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Sample records for maximum doses tolerated

  1. 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

  2. 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

  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. 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

  5. Maximum permissible dose

    International Nuclear Information System (INIS)

    Anon.

    1979-01-01

    This chapter presents a historic overview of the establishment of radiation guidelines by various national and international agencies. The use of maximum permissible dose and maximum permissible body burden limits to derive working standards is discussed

  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 (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).

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. Encoding Strategy for Maximum Noise Tolerance Bidirectional Associative Memory

    National Research Council Canada - National Science Library

    Shen, Dan

    2003-01-01

    In this paper, the Basic Bidirectional Associative Memory (BAM) is extended by choosing weights in the correlation matrix, for a given set of training pairs, which result in a maximum noise tolerance set for BAM...

  13. Maximum concentrations at work and maximum biologically tolerable concentration for working materials 1991

    International Nuclear Information System (INIS)

    1991-01-01

    The meaning of the term 'maximum concentration at work' in regard of various pollutants is discussed. Specifically, a number of dusts and smokes are dealt with. The valuation criteria for maximum biologically tolerable concentrations for working materials are indicated. The working materials in question are corcinogeneous substances or substances liable to cause allergies or mutate the genome. (VT) [de

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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

  19. Ambulatory blood pressure parameters after canrenone addition to existing treatment regimens with maximum tolerated dose of angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor blockers plus hydrochlorothiazide in uncontrolled hypertensive patients

    Directory of Open Access Journals (Sweden)

    Guasti L

    2017-08-01

    Full Text Available Luigina Guasti,1,* Giovanni Gaudio,2,* Alessandro Lupi,3 Marinella D’Avino,4 Carla Sala,5,6 Amedeo Mugellini,7 Vito Vulpis,8 Salvatore Felis,9 Riccardo Sarzani,10,11 Massimo Vanasia,12 Pamela Maffioli,7 Giuseppe Derosa7 1Research Center on Dyslipidemia, Internal Medicine 1, University of Insubria, Varese, Italy; 2Internal Medicine Division, Ospedale Angelo Bellini, ASST Valle Olona Somma, Varese, Italy; 3Cardiology Unit, ASL VCO Verbania-Domodossola, Verbania, Italy; 4Unit for the Treatment of Arterial Hypertension, Ospedale Cardarelli, Napoli, Italy; 5Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy; 6Cardiovascular Unit, Fondazione IRCCSS Policlinico, Milano, Italy; 7Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; 8Unit for the Diagnosis and Treatment of Arterial Hypertension, Department of Internal Medicine, Policlinico di Bari, Bari, Italy; 9Cardiology Unit, Ospedale Garibaldi, Catania, Italy; 10ESH Center of Hypertension, Internal Medicine and Geriatrics, University Politecnica delle Marche, Ancona, Italy; 11IRCCS-INRCA, Ancona, Italy; 12THERABEL GiEnne Pharma, Milano, Italy *These authors contributed equally to this work Background: Blockade of the renin–angiotensin–aldosterone system is a cornerstone in cardiovascular disease prevention and hypertension treatment. The relevance of ambulatory blood pressure monitoring (ABPM has been widely confirmed for both increasing the accuracy of blood pressure (BP measurements, particularly in pharmacological trials, and focusing on 24 h BP prognostic parameters. The aim of this study was to assess the effects of canrenone addition on ambulatory BP in uncontrolled hypertensive patients already treated with the highest tolerated dose of angiotensin-converting enzyme (ACE inhibitors or angiotensin II type 1 receptor (AT1R antagonists plus hydrochlorothiazide (HCT. Methods: ABPM was performed at baseline and after 3

  20. 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.

  1. Maximum likelihood estimation for cytogenetic dose-response curves

    International Nuclear Information System (INIS)

    Frome, E.L; DuFrain, R.J.

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa[γd + g(t, tau)d 2 ], where t is the time and d is dose. The coefficient of the d 2 term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure

  2. Maximum likelihood estimation for cytogenetic dose-response curves

    International Nuclear Information System (INIS)

    Frome, E.L.; DuFrain, R.J.

    1986-01-01

    In vitro dose-response curves are used to describe the relation between chromosome aberrations and radiation dose for human lymphocytes. The lymphocytes are exposed to low-LET radiation, and the resulting dicentric chromosome aberrations follow the Poisson distribution. The expected yield depends on both the magnitude and the temporal distribution of the dose. A general dose-response model that describes this relation has been presented by Kellerer and Rossi (1972, Current Topics on Radiation Research Quarterly 8, 85-158; 1978, Radiation Research 75, 471-488) using the theory of dual radiation action. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting dose-time-response models are intrinsically nonlinear in the parameters. A general-purpose maximum likelihood estimation procedure is described, and estimation for the nonlinear models is illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure

  3. Maximum likelihood estimation for cytogenetic dose-response curves

    Energy Technology Data Exchange (ETDEWEB)

    Frome, E.L; DuFrain, R.J.

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa(..gamma..d + g(t, tau)d/sup 2/), where t is the time and d is dose. The coefficient of the d/sup 2/ term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

  4. Savannah River Site radioiodine atmospheric releases and offsite maximum doses

    International Nuclear Information System (INIS)

    Marter, W.L.

    1990-01-01

    Radioisotopes of iodine have been released to the atmosphere from the Savannah River Site since 1955. The releases, mostly from the 200-F and 200-H Chemical Separations areas, consist of the isotopes, I-129 and 1-131. Small amounts of 1-131 and 1-133 have also been released from reactor facilities and the Savannah River Laboratory. This reference memorandum was issued to summarize our current knowledge of releases of radioiodines and resultant maximum offsite doses. This memorandum supplements the reference memorandum by providing more detailed supporting technical information. Doses reported in this memorandum from consumption of the milk containing the highest I-131 concentration following the 1961 1-131 release incident are about 1% higher than reported in the reference memorandum. This is the result of using unrounded 1-131 concentrations of I-131 in milk in this memo. It is emphasized here that this technical report does not constitute a dose reconstruction in the same sense as the dose reconstruction effort currently underway at Hanford. This report uses existing published data for radioiodine releases and existing transport and dosimetry models

  5. 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

  6. Hazards and maximum permissible doses of radiation for man

    International Nuclear Information System (INIS)

    Walinder, G.

    1977-11-01

    Maximum permissible dose levels are primarely based on risks for genetic damage and cancer. The reason for this is the observation that such late effects of radiation seem to arise even after doses that are to low to give rise to acute effects. In contrast to the tumour incidence found in irradiated human populations no genetic effects of radiation have been observed in man. This does not mean that genetic effects have not been induced but that it has been impossible to find an increase or to discern them among all the congenital defects, that can not be ascribed to the irradiation. As a consequence, the radiological risk estimation has been concentrated on the hazard of malignant diseases. Tumour risks are generally expressed as excess rates of incidence and mortality per million persons per rem. These figures are, however, not obtained from direct epidemiological observations but have been calculated from such data under the assumption of a linear relationship between effect and radiation dose. This formal extrapolation of observed data involves an uncertainty which, of course, is proportionately greater for the calculated effects in the millirem range. However, although the calculated tumour risks can not be said to be founded on direct scientific evidence, there are scientific reasons to believe that the figures derived from the formal extrapolations constitute an upper limit of possible ri02050

  7. Evaluating the maximum patient radiation dose in cardiac interventional procedures

    International Nuclear Information System (INIS)

    Kato, M.; Chida, K.; Sato, T.; Oosaka, H.; Tosa, T.; Kadowaki, K.

    2011-01-01

    Many of the X-ray systems that are used for cardiac interventional radiology provide no way to evaluate the patient maximum skin dose (MSD). The authors report a new method for evaluating the MSD by using the cumulative patient entrance skin dose (ESD), which includes a back-scatter factor and the number of cine-angiography frames during percutaneous coronary intervention (PCI). Four hundred consecutive PCI patients (315 men and 85 women) were studied. The correlation between the cumulative ESD and number of cine-angiography frames was investigated. The irradiation and overlapping fields were verified using dose-mapping software. A good correlation was found between the cumulative ESD and the number of cine-angiography frames. The MSD could be estimated using the proportion of cine-angiography frames used for the main angle of view relative to the total number of cine-angiography frames and multiplying this by the cumulative ESD. The average MSD (3.0±1.9 Gy) was lower than the average cumulative ESD (4.6±2.6 Gy). This method is an easy way to estimate the MSD during PCI. (authors)

  8. 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)

  9. 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

  10. 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:

  11. Application of maximum values for radiation exposure and principles for the calculation of radiation doses

    International Nuclear Information System (INIS)

    2007-08-01

    The guide presents the definitions of equivalent dose and effective dose, the principles for calculating these doses, and instructions for applying their maximum values. The limits (Annual Limit on Intake and Derived Air Concentration) derived from dose limits are also presented for the purpose of monitoring exposure to internal radiation. The calculation of radiation doses caused to a patient from medical research and treatment involving exposure to ionizing radiation is beyond the scope of this ST Guide

  12. Measurement and estimation of maximum skin dose to the patient for different interventional procedures

    International Nuclear Information System (INIS)

    Cheng Yuxi; Liu Lantao; Wei Kedao; Yu Peng; Yan Shulin; Li Tianchang

    2005-01-01

    Objective: To determine the dose distribution and maximum skin dose to the patient for four interventional procedures: coronary angiography (CA), hepatic angiography (HA), radiofrequency ablation (RF) and cerebral angiography (CAG), and to estimate the definitive effect of radiation on skin. Methods: Skin dose was measured using LiF: Mg, Cu, P TLD chips. A total of 9 measuring points were chosen on the back of the patient with two TLDs placed at each point, for CA, HA and RF interventional procedures, whereas two TLDs were placed on one point each at the postero-anterior (PA) and lateral side (LAT) respectively, during the CAG procedure. Results: The results revealed that the maximum skin dose to the patient was 1683.91 mGy for the HA procedure with a mean value of 607.29 mGy. The maximum skin dose at the PA point was 959.3 mGy for the CAG with a mean value of 418.79 mGy; While the maximum and the mean doses at the LAT point were 704 mGy and 191.52 mGy, respectively. For the RF procedure the maximum dose was 853.82 mGy and the mean was 219.67 mGy. For the CA procedure the maximum dose was 456.1 mGy and the mean was 227.63 mGy. Conclusion: All the measured dose values in this study are estimated ones which could not provide the accurate maximum value because it is difficult to measure using a great deal of TLDs. On the other hand, the small area of skin exposed to high dose could be missed as the distribution of the dose is successive. (authors)

  13. The tolerance efficiency of Panicum maximum and Helianthus annuus in TNT-contaminated soil and nZVI-contaminated soil.

