used. For the 100% dose prescribed at the ventral side of the spinal cord the (α(β)) ratio is 1.8 Gy (0.8 - 2.8) and two components of repair are observed: a slow component of repair of 2.44 h (1.18 - ∞) and a fast component of 0.15 h (0.02 - ∞). The proportion of the damage repaired with the slow component is 0.59 (0.18 - 1). For the maximum of 150% of the prescribed dose at the dorsal side of the spinal cord the (α(β)) ratio is 2.7 Gy (1.5 - 4.4); the two components for the kinetics of repair remain the same. Conclusions: Spinal cord

  8. Optimizing cancer radiotheraphy with 2-deoxy-D-glucose. Dose escalation studies in patients with glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Singh, D.; Gupta, J.P. [Dharmshila Cancer Hospital, New Delhi (India); Banerji, A.K. [Vidyasagar Inst. of Mental Health and Neurosciences, New Delhi (India); Dwarakanath, B.S.; Tripathi, R.P.; Mathew, T.L.; Ravindranath, T. [Institute of Nuclear Medicine and Allied Sciences, Delhi (India); Jain, V. [Wright State University, Dayton, OH (United States). Kettering Medical Center

    2005-08-01

    Background and purpose: Higher rates of glucose utilization and glycolysis generally correlate with poor prognosis in several types of malignant tumors. Own earlier studies on model systems demonstrated that the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) could enhance the efficacy of radiotherapy in a dose-dependent manner by selectively sensitizing cancer cells while protecting normal cells. Phase I/II clinical trials indicated that the combination of 2-DG, at an oral dose of 200 mg/kg body weight (BW), with large fractions of {gamma}-radiation was well tolerated in cerebral glioma patients. Since higher 2-DG doses are expected to improve the therapeutic gain, present studies were undertaken to examine the tolerance and safety of escalating 2-DG dose during combined treatment (2-DG + radiotherapy) in glioblastoma multiforme patients. Patients and methods: Untreated patients with histologically proven glioblastoma multiforme (WHO criteria) were included in the study. Seven weekly fractions of {sup 60}C {gamma}-rays (5 Gy/fraction) were delivered to the tumor volume (presurgical CT/MRI evaluation) plus 3 cm margin. Escalating 2-DG doses (200-250-300 mg/kg BW) were administered orally 30 min before irradiation after overnight fasting. Acute toxicity and tolerance were studied by monitoring the vital parameters and side effects. Late radiation damage and treatment responses were studied radiologically and clinically in surviving patients. Results: Transient side effects similar to hypoglycemia were observed in most of the patients. Tolerance and patient compliance to the combined treatment were very good up to a 2-DG dose of 250 mg/kg BW. However, at the higher dose of 300 mg/kg BW, two out of six patients were very restless and could not complete treatment, though significant changes in the vital parameters were not observed even at this dose. No significant damage to the normal brain tissue was observed during follow-up in seven out of ten patients who

  9. Physiologic Doses of Bilirubin Contribute to Tolerance of Islet Transplants by Suppressing the Innate Immune Response.

    Science.gov (United States)

    Adin, Christopher A; VanGundy, Zachary C; Papenfuss, Tracey L; Xu, Feng; Ghanem, Mostafa; Lakey, Jonathan; Hadley, Gregg A

    2017-01-24

    Bilirubin has been recognized as a powerful cytoprotectant when used at physiologic doses and was recently shown to have immunomodulatory effects in islet allograft transplantation, conveying donor-specific tolerance in a murine model. We hypothesized that bilirubin, an antioxidant, acts to suppress the innate immune response to islet allografts through two mechanisms: 1) by suppressing graft release of damage-associated molecular patterns (DAMPs) and inflammatory cytokines, and 2) by producing a tolerogenic phenotype in antigen-presenting cells. Bilirubin was administered intraperitoneally before pancreatic procurement or was added to culture media after islet isolation in AJ mice. Islets were exposed to transplant-associated nutrient deprivation and hypoxia. Bilirubin significantly decreased islet cell death after isolation and hypoxic stress. Bilirubin supplementation of islet media also decreased the release of DAMPs (HMGB1), inflammatory cytokines (IL-1β and IL-6), and chemokines (MCP-1). Cytoprotection was mediated by the antioxidant effects of bilirubin. Treatment of macrophages with bilirubin induced a regulatory phenotype, with increased expression of PD-L1. Coculture of these macrophages with splenocytes led to expansion of Foxp3+ Tregs. In conclusion, exogenous bilirubin supplementation showed cytoprotective and antioxidant effects in a relevant model of islet isolation and hypoxic stress. Suppression of DAMP release, alterations in cytokine profiles, and tolerogenic effects on macrophages suggest that the use of this natural antioxidant may provide a method of preconditioning to improve outcomes after allograft transplantation.

  10. On maximal surfaces in asymptotically flat space-times

    International Nuclear Information System (INIS)

    Bartnik, R.; Chrusciel, P.T.; O Murchadha, N.

    1990-01-01

    Existence of maximal and 'almost maximal' hypersurfaces in asymptotically flat space-times is established under boundary conditions weaker than those considered previously. We show in particular that every vacuum evolution of asymptotically flat data for Einstein equations can be foliated by slices maximal outside a spatially compact set and that every (strictly) stationary asymptotically flat space-time can be foliated by maximal hypersurfaces. Amongst other uniqueness results, we show that maximal hypersurface can be used to 'partially fix' an asymptotic Poincare group. (orig.)