    Science.gov (United States)

    Jiamjitrpanich, Waraporn; Parkpian, Preeda; Polprasert, Chongrak; Laurent, François; Kosanlavit, Rachain

    2012-01-01

    This study was designed to compare the initial method for phytoremediation involving germination and transplantation. The study was also to determine the tolerance efficiency of Panicum maximum (Purple guinea grass) and Helianthus annuus (Sunflower) in TNT-contaminated soil and nZVI-contaminated soil. It was found that the transplantation of Panicum maximum and Helianthus annuus was more suitable than germination as the initiate method of nano-phytoremediation potting test. The study also showed that Panicum maximum was more tolerance than Helianthus annuus in TNT and nZVI-contaminated soil. Therefore, Panicum maximum in the transplantation method should be selected as a hyperaccumulated plant for nano-phytoremediation potting tests. Maximum tolerance dosage of Panicum maximum to TNT-concentration soil was 320 mg/kg and nZVI-contaminated soil was 1000 mg/kg in the transplantation method.

  14. Maximum skin dose assessment in interventional cardiology: large area detectors and calculation methods

    International Nuclear Information System (INIS)

    Quail, E.; Petersol, A.

    2002-01-01

    Advances in imaging technology have facilitated the development of increasingly complex radiological procedures for interventional radiology. Such interventional procedures can involve significant patient exposure, although often represent alternatives to more hazardous surgery or are the sole method for treatment. Interventional radiology is already an established part of mainstream medicine and is likely to expand further with the continuing development and adoption of new procedures. Between all medical exposures, interventional radiology is first of the list of the more expansive radiological practice in terms of effective dose per examination with a mean value of 20 mSv. Currently interventional radiology contribute 4% to the annual collective dose, in spite of contributing to total annual frequency only 0.3% but considering the perspectives of this method can be expected a large expansion of this value. In IR procedures the potential for deterministic effects on the skin is a risk to be taken into account together with stochastic long term risk. Indeed, the International Commission on Radiological Protection (ICRP) in its publication No 85, affirms that the patient dose of priority concern is the absorbed dose in the area of skin that receives the maximum dose during an interventional procedure. For the mentioned reasons, in IR it is important to give to practitioners information on the dose received by the skin of the patient during the procedure. In this paper maximum local skin dose (MSD) is called the absorbed dose in the area of skin receiving the maximum dose during an interventional procedure

  15. 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)

  16. 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.

  17. A Fourier analysis on the maximum acceptable grid size for discrete proton beam dose calculation

    International Nuclear Information System (INIS)

    Li, Haisen S.; Romeijn, H. Edwin; Dempsey, James F.

    2006-01-01

    We developed an analytical method for determining the maximum acceptable grid size for discrete dose calculation in proton therapy treatment plan optimization, so that the accuracy of the optimized dose distribution is guaranteed in the phase of dose sampling and the superfluous computational work is avoided. The accuracy of dose sampling was judged by the criterion that the continuous dose distribution could be reconstructed from the discrete dose within a 2% error limit. To keep the error caused by the discrete dose sampling under a 2% limit, the dose grid size cannot exceed a maximum acceptable value. The method was based on Fourier analysis and the Shannon-Nyquist sampling theorem as an extension of our previous analysis for photon beam intensity modulated radiation therapy [J. F. Dempsey, H. E. Romeijn, J. G. Li, D. A. Low, and J. R. Palta, Med. Phys. 32, 380-388 (2005)]. The proton beam model used for the analysis was a near mono-energetic (of width about 1% the incident energy) and monodirectional infinitesimal (nonintegrated) pencil beam in water medium. By monodirection, we mean that the proton particles are in the same direction before entering the water medium and the various scattering prior to entrance to water is not taken into account. In intensity modulated proton therapy, the elementary intensity modulation entity for proton therapy is either an infinitesimal or finite sized beamlet. Since a finite sized beamlet is the superposition of infinitesimal pencil beams, the result of the maximum acceptable grid size obtained with infinitesimal pencil beam also applies to finite sized beamlet. The analytic Bragg curve function proposed by Bortfeld [T. Bortfeld, Med. Phys. 24, 2024-2033 (1997)] was employed. The lateral profile was approximated by a depth dependent Gaussian distribution. The model included the spreads of the Bragg peak and the lateral profiles due to multiple Coulomb scattering. The dependence of the maximum acceptable dose grid size on the

  18. Application of maximum values for radiation exposure and principles for the calculation of radiation dose

    International Nuclear Information System (INIS)

    2000-01-01

    The guide sets out the mathematical definitions and principles involved in the calculation of the equivalent dose and the effective dose, and the instructions concerning the application of the maximum values of these quantities. further, for monitoring the dose caused by internal radiation, the guide defines the limits derived from annual dose limits (the Annual Limit on Intake and the Derived Air Concentration). Finally, the guide defines the operational quantities to be used in estimating the equivalent dose and the effective dose, and also sets out the definitions of some other quantities and concepts to be used in monitoring radiation exposure. The guide does not include the calculation of patient doses carried out for the purposes of quality assurance

  19. Application of maximum values for radiation exposure and principles for the calculation of radiation dose

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2000-07-01

    The guide sets out the mathematical definitions and principles involved in the calculation of the equivalent dose and the effective dose, and the instructions concerning the application of the maximum values of these quantities. further, for monitoring the dose caused by internal radiation, the guide defines the limits derived from annual dose limits (the Annual Limit on Intake and the Derived Air Concentration). Finally, the guide defines the operational quantities to be used in estimating the equivalent dose and the effective dose, and also sets out the definitions of some other quantities and concepts to be used in monitoring radiation exposure. The guide does not include the calculation of patient doses carried out for the purposes of quality assurance.

  20. 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.

  1. Effect of the Maximum Dose on White Matter Fiber Bundles Using Longitudinal Diffusion Tensor Imaging

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Tong; Chapman, Christopher H. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Tsien, Christina [Department of Radiation Oncology, Washington University at St Louis, St Louis, Missouri (United States); Kim, Michelle; Spratt, Daniel E.; Lawrence, Theodore S. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Cao, Yue, E-mail: yuecao@umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan (United States)

    2016-11-01

    Purpose: Previous efforts to decrease neurocognitive effects of radiation focused on sparing isolated cortical structures. We hypothesize that understanding temporal, spatial, and dosimetric patterns of radiation damage to whole-brain white matter (WM) after partial-brain irradiation might also be important. Therefore, we carried out a study to develop the methodology to assess radiation therapy (RT)–induced damage to whole-brain WM bundles. Methods and Materials: An atlas-based, automated WM tractography analysis was implemented to quantify longitudinal changes in indices of diffusion tensor imaging (DTI) of 22 major WM fibers in 33 patients with predominantly low-grade or benign brain tumors treated by RT. Six DTI scans per patient were performed from before RT to 18 months after RT. The DTI indices and planned doses (maximum and mean doses) were mapped onto profiles of each of 22 WM bundles. A multivariate linear regression was performed to determine the main dose effect as well as the influence of other clinical factors on longitudinal percentage changes in axial diffusivity (AD) and radial diffusivity (RD) from before RT. Results: Among 22 fiber bundles, AD or RD changes in 12 bundles were affected significantly by doses (P<.05), as the effect was progressive over time. In 9 elongated tracts, decreased AD or RD was significantly related to maximum doses received, consistent with a serial structure. In individual bundles, AD changes were up to 11.5% at the maximum dose locations 18 months after RT. The dose effect on WM was greater in older female patients than younger male patients. Conclusions: Our study demonstrates for the first time that the maximum dose to the elongated WM bundles causes post-RT damage in WM. Validation and correlative studies are necessary to determine the ability and impact of sparing these bundles on preserving neurocognitive function after RT.

  2. 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)

  3. 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

  4. 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

  5. Estimation of maximum credible atmospheric radioactivity concentrations and dose rates from nuclear tests

    International Nuclear Information System (INIS)

    Telegadas, K.

    1979-01-01

    A simple technique is presented for estimating maximum credible gross beta air concentrations from nuclear detonations in the atmosphere, based on aircraft sampling of radioactivity following each Chinese nuclear test from 1964 to 1976. The calculated concentration is a function of the total yield and fission yield, initial vertical radioactivity distribution, time after detonation, and rate of horizontal spread of the debris with time. calculated maximum credible concentrations are compared with the highest concentrations measured during aircraft sampling. The technique provides a reasonable estimate of maximum air concentrations from 1 to 10 days after a detonation. An estimate of the whole-body external gamma dose rate corresponding to the maximum credible gross beta concentration is also given. (author)

  6. SU-E-T-578: On Definition of Minimum and Maximum Dose for Target Volume

    Energy Technology Data Exchange (ETDEWEB)

    Gong, Y; Yu, J; Xiao, Y [Thomas Jefferson University Hospital, Philadelphia, PA (United States)

    2015-06-15

    Purpose: This study aims to investigate the impact of different minimum and maximum dose definitions in radiotherapy treatment plan quality evaluation criteria by using tumor control probability (TCP) models. Methods: Dosimetric criteria used in RTOG 1308 protocol are used in the investigation. RTOG 1308 is a phase III randomized trial comparing overall survival after photon versus proton chemoradiotherapy for inoperable stage II-IIIB NSCLC. The prescription dose for planning target volume (PTV) is 70Gy. Maximum dose (Dmax) should not exceed 84Gy and minimum dose (Dmin) should not go below 59.5Gy in order for the plan to be “per protocol” (satisfactory).A mathematical model that simulates the characteristics of PTV dose volume histogram (DVH) curve with normalized volume is built. The Dmax and Dmin are noted as percentage volumes Dη% and D(100-δ)%, with η and d ranging from 0 to 3.5. The model includes three straight line sections and goes through four points: D95%= 70Gy, Dη%= 84Gy, D(100-δ)%= 59.5 Gy, and D100%= 0Gy. For each set of η and δ, the TCP value is calculated using the inhomogeneously irradiated tumor logistic model with D50= 74.5Gy and γ50=3.52. Results: TCP varies within 0.9% with η; and δ values between 0 and 1. With η and η varies between 0 and 2, TCP change was up to 2.4%. With η and δ variations from 0 to 3.5, maximum of 8.3% TCP difference is seen. Conclusion: When defined maximum and minimum volume varied more than 2%, significant TCP variations were seen. It is recommended less than 2% volume used in definition of Dmax or Dmin for target dosimetric evaluation criteria. This project was supported by NIH grants U10CA180868, U10CA180822, U24CA180803, U24CA12014 and PA CURE Grant.