  11. Comparison of dose-responses of contact allergens using the guinea pig maximization test and the local lymph node assay

    NARCIS (Netherlands)

    Och, F.M.M. van; Vandebriel, R.J.; Prinsen, M.K.; Jong, W.H. de; Slob, W.; Loveren, H. van

    2001-01-01

    The guinea pig maximization test (GPMT) has been used as a method for the prediction of skin sensitizing potential for over 30 years. Besides hazard identification, risk assessment of sensitizing chemicals requires the assessment of potency. For the determination of potency based on lowest effective

  12. Optimization of the linear induction accelerator construction for maximizing the bremsstrahlung output

    Energy Technology Data Exchange (ETDEWEB)

    Zinchenko, V F; Tulisov, E V; Chlenov, A M; Shiyan, V D [Research Institute of Scientific Instruments, Turaevo-Lytkarino (Russian Federation)

    1997-12-31

    The results of experimental and theoretical optimization of the linear induction accelerator (LIA) design are presented. The major aim of the investigations was to maximize the bremsstrahlung output near the target face. The work was carried out in two stages: l) modernization of the injector module and 2) focusing of the relativistic electron beam (REB) produced at the exit of the accelerating system (AS) in the increasing axial magnetic field. In addition, the methods of diagnostics of angular and energetic parameters of REB based on measurements of radiation dose fields behind the target are described. (author). 2 figs., 4 refs.

  13. Insulin resistance and maximal oxygen uptake

    DEFF Research Database (Denmark)

    Seibaek, Marie; Vestergaard, Henrik; Burchardt, Hans

    2003-01-01

    BACKGROUND: Type 2 diabetes, coronary atherosclerosis, and physical fitness all correlate with insulin resistance, but the relative importance of each component is unknown. HYPOTHESIS: This study was undertaken to determine the relationship between insulin resistance, maximal oxygen uptake......, and the presence of either diabetes or ischemic heart disease. METHODS: The study population comprised 33 patients with and without diabetes and ischemic heart disease. Insulin resistance was measured by a hyperinsulinemic euglycemic clamp; maximal oxygen uptake was measured during a bicycle exercise test. RESULTS......: There was a strong correlation between maximal oxygen uptake and insulin-stimulated glucose uptake (r = 0.7, p = 0.001), and maximal oxygen uptake was the only factor of importance for determining insulin sensitivity in a model, which also included the presence of diabetes and ischemic heart disease. CONCLUSION...

  14. Gastrointestinal tolerability with ibandronate after previous weekly bisphosphonate treatment.

    Science.gov (United States)

    Derman, Richard; Kohles, Joseph D; Babbitt, Ann

    2009-01-01

    Data from two open-label trials (PRIOR and CURRENT) of women with postmenopausal osteoporosis or osteopenia were evaluated to assess whether monthly oral and quarterly intravenous (IV) ibandronate dosing improved self-reported gastrointestinal (GI) tolerability for patients who had previously experienced GI irritation with bisphosphonate (BP) use. In PRIOR, women who had discontinued daily or weekly BP treatment due to GI intolerance received monthly oral or quarterly IV ibandronate for 12 months. The CURRENT subanalysis included women receiving weekly BP treatment who switched to monthly oral ibandronate for six months. GI symptom severity and frequency were assessed using the Osteoporosis Patient Satisfaction Questionnaire. In PRIOR, mean GI tolerability scores increased significantly at month 1 from screening for both treatment groups (oral: 79.3 versus 54.1; IV: 84.4 versus 51.0; p 90% at Month 10). In the CURRENT subanalysis >60% of patients reported improvements in heartburn or acid reflux and >70% indicated improvement in other stomach upset at month 6. Postmenopausal women with GI irritability with daily or weekly BPs experienced improvement in symptoms with extended dosing monthly or quarterly ibandronate compared with baseline.

  15. Plant tolerance to diesel minimizes its impact on soil microbial characteristics during rhizoremediation of diesel-contaminated soils

    International Nuclear Information System (INIS)

    Barrutia, O.; Garbisu, C.; Epelde, L.; Sampedro, M.C.; Goicolea, M.A.; Becerril, J.M.

    2011-01-01

    Soil contamination due to petroleum-derived products is an important environmental problem. We assessed the impacts of diesel oil on plants (Trifolium repens and Lolium perenne) and soil microbial community characteristics within the context of the rhizoremediation of contaminated soils. For this purpose, a diesel fuel spill on a grassland soil was simulated under pot conditions at a dose of 12,000 mg diesel kg -1 DW soil. Thirty days after diesel addition, T. repens (white clover) and L. perenne (perennial ryegrass) were sown in the pots and grown under greenhouse conditions (temperature 25/18 o C day/night, relative humidity 60/80% day/night and a photosynthetic photon flux density of 400 μmol photon m -2 s -1 ) for 5 months. A parallel set of unplanted pots was also included. Concentrations of n-alkanes in soil were determined as an indicator of diesel degradation. Seedling germination, plant growth, maximal photochemical efficiency of photosystem II (F v /F m ), pigment composition and lipophylic antioxidant content were determined to assess the impacts of diesel on the studied plants. Soil microbial community characteristics, such as enzyme and community-level physiological profiles, were also determined and used to calculate the soil quality index (SQI). The presence of plants had a stimulatory effect on soil microbial activity. L. perenne was far more tolerant to diesel contamination than T. repens. Diesel contamination affected soil microbial characteristics, although its impact was less pronounced in the rhizosphere of L. perenne. Rhizoremediation with T. repens and L. perenne resulted in a similar reduction of total n-alkanes concentration. However, values of the soil microbial parameters and the SQI showed that the more tolerant species (L. perenne) was able to better maintain its rhizosphere characteristics when growing in diesel-contaminated soil, suggesting a better soil health. We concluded that plant tolerance is of crucial importance for the

  16. Iso-effect tables for tolerance of irradiated normal human tissues

    International Nuclear Information System (INIS)

    Cohen, L.; Creditor, M.

    1983-01-01

    Available literature on a radiation injury to human tissues (lung, brain, kidney and intestine) was surveyed. A parameter search program (RAD3) was used to derive best-fitting cell kinetic parameters, on the assumption that radiation injury arises from depletion of parenchymal cells in the irradiated organs. From these parameters iso-effect tables were constructed for a wide range of treatment schedules, including daily treatment as well as fractionation at longer intervals, for each tissue. The tables provide a set of limiting doses, above which the risk of radiation injury becomes substantial. Tolerance limits and dose-time-factors were substantially different in the four tissues. It is concluded that computed iso-effect tables provide a more reliable guide to treatment than conventional time-dose equations

  17. POLITENESS MAXIM OF MAIN CHARACTER IN SECRET FORGIVEN

    Directory of Open Access Journals (Sweden)

    Sang Ayu Isnu Maharani

    2017-06-01

    Full Text Available Maxim of Politeness is an interesting subject to be discussed, since politeness has been criticized from our childhood. We are obliques to be polite to anyone either in speaking or in acting. Somehow we are manage to show politeness in our spoken expression though our intention might be not so polite. For example we must appriciate others opinion although we feel objection toward the opinion. In this article the analysis of politeness is based on maxim proposes by Leech. He proposed six types of politeness maxim. The discussion shows that the main character (Kristen and Kami use all types of maxim in their conversation. The most commonly used are approbation maxim and agreement maxim

  18. Major inter-personal variation in the increase and maximal level of 25-hydroxy vitamin D induced by UVB

    DEFF Research Database (Denmark)

    Datta, Pameli; Philipsen, Peter A.; Olsen, Peter

    2016-01-01

    Vitamin D influences skeletal health as well as other aspects of human health. Even when the most obvious sources of variation such as solar UVB exposure, latitude, season, clothing habits, skin pigmentation and ethnicity are selected for, variation in the serum 25-hydroxy vitamin D (25(OH......)D) response to UVB remains extensive and unexplained. Our study assessed the inter-personal variation in 25(OH)D response to UVR and the maximal obtainable 25(OH)D level in 22 healthy participants (220 samples) with similar skin pigmentation during winter with negligible ambient UVB. Participants received...... identical UVB doses on identical body areas until a maximal level of 25(OH)D was reached. Major inter-personal variation in both the maximal obtainable UVB-induced 25(OH)D level (range 85–216 nmol l−1, mean 134 nmol l−1) and the total increase in 25(OH)D (range 3–139 nmol l−1, mean 48 nmol l−1) was found...

  19. Avaliação da tolerabilidade e do controle de ciclo de dois contraceptivos orais de baixa dose: estudo comparativo aberto Assessment of the tolerability and cycle control of two low-dose oral contraceptives: an open-label study

    Directory of Open Access Journals (Sweden)

    Edmund C. Baracat

    1998-06-01

    Full Text Available Realizou-se um estudo aberto comparativo em nove centros brasileiros para avaliar a tolerabilidade e o controle de ciclo obtido com o uso de dois contraceptivos orais de baixa dose contendo 20 mg etinilestradiol/75 mg gestodeno e 20 mg etinilestradiol/150 mg desogestrel, durante seis ciclos de tratamento. Foram selecionadas 167 mulheres saudáveis com vida sexual ativa (77 no grupo do gestodeno e 90 no grupo do desogestrel, das quais 138 completaram os seis ciclos de tratamento. Em um subgrupo de novas usuárias realizou-se também perfil lipídico e hemostático. Foram avaliados 867 ciclos no total. Ocorreu sangramento irregular em 4,6% dos ciclos com gestodeno e em 8,1% com desogestrel. A tolerabilidade a ambas preparações foi boa, mas houve significativamente mais náusea no grupo do desogestrel. O controle de ciclo foi bom com os dois contraceptivos, sendo que houve freqüência significativamente menor de sangramento irregular no grupo do gestodeno quando se leva em conta que todos os ciclos foram considerados. Não houve alterações clinicamente significativas no perfil hemostático. O perfil lipídico mostrou tendência a tornar-se mais favorável após seis ciclos de tratamento com as duas preparações. Não ocorreu alteração no peso médio das mulheres no grupo do gestodeno; no grupo do desogestrel houve aumento significativo no peso médio de aproximadamente 1 kg após seis meses de tratamento. A adesão ao tratamento foi boa com as duas preparações. Os resultados deste estudo mostram que preparações contendo baixa dose de gestodeno ou desogestrel associados a 20 mg de etinilestradiol são contraceptivos bem tolerados que permitem bom controle de ciclo, sem efeitos colaterais significantes.An open-label comparative study was conducted in nine centers in Brazil to evaluate the tolerability and cycle control of two low-dose oral contraceptives containing 20 mg ethynylestradiol/75 mg gestodene and 20 mg ethynylestradiol/150 mg