  7. SU-E-T-578: On Definition of Minimum and Maximum Dose for Target Volume

    International Nuclear Information System (INIS)

    Gong, Y; Yu, J; Xiao, Y

    2015-01-01

    Purpose: This study aims to investigate the impact of different minimum and maximum dose definitions in radiotherapy treatment plan quality evaluation criteria by using tumor control probability (TCP) models. Methods: Dosimetric criteria used in RTOG 1308 protocol are used in the investigation. RTOG 1308 is a phase III randomized trial comparing overall survival after photon versus proton chemoradiotherapy for inoperable stage II-IIIB NSCLC. The prescription dose for planning target volume (PTV) is 70Gy. Maximum dose (Dmax) should not exceed 84Gy and minimum dose (Dmin) should not go below 59.5Gy in order for the plan to be “per protocol” (satisfactory).A mathematical model that simulates the characteristics of PTV dose volume histogram (DVH) curve with normalized volume is built. The Dmax and Dmin are noted as percentage volumes Dη% and D(100-δ)%, with η and d ranging from 0 to 3.5. The model includes three straight line sections and goes through four points: D95%= 70Gy, Dη%= 84Gy, D(100-δ)%= 59.5 Gy, and D100%= 0Gy. For each set of η and δ, the TCP value is calculated using the inhomogeneously irradiated tumor logistic model with D50= 74.5Gy and γ50=3.52. Results: TCP varies within 0.9% with η; and δ values between 0 and 1. With η and η varies between 0 and 2, TCP change was up to 2.4%. With η and δ variations from 0 to 3.5, maximum of 8.3% TCP difference is seen. Conclusion: When defined maximum and minimum volume varied more than 2%, significant TCP variations were seen. It is recommended less than 2% volume used in definition of Dmax or Dmin for target dosimetric evaluation criteria. This project was supported by NIH grants U10CA180868, U10CA180822, U24CA180803, U24CA12014 and PA CURE Grant

  8. Change in the alpha criterion policy: variable based on the maximum individual dose function

    International Nuclear Information System (INIS)

    Freitas Acosta Perez, C. de; Sordi, G.M.A.A.

    2006-01-01

    The Alpha value is an extremely important criterion because it determines the time that a country takes to achieve its proposals in order to decrease the workers doses involved with ionizing radiation sources. Currently the countries adopt a single value for alpha based on the annual gross national product, GNP, per capita. The aim of this paper is to show that the selection of a curve for the alpha in place of a single value would be more efficient. This curve would provide alpha values that would will be constraints to the biggest individual doses presented in each optimization process as applied both to designs and to operations. These maximum individual doses would represent the dose distribution among the workers team. To build the curve, the alpha values suggested are not based on the GNP per capita but on a distribution function of the maximum individual doses and on the time necessary to reach the proposal of 1/10 of the annual dose limit foreseen in the sequential optimization processes, that is to reach the region where the individual doses are considered acceptable. So, the differential equations will be - d X/dS =α(H m ax). To clarify our sight about the alpha value we started using the uranium mine example presented in ICRP publication 55, adopting the decision-aiding technique known as extended cost-benefit. for right. Then we used the same example in a hypothetical curve with portions: constant, linear, quadratic and exponential. Eventually we discussed briefly the different shapes of the curves that the alpha value can assume in function of the individual doses. Each of these shapes can correspond to the so called 'risk neutral attitude', 'risk adverse attitude' or 'risk prone attitude' suggested in the appendix B of the ICRP publication 55

  9. Studies on the establishment of maximum permissible exposure dose for reference Korean

    International Nuclear Information System (INIS)

    Kim, Y.J.; Lee, K.S.; Chun, K.C.; Kim, C.B.; Chung, K.H.; Kim, S.L.; Kim, M.J.

    1981-01-01

    In order to establish the Reference Korean and maximum permissible exposure dose of Reference Korean, for the first year a total of 9,758 males and 7,019 females were surveyed for the height, weight, a body surface area, and a total of 879 individuals of 180 households located in different 30 localities were analyzed for food consumption and a total of radioactive substances (β-ray) contained in food per capita per day. In this report the external and internal exposure dose were also estimated on the basis of data mostly published in other country as well as in Korea in part

  10. Calculate the maximum expected dose for technical radio physicists a cobalt machine

    International Nuclear Information System (INIS)

    Avila Avila, Rafael; Perez Velasquez, Reytel; Gonzalez Lapez, Nadia

    2009-01-01

    Considering the daily operations carried out by technicians Radiophysics Medical Service Department of Radiation Oncology Hospital V. General Teaching I. Lenin in the city of Holguin, during a working week (Between Monday and Friday) as an important element in calculating the maximum expected dose (MDE). From the exponential decay law which is subject the source activity, we propose corrections to the cumulative doses in the weekly period, leading to obtaining a formula which takes into a cumulative dose during working days and sees no dose accumulation of rest days (Saturday and Sunday). The estimate factor correction is made from a power series expansion convergent is truncated at the n-th term coincides with the week period for which you want to calculate the dose. As initial condition is adopted ambient dose equivalent rate as a given, which allows estimate MDE in the moments after or before this. Calculations were proposed use of an Excel spreadsheet that allows simple and accessible processing the formula obtained. (author)

  11. Prediction of the maximum dosage to man from the fallout of nuclear devices V. Estimation of the maximum dose from internal emitters in aquatic food supply

    International Nuclear Information System (INIS)

    Tamplin, A.R.; Fisher, H.L.; Chapman, W.H.

    1968-01-01

    A method is described for estimating the maximum internal dose that could result from the radionuclides released to an aquatic environment. By means of this analysis one can identify the nuclides that could contribute most to the internal dose, and determine the contribution of each nuclide to the total dose. The calculations required to estimate the maximum dose to an infant's bone subsequent to the construction of a sea-level canal are presented to illustrate the overall method. The results are shown to serve the basic aims of preshot rad-safe analysis and of guidance for postshot documentation. The usefulness of the analysis in providing guidance for device design is further pointed out. (author)

  12. Dose assessment around TR-2 reactor due to maximum credible accident

    International Nuclear Information System (INIS)

    Turgut, M. H.; Adalioglu, U.; Aytekin, A.

    2001-01-01

    The revision of safety analysis report of TR-2 research reactor had been initiated in 1995. The whole accident analysis and accepted scenario for maximum credible accident has been revised according to the new safety concepts and the impact to be given to the environment due to this scenario has been assessed. This paper comprises all results of these calculations. The accepted maximum credible accident scenario is the partial blockage of the whole reactor core which resulted in the release of 25% of the core inventory. The DOSER code which uses very conservative modelling of atmospheric distributions were modified for the assessment calculations. Pasquill conditions based on the local weather observations, topography, and building affects were considered. The thyroid and whole body doses for 16 sectors and up to 10 km of distance around CNAEM were obtained. Release models were puff and a prolonged one of two hours of duration. Release fractions for the active isotopes were chosen from literature which were realistic

  13. Main clinical, therapeutic and technical factors related to patient's maximum skin dose in interventional cardiology procedures

    Science.gov (United States)

    Journy, N; Sinno-Tellier, S; Maccia, C; Le Tertre, A; Pirard, P; Pagès, P; Eilstein, D; Donadieu, J; Bar, O

    2012-01-01

    Objective The study aimed to characterise the factors related to the X-ray dose delivered to the patient's skin during interventional cardiology procedures. Methods We studied 177 coronary angiographies (CAs) and/or percutaneous transluminal coronary angioplasties (PTCAs) carried out in a French clinic on the same radiography table. The clinical and therapeutic characteristics, and the technical parameters of the procedures, were collected. The dose area product (DAP) and the maximum skin dose (MSD) were measured by an ionisation chamber (Diamentor; Philips, Amsterdam, The Netherlands) and radiosensitive film (Gafchromic; International Specialty Products Advanced Materials Group, Wayne, NJ). Multivariate analyses were used to assess the effects of the factors of interest on dose. Results The mean MSD and DAP were respectively 389 mGy and 65 Gy cm−2 for CAs, and 916 mGy and 69 Gy cm−2 for PTCAs. For 8% of the procedures, the MSD exceeded 2 Gy. Although a linear relationship between the MSD and the DAP was observed for CAs (r=0.93), a simple extrapolation of such a model to PTCAs would lead to an inadequate assessment of the risk, especially for the highest dose values. For PTCAs, the body mass index, the therapeutic complexity, the fluoroscopy time and the number of cine frames were independent explanatory factors of the MSD, whoever the practitioner was. Moreover, the effect of technical factors such as collimation, cinematography settings and X-ray tube orientations on the DAP was shown. Conclusion Optimising the technical options for interventional procedures and training staff on radiation protection might notably reduce the dose and ultimately avoid patient skin lesions. PMID:22457404

  14. 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...

  15. 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

  16. Neutron spectrum and dose-equivalent in shuttle flights during solar maximum

    Energy Technology Data Exchange (ETDEWEB)

    Keith, J E; Badhwar, G D; Lindstrom, D J [National Aeronautics and Space Administration, Houston, TX (United States). Lyndon B. Johnson Space Center

    1992-01-01

    This paper presents unambiguous measurements of the spectrum of neutrons found in spacecraft during spaceflight. The neutron spectrum was measured from thermal energies to about 10 MeV using a completely passive system of metal foils as neutron detectors. These foils were exposed to the neutron flux bare, covered by thermal neutron absorbers (Gd) and inside moderators (Bonner spheres). This set of detectors was flown on three U.S. Space Shuttle flights, STS-28, STS-36 and STS-31, during the solar maximum. We show that the measurements of the radioactivity of these foils lead to a differential neutron energy spectrum in all three flights that can be represented by a power law, J(E){approx equal}E{sup -0.765} neutrons cm{sup -2} day {sup -1} MeV{sup -1}. We also show that the measurements are even better represented by a linear combination of the terrestrial neutron albedo and a spectrum of neutrons locally produced in a aluminium by protons, computed by a previous author. We use both approximations to the neutron spectrum to produce a worst case and most probable case for the neutron spectra and the resulting dose-equivalents, computed using ICRP-51 neutron fluence-dose conversion tables. We compare these to the skin dose-equivalents due to charged particles during the same flights. (author).