  20. interactive effect of cowpea variety, dose and exposure time

    African Journals Online (AJOL)

    ACSS

    variety (V), exposure time (T) and dose (D) on the tolerance of C. maculatus to both plant materials. The effect ... laboratories and institutions of higher education in several West .... Each value is the mean±S.E of 20 cowpea seeds. Means ...

  1. Cocaine tolerance: acute versus chronic effects as dependent upon fixed-ratio size.

    OpenAIRE

    Hoffman, S H; Branch, M N; Sizemore, G M

    1987-01-01

    The effects of cocaine on operant behavior were studied by examining fixed-ratio value as a factor in the development of tolerance. Pigeons pecked a response key under a three-component multiple schedule, with each bird being exposed to fixed-ratio values that were categorized as small, medium, or large. Administered acutely, cocaine (1.0 to 10.0 mg/kg) produced dose-related decreases in overall rate of responding. Responding maintained by the largest ratio was decreased by lower doses than t...

  2. Time-dose relationship of erythema in high energy photon irradiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Hidetoshi (Gifu Prefectural Tajimi Hospital (Japan)); Sakuma, Sadayuki

    1992-01-01

    Skin doses of 100 patients who were treated with high energy ionizing irradiation during conventional irradiation therapy were measured by thermoluminescence dosimeter (TLD). In 87 of the 100 patients, acute hyperemic change of the skin (erythema) of the irradiated region was observed. In the other 13 patients, alopetia of the scalp was observed. The following conclusions were reached. The time-dose relationship was linear when erythema tolerance was used as an index, but not when alopecia was used. The tolerance dose for erythema was lower than previously reported. The slope of the isoeffect curve on the log-log plot of total absorbed skin dose against total number of days after the first irradiation was 0.68 when erythema was used as an index. This number is larger than previously reported results. We considered that erythema is significantly influenced by fraction size and that hyperfractionation is a promising method of irradiation, especially in Japan. Combined use of chemotherapeutic agents, such as 5-FU, accelerated erythema. The slope of combined treatment was 0.86. Observing acute hyperemic change of skin is considered to be a useful method of investigating the combined effects of chemotherapeutic agents on irradiation. (author).

  3. Phase I study of conformal radiotherapy with concurrent gemcitabine in locally advanced bladder cancer

    International Nuclear Information System (INIS)

    Sangar, Vijay K.; McBain, Catherine A.; Lyons, Jeanette; Ramani, Vijay; Logue, John; Wylie, James; Clarke, Noel W.; Cowan, Richard A.

    2005-01-01

    Purpose: A prospective phase I trial was conducted to determine the maximal tolerated dose of gemcitabine given once weekly during hypofractionated conformal radiotherapy to patients with locally advanced transitional cell carcinoma of the bladder. Eight male patients, median age 69 years, with Stage T2 (n = 4) or T3 (n = 4) N0M0, were enrolled in cohorts of 3. Treatment comprised conformal radiotherapy (52.5 Gy in 20 fractions) within 4 weeks, with concurrent gemcitabine once weekly for four cycles. The weekly gemcitabine dose was escalated from 100 mg/m 2 in increments of 50 mg/m 2 per cohort. Dose-limiting toxicity was defined as any acute Radiation Therapy Oncology Group (RTOG) toxicity Grade 3 or greater arising in >1 of 3 patients in each cohort. Tumor response was assessed cystoscopically and radiologically at 3 months. Results: All 8 patients completed radiotherapy, and 6 of 8 completed chemoradiotherapy. No acute toxicity greater than RTOG Grade 1 was seen with gemcitabine at 100 mg/m 2 . Dose-limiting toxicity was observed at 150 mg/m 2 with Grade 3 toxicity seen in 2 of 2 patients (one bladder, one bowel). An additional 3 patients received 100 mg/m 2 with minimal toxicity. No hematologic toxicity was encountered. A complete response was seen in 7 (87.5%) of 8 patients, all of whom were disease free at a median follow-up of 19.5 months (range, 14-23 months). No late toxicity (greater than RTOG Grade 0) has been observed. Conclusion: The maximal tolerated dose for gemcitabine given once weekly with concurrent hypofractionated conformal bladder radiotherapy was 150 mg/m 2 , with a maximal recommended dose of 100 mg/m 2 . This dose regimen has now entered Phase II clinical trials

  4. /sup 131/I-BSP liver function test by BSP tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Kanda, K [Minami Osaka Hospital (Japan)