  17. An iterative method applied to optimize the design of PIN photodiodes for enhanced radiation tolerance and maximum light response

    International Nuclear Information System (INIS)

    Cedola, A.P.; Cappelletti, M.A.; Casas, G.; Peltzer y Blanca, E.L.

    2011-01-01

    An iterative method based on numerical simulations was developed to enhance the proton radiation tolerance and the responsivity of Si PIN photodiodes. The method allows to calculate the optimal values of the intrinsic layer thickness and the incident light wavelength, in function of the light intensity and the maximum proton fluence to be supported by the device. These results minimize the effects of radiation on the total reverse current of the photodiode and maximize its response to light. The implementation of the method is useful in the design of devices whose operation point should not suffer variations due to radiation.

  18. 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…

  19. EPR spectrum deconvolution and dose assessment of fossil tooth enamel using maximum likelihood common factor analysis

    International Nuclear Information System (INIS)

    Vanhaelewyn, G.; Callens, F.; Gruen, R.

    2000-01-01

    In order to determine the components which give rise to the EPR spectrum around g = 2 we have applied Maximum Likelihood Common Factor Analysis (MLCFA) on the EPR spectra of enamel sample 1126 which has previously been analysed by continuous wave and pulsed EPR as well as EPR microscopy. MLCFA yielded agreeing results on three sets of X-band spectra and the following components were identified: an orthorhombic component attributed to CO - 2 , an axial component CO 3- 3 , as well as four isotropic components, three of which could be attributed to SO - 2 , a tumbling CO - 2 and a central line of a dimethyl radical. The X-band results were confirmed by analysis of Q-band spectra where three additional isotropic lines were found, however, these three components could not be attributed to known radicals. The orthorhombic component was used to establish dose response curves for the assessment of the past radiation dose, D E . The results appear to be more reliable than those based on conventional peak-to-peak EPR intensity measurements or simple Gaussian deconvolution methods

  20. Comparison of measured and estimated maximum skin doses during CT fluoroscopy lung biopsies

    Energy Technology Data Exchange (ETDEWEB)

    Zanca, F., E-mail: Federica.Zanca@med.kuleuven.be [Department of Radiology, Leuven University Center of Medical Physics in Radiology, UZ Leuven, Herestraat 49, 3000 Leuven, Belgium and Imaging and Pathology Department, UZ Leuven, Herestraat 49, Box 7003 3000 Leuven (Belgium); Jacobs, A. [Department of Radiology, Leuven University Center of Medical Physics in Radiology, UZ Leuven, Herestraat 49, 3000 Leuven (Belgium); Crijns, W. [Department of Radiotherapy, UZ Leuven, Herestraat 49, 3000 Leuven (Belgium); De Wever, W. [Imaging and Pathology Department, UZ Leuven, Herestraat 49, Box 7003 3000 Leuven, Belgium and Department of Radiology, UZ Leuven, Herestraat 49, 3000 Leuven (Belgium)

    2014-07-15

    Purpose: To measure patient-specific maximum skin dose (MSD) associated with CT fluoroscopy (CTF) lung biopsies and to compare measured MSD with the MSD estimated from phantom measurements, as well as with the CTDIvol of patient examinations. Methods: Data from 50 patients with lung lesions who underwent a CT fluoroscopy-guided biopsy were collected. The CT protocol consisted of a low-kilovoltage (80 kV) protocol used in combination with an algorithm for dose reduction to the radiology staff during the interventional procedure, HandCare (HC). MSD was assessed during each intervention using EBT2 gafchromic films positioned on patient skin. Lesion size, position, total fluoroscopy time, and patient-effective diameter were registered for each patient. Dose rates were also estimated at the surface of a normal-size anthropomorphic thorax phantom using a 10 cm pencil ionization chamber placed at every 30°, for a full rotation, with and without HC. Measured MSD was compared with MSD values estimated from the phantom measurements and with the cumulative CTDIvol of the procedure. Results: The median measured MSD was 141 mGy (range 38–410 mGy) while the median cumulative CTDIvol was 72 mGy (range 24–262 mGy). The ratio between the MSD estimated from phantom measurements and the measured MSD was 0.87 (range 0.12–4.1) on average. In 72% of cases the estimated MSD underestimated the measured MSD, while in 28% of the cases it overestimated it. The same trend was observed for the ratio of cumulative CTDIvol and measured MSD. No trend was observed as a function of patient size. Conclusions: On average, estimated MSD from dose rate measurements on phantom as well as from CTDIvol of patient examinations underestimates the measured value of MSD. This can be attributed to deviations of the patient's body habitus from the standard phantom size and to patient positioning in the gantry during the procedure.

  1. Comparison of measured and estimated maximum skin doses during CT fluoroscopy lung biopsies

    International Nuclear Information System (INIS)

    Zanca, F.; Jacobs, A.; Crijns, W.; De Wever, W.

    2014-01-01

    Purpose: To measure patient-specific maximum skin dose (MSD) associated with CT fluoroscopy (CTF) lung biopsies and to compare measured MSD with the MSD estimated from phantom measurements, as well as with the CTDIvol of patient examinations. Methods: Data from 50 patients with lung lesions who underwent a CT fluoroscopy-guided biopsy were collected. The CT protocol consisted of a low-kilovoltage (80 kV) protocol used in combination with an algorithm for dose reduction to the radiology staff during the interventional procedure, HandCare (HC). MSD was assessed during each intervention using EBT2 gafchromic films positioned on patient skin. Lesion size, position, total fluoroscopy time, and patient-effective diameter were registered for each patient. Dose rates were also estimated at the surface of a normal-size anthropomorphic thorax phantom using a 10 cm pencil ionization chamber placed at every 30°, for a full rotation, with and without HC. Measured MSD was compared with MSD values estimated from the phantom measurements and with the cumulative CTDIvol of the procedure. Results: The median measured MSD was 141 mGy (range 38–410 mGy) while the median cumulative CTDIvol was 72 mGy (range 24–262 mGy). The ratio between the MSD estimated from phantom measurements and the measured MSD was 0.87 (range 0.12–4.1) on average. In 72% of cases the estimated MSD underestimated the measured MSD, while in 28% of the cases it overestimated it. The same trend was observed for the ratio of cumulative CTDIvol and measured MSD. No trend was observed as a function of patient size. Conclusions: On average, estimated MSD from dose rate measurements on phantom as well as from CTDIvol of patient examinations underestimates the measured value of MSD. This can be attributed to deviations of the patient's body habitus from the standard phantom size and to patient positioning in the gantry during the procedure

  2. 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

  3. 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...

  4. 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

  5. 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

  6. [MAXIMUM SINGLE DOSE OF COLLOIDAL SILVER NEGATIVELY AFFECTS ERYTHROPOIESIS IN VITRO].

    Science.gov (United States)

    Tishevskayal, N V; Zakharovl, Y M; Bolotovl, A A; Arkhipenko, Yu V; Sazontova, T G

    2015-01-01

    Erythroblastic islets (EI) of rat bone marrow were cultured for 24 h in the presence of silver nanoparticles (1.07 · 10(-4) mg/ml; 1.07 · 10(-3) mg/ml; and 1.07 · 10(-2) mg/mL). The colloidal silver at 1.07 · 10(-3) mg/ml concentration inhibited the formation of new Elby disrupting contacts of bone marrow macrophages with CFU-E (erythropoiesis de novo) by 65.3% (p Colloidal silver nanoparticles suppressed the reconstruction of erythropoiesis and inhibited the formation of new EI by disrupting contacts of CFU-E and central macrophages with matured erythroidal "crown" (erythropoiesis de repeto). The colloidal silver concentration of 1.07 · 10(-3) mg/ml in the culture medium also reduced the number of self-reconstructing EI by 67.5% (p colloidal silver reduced this value by 93.7% (p Silver nanoparticles retarded maturation of erythroid cells at the stage of oxiphylic normoblast denucleation: 1.07 · 10(-3) mg/ml colloidal silver increased the number of mature El by 53% (p colloidal silver in concentration equivalent to the maximum single dose is related to the effect of silver nanoparticles rather than glycerol present in the colloidal suspension.

  7. 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.

  8. 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

  9. PRODUTIVIDADE DE CAPIM-MOMBAÇA (Panicum maximum, COM DIFERENTES DOSES DE BIOFERTILIZANTE / MOMBAÇA GRASS PRODUCTIVITY (Panicum maximum, WITH DIFFERENT DOSES OF BIOFERTILIZER

    Directory of Open Access Journals (Sweden)

    A. Simonetti

    2016-03-01

    Full Text Available O presente estudo teve por objetivo verificar a influência da aplicação do dejeto de bovino leiteiro tratados em biodigestores anaeróbios, na forma de biofertilizante, sobre a produtividade da capim Mombaça, em condições de sequeiro.  O trabalho foi conduzido no Instituto de Biotecnologia – IBIOTEC, pertencente à UNIARA, Araraquara – SP. Para obtenção do biofertilizante, foi feita a diluição dos dejetos em água e armazenado em um biodigestor modelo indiano de fibra de vidro com capacidade útil de 1000 L, instalado no referido instituto. As fertilizações foram feitas a lanço após cada rebaixamento das parcelas. O delineamento utilizado foi em blocos casualizados, com quatro tratamentos e quatro repetições, com diferentes doses do biofertilizante, sendo: 0; 50m³; 100m³ e 200m³/ha-1.  As variáveis avaliadas foram: altura, produção por hectare (matéria seca e matéria verde, e qualidade bromatológica. Foram observados que os tratamentos que receberam a maior dosagem de biofertilizante, apresentaram maiores valores para produtividade Matéria Seca, Matéria Verde e teor de proteína. Conclui-se que a aplicação de biofertilizante é benéfico ao sistema de pastagem, porém suas doses devem ser estudadas e a sua resposta na produção pode obtidas a longo prazo.

  10. 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

  11. 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

  12. 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.