    1974-11-01

    /sup 131/I-BSP liver function test after BSP intravenous tolerance was discussed, assuming that the reason why measurements of /sup 131/I-BSP retention rate at 30 minutes and /sup 131/I-BSP disappearance rate in blood showed respectable overlapping between normal group and group with slight liver disorders as compared with BSP test and the reason why differential diagnosis was difficult were due to underestimate of tolerance volume of /sup 131/I-BSP. /sup 131/I-BSP was observed with time as to 70 persons with normal liver function and 257 cases of liver diseases, using 5, 3 and 2 mg of non-radioactive BSP tolerance volume per kilogram of body weight. /sup 131/I-BSP retention rate at 30 minutes and /sup 131/I-BSP disappearance rate in blood are possible to separate overlapping over control in each measurement value at 3 to 5 mg/kg of tolerance, and in comparison of 3 mg and 5 mg, the latter showed a little excellent result. So, it was decided that tolerance of 3 mg/kg was a proper dose, considering tolerance to liver cells. /sup 131/I-BSP retention rate at 30 minutes was a little excellent in accuracy and disappearance rate in blood after BSP tolerance is simple and profitable for practical use because collection of blood was only one time and measurement could be made with whole blood. As mentioned above, this method is seemed to be useful to practice of liver function test.

  5. Paralysis following stereotactic spinal irradiation in pigs suggests a tolerance constraint for single-session irradiation of the spinal nerve

    International Nuclear Information System (INIS)

    Medin, Paul M.; Foster, Ryan D.; Kogel, Albert J. van der; Meyer, Jeffrey; Sayre, James W.; Huang, Hao; Öz, Orhan K.

    2013-01-01

    Background and purpose: Paralysis observed during a study of vertebral bone tolerance to single-session irradiation led to further study of the dose-related incidence of motor peripheral neuropathy. Materials and methods: During a bone tolerance study, cervical spinal nerves of 15 minipigs received bilateral irradiation to levels C5–C8 distributed into three dose groups with mean maximum spinal nerve doses of 16.9 ± 0.3 Gy (n = 5), 18.7 ± 0.5 Gy (n = 5), and 24.3 ± 0.8 Gy (n = 5). Changes developing in the gait of the group of pigs receiving a mean maximum dose of 24.3 Gy after 10–15 weeks led to the irradiation of two additional animals. They received mean maximum dose of 24.9 ± 0.2 Gy (n = 2), targeted to the left spinal nerves of C5–C8. The followup period was one year. Histologic sections from spinal cords and available spinal nerves were evaluated. MR imaging was performed on pigs in the 24.9 Gy group. Results: No pig that received a maximum spinal nerve point dose ⩽19.0 Gy experienced a change in gait while all pigs that received ⩾24.1 Gy experienced paralysis. Extensive degeneration and fibrosis were observed in irradiated spinal nerves of the 24.9 Gy animals. All spinal cord sections were normal. Irradiated spinal nerve regions showed increased thickness and hypointensity on MR imaging. Conclusion: The single-session tolerance dose of the cervical spinal nerves lies between 19.0 and 24.1 Gy for this model

  6. A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

    Science.gov (United States)

    Deming, Dustin A; Ninan, Jacob; Bailey, Howard H; Kolesar, Jill M; Eickhoff, Jens; Reid, Joel M; Ames, Matthew M; McGovern, Renee M; Alberti, Dona; Marnocha, Rebecca; Espinoza-Delgado, Igor; Wright, John; Wilding, George; Schelman, William R

    2014-04-01

    Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

  7. Multi-generation cadmium acclimation and tolerance in Daphnia magna Straus

    International Nuclear Information System (INIS)

    Muyssen, Brita T.A.; Janssen, Colin R.

    2004-01-01

    The cladoceran Daphnia magna was acclimated for seven generations to cadmium concentrations ranging from 0 (control) to 250 μg/l Cd (corresponding to a free ion activity of 4.60 nM Cd 2+ ). Acute and chronic cadmium tolerance as well as cadmium accumulation were monitored as a function of acclimation time. After two to three generations of acclimation to concentrations ranging from 0.23 to 1.11 nM Cd 2+ increases in acute tolerance were maximal (factor 7.2) and significant. Acclimation for seven generations to the same acclimation concentrations did result in an increased chronic cadmium tolerance (21 days EC 50 values increased). Organisms acclimated to 1.93 nM Cd 2+ were equally or more sensitive than non-acclimated daphnids in acute and chronic toxicity tests. Cadmium contents in D. magna increased significantly as a function of the acclimation concentration. Maximum body burdens of 236±30 μg Cd/g dry weight were measured in organisms exposed to 4.60 nM Cd 2+ , but detoxification mechanisms were only successful up to 82±20 μg Cd/g dry weight as this concentration did not cause major decreases in survival and reproduction in chronic toxicity tests. As the potential positive effect of acclimation on cadmium tolerance disappeared with successive acclimation generations and increasing acclimation concentrations, it is concluded that multi-generation acclimation studies are important for the evaluation of the long-term effects of environmental toxicants. - Multi-generation acclimation studies are important for evaluating long-term effects of aquatic pollutants

  8. Normal tissue tolerance to external beam radiation therapy: Larynx and pharynx; Dose de tolerance a l'irradiation des tissus sains: larynx et pharynx

    Energy Technology Data Exchange (ETDEWEB)