  13. Determination of the maximum individual dose exposure resulting from a hypothetical LEU plate-melt accident

    International Nuclear Information System (INIS)

    Abdelhady, Amr

    2013-01-01

    Highlights: ► Studying the radioactive release results from hypothetical plate-melt accident. ► Hotspot code was used to study the dose distributions around the reactor. ► A 90% decrease in the received dose in proper operation of filtration. ► The received dose is lower than the annual permissible dose after filtration. - Abstract: The objective of this study was to provide an estimate of the potential impact of accidental radioactive release from the testing cell of the Egyptian second research reactor ETRR-2 on the dose level of public around the reactor. The assessment was performed for two cases: an evaluation of the impact that accidental release has on the dose that would be received by public around the reactor in case of proper operation of testing cell filtration system; and an assessment of the potential dose in case of loss of testing cell filtration system. The results show that the filtration system has a great role in decreasing the dose received by an individual located outside the reactor to a dose level lower than the annual permissible dose

  14. 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.

  15. Maximum likelihood estimation of dose-response parameters for therapeutic operating characteristic (TOC) analysis of carcinoma of the nasopharynx

    International Nuclear Information System (INIS)

    Metz, C.E.; Tokars, R.P.; Kronman, H.B.; Griem, M.L.

    1982-01-01

    A Therapeutic Operating Characteristic (TOC) curve for radiation therapy plots, for all possible treatment doses, the probability of tumor ablation as a function of the probability of radiation-induced complication. Application of this analysis to actual therapeutic situation requires that dose-response curves for ablation and for complication be estimated from clinical data. We describe an approach in which ''maximum likelihood estimates'' of these dose-response curves are made, and we apply this approach to data collected on responses to radiotherapy for carcinoma of the nasopharynx. TOC curves constructed from the estimated dose-response curves are subject to moderately large uncertainties because of the limitations of available data.These TOC curves suggest, however, that treatment doses greater than 1800 rem may substantially increase the probability of tumor ablation with little increase in the risk of radiation-induced cervical myelopathy, especially for T1 and T2 tumors

  16. MAK and BAT values list 2016. Maximum permissible concentrations at the place of work and biological tolerance values for working materials

    International Nuclear Information System (INIS)

    2016-01-01

    The MAK and BAT values list 2016 includes the maximum permissible concentrations at the place of work and biological tolerance values for working materials. The following working materials are covered: carcinogenic working materials, sensitizing materials and aerosols. The report discusses the restriction of exposure peaks, skin resorption, MAK (maximum working place concentration) values during pregnancy, germ cell mutagens and specific working materials. Importance and application of BAT (biological working material tolerance) values, list of materials, carcinogens, biological guide values and reference values are also included.

  17. MAK and BAT values list 2014. Maximum permissible concentrations at the place of work and biological tolerance values for working materials

    International Nuclear Information System (INIS)

    2014-01-01

    The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2014 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

  18. MAK and BAT values list 2015. Maximum permissible concentrations at the place of work and biological tolerance values for working materials

    International Nuclear Information System (INIS)

    2015-01-01

    The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2015 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

  19. MAK and BAT values list 2017. Maximum permissible concentrations at the place of work and biological tolerance values for working materials

    International Nuclear Information System (INIS)

    2017-01-01

    The MAK and BAT values list 2017 includes the maximum permissible concentrations at the place of work and biological tolerance values for working materials. The following working materials are covered: carcinogenic working materials, sensitizing materials and aerosols. The report discusses the restriction of exposure peaks, skin resorption, MAK (maximum working place concentration) values during pregnancy, germ cell mutagens and specific working materials. Importance and application of BAT (biological working material tolerance) values, list of materials, carcinogens, biological guide values and reference values are also included.

  20. 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

  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. 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.

  3. 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)

  4. 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

  5. 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

  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. 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.

  8. 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.

  9. Tolerance

    DEFF Research Database (Denmark)

    Tønder, Lars

    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 d...... these alternatives by returning to the notion of tolerance as the endurance of pain, linking this notion to exemplars and theories relevant to the politics of multiculturalism, religious freedom, and free speech....

  10. 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

  11. 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

  12. 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

  13. 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.

  14. Effects of Minimum and Maximum Doses of Furosemide on Fractional Shortening Parameter in Echocardiography of the New Zealand White Rabbit

    Directory of Open Access Journals (Sweden)

    Roham Vali, Mohammad Nasrollahzadeh Masouleh* and Siamak Mashhady Rafie1

    2013-04-01

    Full Text Available There is no data on the effect of maximum and minimum doses of furosemide on heart's work performance and amount of fractional shortening (FS in echocardiography of rabbit. This study was designed to validate probability of the mentionable effect. Twenty-four healthy female New Zealand white rabbits were divided into four equal groups. Maximum and minimum doses of furosemide were used for the first and second groups and the injection solution for the third and fourth groups was sodium chloride 0.9% which had the same calculated volumes of furosemide for the first two groups, respectively. The left ventricle FS in statutory times (0, 2, 5, 15, 30 minutes was determined by echocardiography. Measurements of Mean±SD, maximum and minimum amounts for FS values in all groups before injection and in statutory times were calculated. Statistical analysis revealed non-significant correlation between the means of FS. The results of this study showed that furosemide can be used as a diuretic agent for preparing a window approach in abdominal ultrasonography examination with no harmful effect on cardiac function.

  15. 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

  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. 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.

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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.

  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. 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

  6. 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

  7. 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.

  8. 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

  9. Influence of the Target Vessel on the Location and Area of Maximum Skin Dose during Percutaneous Coronary Intervention

    International Nuclear Information System (INIS)

    Chida, K.; Fuda, K.; Kagaya, Y.; Saito, H.; Takai, Y.; Kohzuki, M.; Takahash i, S.; Yamada, S.; Zuguchi, M.

    2007-01-01

    Background: A number of cases involving radiation-associated patient skin injury attributable to percutaneous coronary intervention (PCI) have been reported. Knowledge of the location and area of the patient's maximum skin dose (MSD) in PCI is necessary to reduce the risk of skin injury. Purpose: To determine the location and area of the MSD in PCI, and separately analyze the effects of different target vessels. Material and Methods: 197 consecutive PCI procedures were studied, and the location and area of the MSD were calculated by a skin-dose mapping software program: Caregraph. The target vessels of the PCI procedures were divided into four groups based on the American Heart Association (AHA) classification. Results: The sites of the MSD for AHA no.1-3, AHA no.4, and AHA no.11-15 were located mainly on the right back skin, the lower right or center back skin, and the upper back skin areas, respectively, whereas the MSD sites for the AHA no. 5-10 PCI were widely spread. The MSD area for the AHA no. 4 PCI was larger than that for the AHA no. 11-15 PCI (P<0.0001). Conclusion: Although the radiation associated with PCI can be widely spread and variable, we observed a tendency regarding the location and area of the MSD when we separately analyzed the data for different target vessels. We recommend the use of a smaller radiation field size and the elimination of overlapping fields during PCI

  10. 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

  11. 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.

  12. 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)

  13. 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.

  14. The consequences of a reduction in the administratively applied maximum annual dose equivalent level for an individual in a group of occupationally exposed workers

    International Nuclear Information System (INIS)

    Harrison, N.T.

    1980-02-01

    An analysis is described for predicting the consequences of a reduction in the administratively applied maximum dose equivalent level to individuals in a group of workers occupationally exposed to ionising radiations, for the situation in which no changes are made to the working environment. This limitation of the maximum individual dose equivalent is accommodated by allowing the number of individuals in the working group to increase. The derivation of the analysis is given, together with worked examples, which highlight the important assumptions that have been made and the conclusions that can be drawn. The results are obtained in the form of the capacity of the particular working environment to accommodate the limitation of the maximum individual dose equivalent, the increase in the number of workers required to carry out the productive work and any consequent increase in the occupational collective dose equivalent. (author)

  15. Maximum dose angle for oblique incidence on primary beam protective barriers in the design of medical radiation therapy facilities

    International Nuclear Information System (INIS)

    Fondevila, Damian; Arbiser, Silvio; Sansogne, Rosana; Brunetto, Monica; Dosoretz, Bernardo

    2008-01-01

    Primary barrier determinations for the shielding of medical radiation therapy facilities are generally made assuming normal beam incidence on the barrier, since this is geometrically the most unfavorable condition for that shielding barrier whenever the occupation line is allowed to run along the barrier. However, when the occupation line (for example, the wall of an adjacent building) runs perpendicular to the barrier (especially roof barrier), then two opposing factors come in to play: increasing obliquity angle with respect to the barrier increases the attenuation, while the distance to the calculation point decreases, hence, increasing the dose. As a result, there exists an angle (α max ) for which the equivalent dose results in a maximum, constituting the most unfavorable geometric condition for that shielding barrier. Based on the usual NCRP Report No. 151 model, this article presents a simple formula for obtaining α max , which is a function of the thickness of the barrier (t E ) and the equilibrium tenth-value layer (TVL e ) of the shielding material for the nominal energy of the beam. It can be seen that α max increases for increasing TVL e (hence, beam energy) and decreases for increasing t E , with a range of variation that goes from 13 to 40 deg for concrete barriers thicknesses in the range of 50-300 cm and most commercially available teletherapy machines. This parameter has not been calculated in the existing literature for radiotherapy facilities design and has practical applications, as in calculating the required unoccupied roof shielding for the protection of a nearby building located in the plane of the primary beam rotation

  16. Maximum dose angle for oblique incidence on primary beam protective barriers in the design of medical radiation therapy facilities.

    Science.gov (United States)

    Fondevila, Damián; Arbiser, Silvio; Sansogne, Rosana; Brunetto, Mónica; Dosoretz, Bernardo

    2008-05-01

    Primary barrier determinations for the shielding of medical radiation therapy facilities are generally made assuming normal beam incidence on the barrier, since this is geometrically the most unfavorable condition for that shielding barrier whenever the occupation line is allowed to run along the barrier. However, when the occupation line (for example, the wall of an adjacent building) runs perpendicular to the barrier (especially roof barrier), then two opposing factors come in to play: increasing obliquity angle with respect to the barrier increases the attenuation, while the distance to the calculation point decreases, hence, increasing the dose. As a result, there exists an angle (alpha(max)) for which the equivalent dose results in a maximum, constituting the most unfavorable geometric condition for that shielding barrier. Based on the usual NCRP Report No. 151 model, this article presents a simple formula for obtaining alpha(max), which is a function of the thickness of the barrier (t(E)) and the equilibrium tenth-value layer (TVL(e)) of the shielding material for the nominal energy of the beam. It can be seen that alpha(max) increases for increasing TVL(e) (hence, beam energy) and decreases for increasing t(E), with a range of variation that goes from 13 to 40 deg for concrete barriers thicknesses in the range of 50-300 cm and most commercially available teletherapy machines. This parameter has not been calculated in the existing literature for radiotherapy facilities design and has practical applications, as in calculating the required unoccupied roof shielding for the protection of a nearby building located in the plane of the primary beam rotation.

  17. 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,

  18. 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

  19. 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.

  20. Estimated radiological doses to the maximumly exposed individual and downstream populations from releases of tritium, strontium-90, ruthenium-106, and cesium-137 from White Oak Dam

    International Nuclear Information System (INIS)

    Little, C.A.; Cotter, S.J.

    1980-01-01

    Concentrations of tritium, 90 Sr, 106 Ru, and 137 Cs in the Clinch River for 1978 were estimated by using the known 1978 releases of these nuclides from the White Oak Dam and diluting them by the integrated annual flow rate of the Clinch River. Estimates of 50-year dose commitment to a maximumly exposed individual were calculated for both aquatic and terestrial pathways of exposure. The maximumly exposed individual was assumed to reside at the mouth of White Oak Creek where it enters the Clinch River and obtain all foodstuffs and drinking water at that location. The estimated total-body dose from all pathways to the maximumly exposed individual as a result of 1978 releases was less than 1% of the dose expected from natural background. Using appropriate concentrations of to subject radionuclides diluted downstream, the doses to populations residing at Harriman, Kingston, Rockwood, Spring City, Soddy-Daisy, and Chattanooga were calculated for aquatic exposure pathways. The total-body dose estimated for aquatic pathways for the six cities was about 0.0002 times the expected dose from natural background. For the pathways considered in this report, the nuclide which contributed the largest fraction of dose was 90 Sr. The largest dose delivered by 90 Sr was to the bone of the subject individual or community

  1. 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)

  2. 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.

  3. 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

  4. SU-G-201-14: Is Maximum Skin Dose a Reliable Metric for Accelerated Partial Breast Irradiation with Brachytherapy?

    International Nuclear Information System (INIS)

    Park, S; Ragab, O; Patel, S; Demanes, J; Kamrava, M; Kim, Y

    2016-01-01

    Purpose: To evaluate the reliability of the maximum point dose (Dmax) to the skin surface as a dosimetric constraint, we investigated the correlation between Dmax at the skin surface and dose metrics at various definitions of skin thickness. Methods: 42 patients treated with APBI using a Strut Adjusted Volume Implant (SAVI) applicator between 2010 and 2014 were retrospectively reviewed. Target (PTV-EVAL) and organs at risk (OARs: skin, lung, and ribs) were delineated on a CT following NSABP B-39 guidelines. Six skin structures were contoured: a rind 3cm external to the body surface and 1, 2, 3, 4, and 5mm thick rinds deep to the body surface. Inverse planning simulated annealing optimization was used to deliver 32–34Gy in 8-10 fractions to the target while minimizing OAR doses. Dmax, D0.1cc, D1.0cc, and D2.0cc to the various skin structures were calculated. Linear regressions between the metrics were evaluated using the coefficient of determination (R"2). Results: The average±SD PTV-EVAL volume and cavity-to-skin distances were 71.1±28.5cc and 6.9±5.0mm. The target V90 and V95 were 97.3±2.3% and 95.1±3.2%. The Dmax to the skin structures were 78.7±10.2% (skin surface), 82.2±10.7% (skin-1mm), 89.4±12.6% (skin-2mm), 97.9±15.4% (skin-3mm), 114.1±32.5% (skin-4mm), and 157.0±85.3% (skin-5mm). Linear regression analysis showed D1.0cc and D2.0cc to the skin 1mm and Dmax to the skin-4mm and 5mm were poorly correlated with other metrics (R"2=0.413±0.204). Dmax to the skin surface was well correlated (R"2=0.910±0.047) and D1.0cc to the skin-3mm was strongly correlated with all subsurface skin layers (R"2=0.935±0.050). Conclusion: Dmax to the skin surface is a relevant metric for breast skin dose. Contouring discontinuities in the skin with a 1mm subsurface rind and the active dwells in the skin 4 and 5mm introduced significant variations in skin DVH. D0.1cc, D1.0cc, and D2.0cc to a 3mm skin rind are more robust metrics in breast brachytherapy.

  5. 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.

  6. Normal tissue tolerance to external beam radiation therapy: Skin; Dose de tolerance des tissus sains: la peau et les phaneres

    Energy Technology Data Exchange (ETDEWEB)

    Ginot, A.; Doyen, J.; Hannoun-Levi, J.M.; Courdi, A. [Service d' oncologie-radiotherapie, centre Antoine-Lacassagne, 06 - Nice (France)

    2010-07-15

    Acute skin toxicity is frequent during radiation therapy and can lead to temporary arrest of the treatment. Chronic toxicity can occur and conduct to cosmetic problems. Alopecia is the most frequent toxicity concerning hair and is most of the time reversible. Several factors linked to patients influence skin toxicity, such as under-nutrition, old age, obesity, smoking, skin diseases, autoimmune diseases, failure of DNA reparation. Skin, hair and nail toxicities depend also on radiation schedule. Acute toxicity is greater when dose per fraction increases. Chronic and acute toxicities are more often when total dose increases. Under 45 Gy, the risk of severe skin toxicity is low, and begins above 50 Gy. Skin toxicity depends also on the duration of radiotherapy and split course schedules are associated with less toxicities. Irradiation surface seems to influence skin toxicity but interaction is more complex. Reirradiation is often feasible in case of cancer recurrence but with a risk of grade 3-4 toxicity above all in head and neck cancer. The benefit/risk ratio has to be always precisely evaluated. Permanent alopecia is correlated with the follicle dose. Modern techniques of radiation therapy allow to spare skin. (authors)

  7. 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

  8. 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.

  9. 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

  10. Normal tissue tolerance to external beam radiation therapy: Thyroid; Dose de tolerance des tissus sains: la thyroide

    Energy Technology Data Exchange (ETDEWEB)

    Berges, O.; Giraud, P. [Service d' oncologie-radiotherapie, hopital europeen Georges-Pompidou, universite Paris Descartes, 75 - Paris (France); Belkacemi, Y. [Service d' oncologie-radiotherapie, CHU Henri-Mondor, universite Paris 12, 94 - Creteil (France)

    2010-07-15

    The thyroid is the most developed endocrine gland of the body. Due to its anatomical location, it may be exposed to ionizing radiation in external radiotherapy involving head and neck. This review aims to describe the thyroid radiation disorders, probably under-reported in the literature, their risk factors and follow-up procedures. The functional changes after external beam radiation consists mainly of late effects occurring beyond 6 months, and are represented by the clinical and subclinical hypothyroidism. Its incidence is approximately 20 to 30% and it can occur after more than 25 years after radiation exposure. Hyperthyroidism and auto-immune manifestations have been described in a lesser proportion. The morphological changes consist of benign lesions, primarily adenomas, and malignant lesions, the most feared and which incidence is 0.35%. The onset of hypothyroidism depends of the total dose delivered to the gland, and the irradiated. Modern techniques of conformal radiotherapy with modulated intensity could improve the preservation of the thyroid, at the expense of the increase in low doses and the theoretical risk of secondary cancers. (authors)

  11. Toxicokinetics of fumonisin B1 in turkey poults and tissue persistence after exposure to a diet containing the maximum European tolerance for fumonisins in avian feeds.

    Science.gov (United States)

    Tardieu, Didier; Bailly, Jean-Denis; Skiba, Fabien; Grosjean, François; Guerre, Philippe

    2008-09-01

    The kinetic of fumonisin B1 (FB1) after a single IV and oral dose, and FB1 persistence in tissue were investigated in turkey poults by HPLC after purification of samples on columns. After IV administration (single-dose: 10mg FB1/kg bw), serum concentration-time curves were best described by a three-compartment open model. Elimination half-life and mean residence time of FB1 were 85 and 52min, respectively. After oral administration (single-dose: 100mg FB1/kg bw) bioavailability was 3.2%; elimination half-life and mean residence time were 214 and 408min, respectively. Clearance of FB1 was 7.6 and 7.5ml/min/kg for IV and oral administration, respectively. Twenty-four hours after the administration of FB1 by the intravenous route, liver and kidney contained the highest levels of FB1 in tissues, level in muscle was low or below the limit of detection (LD, 13microg/kg). The persistence of FB1 in tissue was also studied after administration for 9 weeks of a feed that contained 5, 10 and 20mg FB1+FB2/kg diet. Eight hours after the last intake of 20mg FB1+FB2/kg feed (maximum recommended concentration of fumonisins established by the EU for avian feed), hepatic and renal FB1 concentrations were 119 and 22microg/kg, level in muscles was below the LD.

  12. 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

  13. 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.

  14. 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

  15. Spinal cord tolerance to single-session uniform irradiation in pigs: Implications for a dose-volume effect

    International Nuclear Information System (INIS)

    Medin, Paul M.; Foster, Ryan D.; Kogel, Albert J. van der; Sayre, James W.; McBride, William H.; Solberg, Timothy D.