    Debelleix, C. [Service de radiotherapie, centre hospitalier Dax-Cote d' Argent, 40 - Dax (France); Service de radiotherapie, hopital Saint-Andre, CHU de Bordeaux, 33 - Bordeaux (France); Pointreau, Y.; Calais, G. [Service de radiotherapie, centre regional universitaire de cancerologie Henry-S.-Kaplan, hopital Bretonneau, CHU de Tours, 37 - Tours (France); Universite Francois-Rabelais, 37 - Tours (France); Pointreau, Y. [CNRS, UMR 6239 Genetique, immunotherapie, chimie et cancer, 37 - Tours (France); Laboratoire de pharmacologie-toxicologie, CHRU de Tours, 37 - Tours (France); Lafond, C.; Denis, F. [Centre Jean-Bernard, clinique Victor-Hugo, 72 - Le Mans (France); Bourhis, J.H. [Institut Gustave-Roussy, 94 - Villejuif (France)

    2010-07-15

    For head and neck cancers, the radiation dose usually needed to sterilize a macroscopic tumour is at least 70 Gy in conventional fractionation. In the larynx, this dose level enables optimal tumour control while exposing the patient to a limited risk of severe complications. For oropharynx and nasopharynx tumors, it is sometimes possible to limit the dose received by the larynx according to the extent of the primary lesion. Thus, if the tumour constraints permit, the maximum dose to the larynx must be less than 63 to 66 Gy. To reduce the risk of laryngeal edema, it is recommended if possible to limit the mean non-involved larynx dose to 40 to 45 Gy. In the pharynx, literature's data suggested to minimize the volume of the pharyngeal constrictor muscles receiving a dose greater than or equal to 60 Gy. Limiting the volume receiving a dose greater than or equal to 50 Gy reduces the risk of dysphagia. These dose constraints should be tailored to each patient taking into account the extent of the initial primary lesion, the possible addition of chemotherapy or a modified fractionation radiotherapy. (authors)

  9. Natural maximal νμ-ντ mixing

    International Nuclear Information System (INIS)

    Wetterich, C.

    1999-01-01

    The naturalness of maximal mixing between myon- and tau-neutrinos is investigated. A spontaneously broken nonabelian generation symmetry can explain a small parameter which governs the deviation from maximal mixing. In many cases all three neutrino masses are almost degenerate. Maximal ν μ -ν τ -mixing suggests that the leading contribution to the light neutrino masses arises from the expectation value of a heavy weak triplet rather than from the seesaw mechanism. In this scenario the deviation from maximal mixing is predicted to be less than about 1%. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

  10. Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer.

    Science.gov (United States)

    Matulonis, Ursula; Berlin, Suzanne; Lee, Hang; Whalen, Christin; Obermayer, Elizabeth; Penson, Richard; Liu, Joyce; Campos, Susana; Krasner, Carolyn; Horowitz, Neil

    2015-08-01

    Combining histone deacetylase inhibitors and chemotherapy is synergistic. This phase I study combined escalating vorinostat doses with constant doses of carboplatin and gemcitabine for the treatment of recurrent platinum-sensitive ovarian cancer. The objectives of this study were to determine the maximally tolerated dose of this combination; secondary objectives included preliminary response rate of this regimen and toxicity profile. Fifteen patients with relapsed ovarian cancer were enrolled into this phase I study. Doses of carboplatin and gemcitabine were AUC 4 on day 1 and 1000 mg/m(2) on days 1 and 8, respectively; cycles were administered every 21 days. Vorinostat was tested using four different schedules. The first dose level (DL A) tested vorinostat as daily oral dosing from days 1 to 14. DL B tested twice daily (BID) vorinostat dosing on days 1-3 and 8-10. DL C tested BID vorinostat dosing on days 1, 2, 8, and 9, starting vorinostat 1 day prior to initiation of carboplatin and gemcitabine, and DL D tested vorinostat on days 1 and 2 with chemotherapy starting on day 2. All four DLs tested resulted in dose-limiting toxicities, and no MTD was determined. Toxicities were mostly hematologic. Seven patients were evaluable for RECIST assessment, and six of them had partial responses (PR) via RECIST. Combination of carboplatin, gemcitabine, and vorinostat has activity in relapsed platinum-sensitive ovarian cancer, but was difficult to combine because of hematologic toxicities in this phase I study. No maximally tolerated dose was found, and the study was terminated early.

  11. Gaussian maximally multipartite-entangled states

    Science.gov (United States)

    Facchi, Paolo; Florio, Giuseppe; Lupo, Cosmo; Mancini, Stefano; Pascazio, Saverio

    2009-12-01

    We study maximally multipartite-entangled states in the context of Gaussian continuous variable quantum systems. By considering multimode Gaussian states with constrained energy, we show that perfect maximally multipartite-entangled states, which exhibit the maximum amount of bipartite entanglement for all bipartitions, only exist for systems containing n=2 or 3 modes. We further numerically investigate the structure of these states and their frustration for n≤7 .

  12. Gaussian maximally multipartite-entangled states

    International Nuclear Information System (INIS)

    Facchi, Paolo; Florio, Giuseppe; Pascazio, Saverio; Lupo, Cosmo; Mancini, Stefano

    2009-01-01

    We study maximally multipartite-entangled states in the context of Gaussian continuous variable quantum systems. By considering multimode Gaussian states with constrained energy, we show that perfect maximally multipartite-entangled states, which exhibit the maximum amount of bipartite entanglement for all bipartitions, only exist for systems containing n=2 or 3 modes. We further numerically investigate the structure of these states and their frustration for n≤7.