    2013-01-01

    Background and purpose: This study was performed to test the hypothesis that spinal cord radiosensitivity is significantly modified by uniform versus laterally non-uniform dose distributions. Materials and methods: A uniform dose distribution was delivered to a 4.5–7.0 cm length of cervical spinal cord in 22 mature Yucatan minipigs for comparison with a companion study in which a laterally non-uniform dose was given [1]. Pigs were allocated into four dose groups with mean maximum spinal cord doses of 17.5 ± 0.1 Gy (n = 7), 19.5 ± 0.2 Gy (n = 6), 22.0 ± 0.1 Gy (n = 5), and 24.1 ± 0.2 Gy (n = 4). The study endpoint was motor neurologic deficit determined by a change in gait within one year. Spinal cord sections were stained with a Luxol fast blue/periodic acid Schiff combination. Results: Dose–response curves for uniform versus non-uniform spinal cord irradiation were nearly identical with ED 50 ’s (95% confidence interval) of 20.2 Gy (19.1–25.8) and 20.0 Gy (18.3–21.7), respectively. No neurologic change was observed for either dose distribution when the maximum spinal cord dose was ⩽17.8 Gy while all animals experienced deficits at doses ⩾21.8 Gy. Conclusion: No dose-volume effect was observed in pigs for the dose distributions studied and the endpoint of motor neurologic deficit; however, partial spinal cord irradiation resulted in less debilitating neurologic morbidity and histopathology

  16. Chronic ingestion of a low dose of caffeine induces tolerance to the performance benefits of caffeine.

    Science.gov (United States)

    Beaumont, Ross; Cordery, Philip; Funnell, Mark; Mears, Stephen; James, Lewis; Watson, Phillip

    2017-10-01

    This study examined effects of 4 weeks of caffeine supplementation on endurance performance. Eighteen low-habitual caffeine consumers (caffeine (1.5-3.0 mg · kg -1 day -1 ; titrated) or placebo for 28 days. Groups were matched for age, body mass, V̇O 2peak and W max (P > 0.05). Before supplementation, all participants completed one V̇O 2peak test, one practice trial and 2 experimental trials (acute 3 mg · kg -1 caffeine [precaf] and placebo [testpla]). During the supplementation period a second V̇O 2peak test was completed on day 21 before a final, acute 3 mg · kg -1 caffeine trial (postcaf) on day 29. Trials consisted of 60 min cycle exercise at 60% V̇O 2peak followed by a 30 min performance task. All participants produced more external work during the precaf trial than testpla, with increases in the caffeine (383.3 ± 75 kJ vs. 344.9 ± 80.3 kJ; Cohen's d effect size [ES] = 0.49; P = 0.001) and placebo (354.5 ± 55.2 kJ vs. 333.1 ± 56.4 kJ; ES = 0.38; P = 0.004) supplementation group, respectively. This performance benefit was no longer apparent after 4 weeks of caffeine supplementation (precaf: 383.3 ± 75.0 kJ vs. postcaf: 358.0 ± 89.8 kJ; ES = 0.31; P = 0.025), but was retained in the placebo group (precaf: 354.5 ± 55.2 kJ vs. postcaf: 351.8 ± 49.4 kJ; ES = 0.05; P > 0.05). Circulating caffeine, hormonal concentrations and substrate oxidation did not differ between groups (all P > 0.05). Chronic ingestion of a low dose of caffeine develops tolerance in low-caffeine consumers. Therefore, individuals with low-habitual intakes should refrain from chronic caffeine supplementation to maximise performance benefits from acute caffeine ingestion.

  17. 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)

  18. MAK and BAT values list 2014. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2014. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2014-11-01

    The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2014 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

  19. MAK and BAT values list 2013. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2013. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-08-01

    The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2013 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

  20. MAK and BAT values list 2017. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2017. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2017-08-01

    The MAK and BAT values list 2017 includes the maximum permissible concentrations at the place of work and biological tolerance values for working materials. The following working materials are covered: carcinogenic working materials, sensitizing materials and aerosols. The report discusses the restriction of exposure peaks, skin resorption, MAK (maximum working place concentration) values during pregnancy, germ cell mutagens and specific working materials. Importance and application of BAT (biological working material tolerance) values, list of materials, carcinogens, biological guide values and reference values are also included.

  1. MAK and BAT values list 2015. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2015. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2015-11-01

    The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2015 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

  2. [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.

  3. 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

  4. Brachial plexus dose tolerance in head and neck cancer patients treated with sequential intensity modulated radiation therapy

    International Nuclear Information System (INIS)

    Thomas, Tarita O; Refaat, Tamer; Choi, Mehee; Bacchus, Ian; Sachdev, Sean; Rademaker, Alfred W; Sathiaseelan, Vythialingam; Karagianis, Achilles; Mittal, Bharat B

    2015-01-01

    We aimed to study the radiation induced brachial plexopathy in patients with head and neck squamous cell carcinoma (HNSCC) treated with Sequential Intensity Modulated Radiation Therapy (S-IMRT). This IRB approved study included 68 patients with HNSCC treated consecutively. Detailed dose volume histogram data was generated for ipsilateral and contralateral brachial plexus (BP) volumes receiving a specified dose (Vds) i.e. V50-V75 and dose in Gray covering specified percent of BP volume (Dvs) i.e. D5-D30 and maximum point doses (Dmax). To assess BP injury all patients’ charts were reviewed in detail for sign and symptoms of BP damage. Post-hoc comparisons were done using Tukey-Kramer method to account for multiple significance testing. The mean and maximum doses to BP were significantly different (p < .05) based on tumor site, nodal status and tumor stage. The mean volume to the ipsilateral BP for V50, V60, V70, and V75 were 7.01 cc, 4.37 cc, 1.47 cc and 0.24 cc, respectively. The mean dose delivered to ≤5% of ipsilateral BP was 68.70 Gy (median 69.5Gy). None of the patients had acute or late brachial plexopathy or any other significant neurological complications, with a minimum follow up of two years (mean 54 months). In this study cohort, at a minimum of two-years follow up, the mean dose of 68.7Gy, a median dose to 69.5Gy to ≤5% of ipsilateral BP, and a median Dmax of 72.96Gy did not result in BP injury when patients were treated with S-IMRT technique. However, longer follow up is needed

  5. 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.

  6. Diode laser trans - scleral cyclo - ablation as a primary surgical treatment for primary open - angle glaucoma after maximum tolerated medical therapy

    International Nuclear Information System (INIS)

    Mahmood, K.; Khan, M.T.; Butt, J.B.Y.

    2011-01-01

    The incidence rate and prevalence of glaucoma in Pakistan is similar to that of other dark - colored population countries. Primary trabeculectomy is still a preferred surgical approach. Diode laser is widely accepted as the therapy of choice in severe glaucoma cases. The purpose of this study was to deter-mine the role of Diode Laser Transscleral Cyclo-ablation as a primary surgical treatment option in Primary Open Angle Glaucoma after maximum tolerated medical therapy. This quasi - experimental study was con-ducted at Layton Rahmatullah Benevolent Trust Free Eye Care and Cancer Hospital, Lahore. Sixty patients fulfilling the inclusion criteria were selected from the Glaucoma unit for this study. 25 - 30 burns of Diode Laser were applied to 270 degrees avoiding 3 and 9 O clock positions, 1.5 mm posterior to the limbus. Laser was set at duration of 1 second and power between 1000 and 1500 mw. Patients were followed up for a period of one year. Results: Out of a total of 60 eyes with mean age 52.73 +- 7.40 years, 36 (60%) were male and 24 (40%) were female. The mean pre-operative Intra Ocular Pressure IOP was 41.0 +- 7.0 mmHg (The pre-operative IOP ranged from 28 mmHg to 60 mmHg). The mean post-operative IOP was 18.97 mmHg on day one, 16.75 mmHg at 1 week, 15.68 mmHg at 1 month, 15.00 mmHg at 6 months and by the end of a year it was about 14.15 mmHg (The post-operative IOP ranged from 6 mmHg to 52 mmHg). There was a significant drop of more than 50% of post-operative IOP as compared to pre-operative IOP. Conclusion: Diode Laser Transscleral Cycloablation is a practical, rapid, well - tolerated procedure that provides a significant lowering of intraocular pressure with few complications and can considered as alternative treatment in POAG if medical therapy fails. (author)

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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...

  12. The ICRP Proposed Maximum Public Dose Constraints of o.3 mSv/y: a Major Issue for the Nuclear Industry

    International Nuclear Information System (INIS)

    Saint-Pierre, S.; Coates, R.

    2004-01-01

    The International Commission on Radiological Protection (ICRP) is currently developing a new set of Recommendations on Radiological Protection. A value of 0.3mSv/y for the maximum public dose constraint has been discussed by ICRP. This value represents a major concern for the nuclear industry at large. The primary issue arises from the lack of any new scientific evidence on public health effects from ionising radiation to support, in practice, the proposed reduction by about a factor of 3 (from 1 to 0.3 mSv/y) of the upper bound value for public dose impact from a nuclear activity or site. Such a change would create a de facto limit on public exposure from specific sources at a dose level of about one tenth of average natural background and an even smaller fraction of the typical range of background exposures and exposures from medical sources. This cannot be justified on public health grounds. The WNA supports ICRP's renewed intention, as expressed at the NEA-ICRP Stakeholder Forum in Lanzarote (April 2003), to retain the concept of a public dose limit at 1 mSv/y. We strongly believe that the current system comprising of the dose limit and the ALARA Principle provides the necessary flexibility and tools for regulators to address all situations in all countries. The WNA consider that the question of setting an upper bound dose constraint (below 1 mSv/y) at the country/site specific level is best left for discussion and agreement between the local stakeholders rather than at an international level. When considering the potential practical implications of a maximum dose constraint, it is important to look beyond the very low off-site dose impacts (on the public) resulting from annual routine radioactive discharges of nuclear industrial sites. There are many off-site and on-site practical situations, related to public exposures (both workers and the public) and worker classification as well as activities such transportation, decommissioning and site remediation, for

  13. The ICRP Proposed Maximum Public Dose Constraints of o.3 mSv/y: a Major Issue for the Nuclear Industry

    Energy Technology Data Exchange (ETDEWEB)

    Saint-Pierre, S.; Coates, R.

    2004-07-01

    The International Commission on Radiological Protection (ICRP) is currently developing a new set of Recommendations on Radiological Protection. A value of 0.3mSv/y for the maximum public dose constraint has been discussed by ICRP. This value represents a major concern for the nuclear industry at large. The primary issue arises from the lack of any new scientific evidence on public health effects from ionising radiation to support, in practice, the proposed reduction by about a factor of 3 (from 1 to 0.3 mSv/y) of the upper bound value for public dose impact from a nuclear activity or site. Such a change would create a de facto limit on public exposure from specific sources at a dose level of about one tenth of average natural background and an even smaller fraction of the typical range of background exposures and exposures from medical sources. This cannot be justified on public health grounds. The WNA supports ICRP's renewed intention, as expressed at the NEA-ICRP Stakeholder Forum in Lanzarote (April 2003), to retain the concept of a public dose limit at 1 mSv/y. We strongly believe that the current system comprising of the dose limit and the ALARA Principle provides the necessary flexibility and tools for regulators to address all situations in all countries. The WNA consider that the question of setting an upper bound dose constraint (below 1 mSv/y) at the country/site specific level is best left for discussion and agreement between the local stakeholders rather than at an international level. When considering the potential practical implications of a maximum dose constraint, it is important to look beyond the very low off-site dose impacts (on the public) resulting from annual routine radioactive discharges of nuclear industrial sites. There are many off-site and on-site practical situations, related to public exposures (both workers and the public) and worker classification as well as activities such transportation, decommissioning and site remediation

  14. 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

  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. 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...