  13. Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a single ascending dose study in opioid-naïve healthy volunteers.

    Science.gov (United States)

    Rauck, Richard; Oh, D Alexander; Parikh, Neha; Koch, Christian; Singla, Neil; Yu, Jin; Nalamachu, Srinivas; Vetticaden, Santosh

    2017-11-01

    Fentanyl sublingual spray offers rapid pain relief in opioid-tolerant cancer patients, and may be useful in acute or post-operative pain. Both opioid-naïve and non-tolerant patients are likely to receive opioids in these settings. Understanding the relationship between systemic exposure of fentanyl sublingual spray and effects on respiratory function in opioid-naïve or non-tolerant populations is important to ensure patient safety. This study evaluated single-dose fentanyl sublingual spray in opioid-naïve participants. Participants were randomized to receive single-dose fentanyl sublingual spray (100, 200, 400, 600, 800 mcg) or fentanyl citrate IV in one of five cohorts. Dosing occurred following a 10-h fast, with fasting continuing for 4 h post-dose. Dose proportionality was assessed using analysis of variance and linear regression techniques. PK assessments and safety monitoring were performed through 24 h post-dose. Safety assessments, including adverse event (AE) monitoring, occurred from dosing through Day 7. Fifty participants (19-53 years) received fentanyl sublingual spray or fentanyl citrate IV. Mean maximum plasma concentrations were reached between 0.27-0.60 h post-dose for fentanyl sublingual spray. Peak (C max ) and total (AUC 0- t , AUC 0-∞ ) fentanyl exposures increased in a linear, but more than dose-proportional manner, with higher doses. The most common AEs were somnolence, nausea, and vomiting. All AEs were mild or moderate in severity. Doses at 400, 600, and 800 mcg were associated with nausea and vomiting, requiring pharmacologic intervention. Hypoxia episodes requiring nasal cannula oxygenation were observed with 600mcg and 800mcg doses. Overall, single-dose fentanyl sublingual spray (100-800 mcg) was generally well tolerated, with greater incidences of AEs (e.g. nausea, vomiting, hypoxia) at higher doses. Doses up to 200 mcg may be safely administered to healthy opioid-naïve individuals with routine monitoring; doses

  14. Utility maximization and mode of payment

    NARCIS (Netherlands)

    Koning, R.H.; Ridder, G.; Heijmans, R.D.H.; Pollock, D.S.G.; Satorra, A.

    2000-01-01

    The implications of stochastic utility maximization in a model of choice of payment are examined. Three types of compatibility with utility maximization are distinguished: global compatibility, local compatibility on an interval, and local compatibility on a finite set of points. Keywords:

  15. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

    Science.gov (United States)

    Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

    2014-08-01

    Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

  16. Habitual coffee and tea drinkers experienced increases in blood pressure after consuming low to moderate doses of caffeine; these increases were larger upright than in the supine posture.

    Science.gov (United States)

    McMullen, Michael K; Whitehouse, Julie M; Shine, Gillian; Towell, Anthony

    2011-04-01

    Caffeine users have been encouraged to consume caffeine regularly to maintain their caffeine tolerance and so avoid caffeine's acute pressor effects. In controlled conditions complete caffeine tolerance to intervention doses of 250 mg develops rapidly following several days of caffeine ingestion, nevertheless, complete tolerance is not evident for lower intervention doses. Similarly complete caffeine tolerance to 250 mg intervention doses has been demonstrated in habitual coffee and tea drinkers' but for lower intervention doses complete tolerance is not evident. This study investigated a group of habitual caffeine users following their self-determined consumption pattern involving two to six servings daily. Cardiovascular responses following the ingestion of low to moderate amounts caffeine (67, 133 and 200 mg) were compared with placebo in a double-blind, randomised design without caffeine abstinence. Pre-intervention and post-intervention (30 and 60 min) 90 s continuous cardiovascular recordings were obtained with the Finometer in both the supine and upright postures. Participants were 12 healthy habitual coffee and tea drinkers (10 female, mean age 36). Doses of 67 and 133 mg increased systolic pressure in both postures while in the upright posture diastolic pressure and aortic impedance increased while arterial compliance decreased. These vascular changes were larger upright than supine for 133 mg caffeine. Additionally 67 mg caffeine increased dp/dt and indexed peripheral resistance in the upright posture. For 200 mg caffeine there was complete caffeine tolerance. Cardiovascular responses to caffeine appear to be associated with the size of the intervention dose. Habitual tea and coffee drinking does not generate complete tolerance to caffeine as has been previously suggested. Both the type and the extent of caffeine induced cardiovascular changes were influenced by posture.

  17. Engineering tolerance to industrially relevant stress factors in yeast cell factories.

    Science.gov (United States)

    Deparis, Quinten; Claes, Arne; Foulquié-Moreno, Maria R; Thevelein, Johan M

    2017-06-01

    The main focus in development of yeast cell factories has generally been on establishing optimal activity of heterologous pathways and further metabolic engineering of the host strain to maximize product yield and titer. Adequate stress tolerance of the host strain has turned out to be another major challenge for obtaining economically viable performance in industrial production. Although general robustness is a universal requirement for industrial microorganisms, production of novel compounds using artificial metabolic pathways presents additional challenges. Many of the bio-based compounds desirable for production by cell factories are highly toxic to the host cells in the titers required for economic viability. Artificial metabolic pathways also turn out to be much more sensitive to stress factors than endogenous pathways, likely because regulation of the latter has been optimized in evolution in myriads of environmental conditions. We discuss different environmental and metabolic stress factors with high relevance for industrial utilization of yeast cell factories and the experimental approaches used to engineer higher stress tolerance. Improving stress tolerance in a predictable manner in yeast cell factories should facilitate their widespread utilization in the bio-based economy and extend the range of products successfully produced in large scale in a sustainable and economically profitable way. © FEMS 2017.

  18. Engineering tolerance to industrially relevant stress factors in yeast cell factories

    Science.gov (United States)

    Deparis, Quinten; Claes, Arne; Foulquié-Moreno, Maria R.

    2017-01-01

    Abstract The main focus in development of yeast cell factories has generally been on establishing optimal activity of heterologous pathways and further metabolic engineering of the host strain to maximize product yield and titer. Adequate stress tolerance of the host strain has turned out to be another major challenge for obtaining economically viable performance in industrial production. Although general robustness is a universal requirement for industrial microorganisms, production of novel compounds using artificial metabolic pathways presents additional challenges. Many of the bio-based compounds desirable for production by cell factories are highly toxic to the host cells in the titers required for economic viability. Artificial metabolic pathways also turn out to be much more sensitive to stress factors than endogenous pathways, likely because regulation of the latter has been optimized in evolution in myriads of environmental conditions. We discuss different environmental and metabolic stress factors with high relevance for industrial utilization of yeast cell factories and the experimental approaches used to engineer higher stress tolerance. Improving stress tolerance in a predictable manner in yeast cell factories should facilitate their widespread utilization in the bio-based economy and extend the range of products successfully produced in large scale in a sustainable and economically profitable way. PMID:28586408

  19. Fecundity compensation and tolerance to a sterilizing pathogen in Daphnia.

    Science.gov (United States)

    Vale, P F; Little, T J

    2012-09-01

    Hosts are armed with several lines of defence in the battle against parasites: they may prevent the establishment of infection, reduce parasite growth once infected or persevere through mechanisms that reduce the damage caused by infection, called tolerance. Studies on tolerance in animals have focused on mortality, and sterility tolerance has not been investigated experimentally. Here, we tested for genetic variation in the multiple steps of defence when the invertebrate Daphnia magna is infected with the sterilizing bacterial pathogen Pasteuria ramosa: anti-infection resistance, anti-growth resistance and the ability to tolerate sterilization once infected. When exposed to nine doses of a genetically diverse pathogen inoculum, six host genotypes varied in their average susceptibility to infection and in their parasite loads once infected. How host fecundity changed with increasing parasite loads did not vary between genotypes, indicating that there was no genetic variation for this measure of fecundity tolerance. However, genotypes differed in their level of fecundity compensation under infection, and we discuss how, by increasing host fitness without targeting parasite densities, fecundity compensation is consistent with the functional definition of tolerance. Such infection-induced life-history shifts are not traditionally considered to be part of the immune response, but may crucially reduce harm (in terms of fitness loss) caused by disease, and are a distinct source of selection on pathogens. © 2012 The Authors. Journal of Evolutionary Biology © 2012 European Society For Evolutionary Biology.

  20. Acute radiation reactions in oral and pharyngeal mucosa: tolerable levels in altered fractionation schedules

    International Nuclear Information System (INIS)

    Fowler, Jack F.; Harari, Paul M.; Leborgne, Felix; Leborgne, Jose H.

    2003-01-01

    Purpose:To investigate whether a predictive estimate can be obtained for a 'tolerance level' of acute oral and pharyngeal mucosal reactions in patients receiving head and neck radiotherapy, using an objective set of dose and time data. Materials and methods:Several dozen radiotherapy schedules for treating head and neck cancer have been reviewed, together with published estimates of whether they were tolerated or (in a number of schedules) not. Those closest to the borderline were given detailed analysis. Total doses and biologically effective doses (BED or ERD) were calculated for a range of starting times of cellular repopulation and rates of daily proliferation. Starting times of proliferation from 5 to 10 days and daily cellular doubling rates of 1-3 days were considered. The standard published form of BED with its linear overall time factor was used: BED=nd1+((d)/(α/β))-((Ln2T-T k )/(αT p )) (see text for parameters). Results: A clear progression from acceptable to intolerable mucosal reactions was found, which correlated with total biologically effective dose (BED in our published modeling), for all the head and neck cancer radiotherapy schedules available for study, when ranked into categories of 'intolerable' or 'tolerable'. A review of published mechanisms for mucosal reactions suggested that practical schedules used for treatment caused stimulated compensatory proliferation to start at about 7 days. The starting time of compensatory proliferation had little predictive value in our listing, so we chose the starting time of 7 days. Very short and very long daily doubling rates also had little reliability, so we suggest choosing a doubling time of 2.5 days as a datum. With these parameters a 'tolerance zone of uncertainty' could be identified which predicted acute-reaction acceptability or not of a schedule within a range of about 2-10 Gy in total BED. If concurrent chemoradiotherapy is used, our provisional suggestion is that this zone should be reduced