  17. Validation of calculated tissue maximum ratio obtained from measured percentage depth dose (PPD) data for high energy photon beam ( 6 MV and 15 MV)

    International Nuclear Information System (INIS)

    Osei, J.E.

    2014-07-01

    During external beam radiotherapy treatments, high doses are delivered to the cancerous cell. Accuracy and precision of dose delivery are primary requirements for effective and efficiency in treatment. This leads to the consideration of treatment parameters such as percentage depth dose (PDD), tissue air ratio (TAR) and tissue phantom ratio (TPR), which show the dose distribution in the patient. Nevertheless, tissue air ratio (TAR) for treatment time calculation, calls for the need to measure in-air-dose rate. For lower energies, measurement is not a problem but for higher energies, in-air measurement is not attainable due to the large build-up material required for the measurement. Tissue maximum ratio (TMR) is the quantity required to replace tissue air ratio (TAR) for high energy photon beam. It is known that tissue maximum ratio (TMR) is an important dosimetric function in radiotherapy treatment. As the calculation methods used to determine tissue maximum ratio (TMR) from percentage depth dose (PDD) were derived by considering the differences between TMR and PDD such as geometry and field size, where phantom scatter or peak scatter factors are used to correct dosimetric variation due to field size difference. The purpose of this study is to examine the accuracy of calculated tissue maximum ratio (TMR) data with measured TMR values for 6 MV and 15 MV photon beam at Sweden Ghana Medical Centre. With the help of the Blue motorize water phantom and the Omni pro-Accept software, Pdd values from which TMRs are calculated were measured at 100 cm source-to-surface distance (SSD) for various square field sizes from 5x5 cm to 40x40 cm and depth of 1.5 cm to 25 cm for 6 MV and 15 MV x-ray beam. With the same field sizes, depths and energies, the TMR values were measured. The validity of the calculated data was determined by making a comparison with values measured experimentally at some selected field sizes and depths. The results show that; the reference depth of maximum

  18. Effect of low doses of gamma radiation on barley tolerance grown under saline conditions

    International Nuclear Information System (INIS)

    Charbaji, T.; Khalifa, Kh; Al-Ain, F.

    2003-01-01

    A field experiment was conducted at Al-Hijanah, an area located at about 35 km south east of Damascus. Seeds of two barley varieties [White Arabi (WA) and Pakistani 30163 (PK) were irradiated with 2 doses 0 and 15 Gy of gamma irradiation. Then, they were shown on salty soil (17.6-18,9 m mos/cm) and irrigated with salty water (5.12-5.75 m mos/cm). A dose of 15 Gy of gamma irradiation was shown to positively affect the percent germination of PK but had no similar effect on WA. The results were obtained at 3 different growth stages: first, the heading stage, 15 Gy dose increased shoots dry weight, Mg ++ , P content and percent of WA, whereas N percent of PK was decreased. When the seeds were irradiated by the same dose. K + content in WA was significantly higher than that in PK. Second, physiological maturity stage, the same dose (15 Gy) increased shoot dry, but affected negatively K + and Na + contents in PK variety. As for WA variety, Mg ++ and P contents were increased, whereas Na + and Cl - were slightly decreased. Third, harvest stage, gamma irradiation had a positive effect on total yield, grain yield, nitrogen yield and harvest index of PK variety. A positive effect was produced on straw yield, 1000-grain weight, and nitrogen yield of WA variety. (author)

  19. 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

  20. Tibolone and low-dose continuous combined hormone treatment : vaginal bleeding pattern, efficacy and tolerability

    NARCIS (Netherlands)

    Hammar, M. L.; van de Weijer, P.; Franke, H. R.; Pornel, B.; von Mauw, E. M. J.; Nijland, E. A.

    2007-01-01

    Objectives The primary objective was to compare the vaginal bleeding pattern during administration of tibolone and low-dose continuous combined estradiol plus norethisterone acetate (E-2/NETA). The secondary objectives were efficacy on vasomotor symptoms and vaginal atrophy. Design A randomised,

  1. 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

  2. Peripheral nerve and ureteralo tolerance to intraoperative radiation therapy; Clinical and dose-response analysis

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, E.G.; Gunderson, L.L.; Martin, J.K.; Baers, R.W.; Nagorney, D.M.; Podratz, K.C. (Mayo Clinic, Rochester, MN (USA))

    1990-07-01

    Between April 1981 and July 1984, 51 received intraoperative radiation therapy (IORT) as a component of therapy for the management of primary of recurrent pelvic malignancies which were initially unresectable for cure. For these patients, curative surgical alternatives did not exist, or would have involved extensive procedures such as pelvic exenteration, distal sacrectomy, hemipelvectomy, or hemicorporectemy. The primary disease was colorectal in 38 patients. Treatment consisted of external beam radiation (range 3000 to 6890 cGy, median 5040 cGy), surgical debulking when feasible, and an intraoperative electron beam boost to the gross of microscopic residual desease (dose range 1000 to 2500 cGy, median 1750 cGy) utilizing 9-18 MeV electrons. The most common IORT associated toxicities were peripheral neurophaty and ureteral obstruction. None were life-threatening or fatal in severity. Of the 50 patients evaluable for neurotoxicity analysis, 16 (32%) developed peripheral neurophaty consisting of pain in 16 patients, numbness and tingling in 11, and weakness in 8. The pain, numbness and tingling resolved in about 40% of patients, while weakness resolved in only 1 of 8. Sixteen ureters were initially unobstructed by tumor at the time of IORT. Of these, 10 (63%) subsequently showed evidence of obstruction and hydronephrosis. The development of neurotoxicity was more common at IORT doses of 1500 cGy or more versus 1000 cGy. Ureteral obstruction with hydronephrosis occurred more frequently at IORT doses of 1250 cGy or more compared to 1000 cGy. There was no relationship between the likelihood of developing complications and the total external beam dose. The observed dependence of human nerve toxicity primarily on the IORT dose is consistent with data generated form animal experiments. (author). 21 refs.; 4 tabs.

  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. Acute hematological tolerance to multiple fraction, whole body, low dose irradiation in an experimental murine system

    International Nuclear Information System (INIS)

    Melamed, J.S.; Chen, M.G.; Brown, J.W.; Katagiri, C.A.

    1980-01-01

    Using a dose fractionation scheme patterned after the current regimen for treatment of disseminated non-Hodgkin lymphoma, the authors studied the effects of irradation on progenitor and effector cells for hematopoiesis in five-month-old BC3F 1 mice. Fractions of 20 or 50 rad (0.2 or 0.5 Gy) total body irradation were given twice weekly to a final total dose of 200 or 500 rad (2 or 5 Gy), respectively. Weekly assays revealed a marked, sustained depression of stem cell activity, measured as numbers of spleen colony-forming units (CFU-S) and in vitro colony-forming cells (CFU-C), without corresponding depression of effector cells (red and white cells, and platelets). The lack of correlation between numbers of stem cells and peripheral elements is relevant to clinical assessment of marrow reserve

  5. Clinical study of a new therapy for nerve agent poisoning: Ascending dose tolerance study of HI-6 + atropine

    Energy Technology Data Exchange (ETDEWEB)

    Clement, J.G.; Bailey, D.G.; Madill, H.D.; Spence, J.D.

    1993-05-13

    HI-6 was rapidly absorbed from an IM injection site. Maximum HI-6 plasma concentrations of 1.88, 4.96, 8.31 15.0 ug/ml were found 28-36 min after administration and maintained above 4 ug/ml concentration for 0, 39, 112 172.5 min following administration of 62.5, 125, 250 or 500 mg HI-6 + atropine (2 mg), respectively. The calculated half life of HI-6 was 78.2 min following 62.5 mg HI-6 + atropine dose and approximately 64-67 min following 125-500 mg HI-6 + atropine doses. Approximately 50 % of the total dose of HI-6 was eliminated unchanged in the urine. There were significant changes (p < 0.05) in AST, CPK, creatinine and gamma GT following the 500 mg HI-6 + atropine dose but they were not considered to be clinically significant. Urinalysis, hematology and semen analysis over the 24 hr observation period was uneventful. There were no clinically significant changes in heart rate or ECG trace, respiration or blood pressure, visual and mental acuity following HI-6 + atropine.

  6. 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.

  7. Hypofractionated stereotactic radiotherapy to the rat hippocampus. Determination of dose response and tolerance

    International Nuclear Information System (INIS)

    Ernst-Stecken, A.; Roedel, F.; Grabenbauer, G.; Sauer, R.; Jeske, I.; Bluemcke, I.; Hess, A.; Ganslandt, O.; Brune, K.

    2007-01-01

    Purpose: To determine the effect of hypofractionated stereotactic radiotherapy (hfSRT) on adult rat brain tissue (necrosis, impact on blood-brain barrier, signal changes on high-field magnetic resonance imaging [MRI]). Material and Methods: Adult male Wistar rats underwent MRI and CT scanning of the brain and respective images were introduced into the Novalis trademark radiosurgery device (BrainLab, Feldkirchen, Germany). All animals (body weight 350 g) were irradiated weekly with doses of 2 x 10 Gy (n = 3 animals), 3 x 10 Gy (n = 3 animals) and 4 x 10 Gy (n = 3 animals), targeted to the left hippocampus after image-guided positioning. 4.7-T T2-weighted MRI scanning was performed in each animal. Animals were sacrificed 8, 12, and 16 weeks after hfSRT and brains were immersion-fixed in 4% paraformaldehyde for subsequent histopathologic analysis. Results: In concordance with isodose distributions, pathologic signal hyperintensities in MRI were recorded from 4 x 10 Gy after 8 weeks, 3 x 10 Gy after 12 weeks, while 2 x 10 Gy induced slight detectable alterations only after 16 weeks. Subsequent histopathologic analysis revealed hippocampal cell necrosis with significantly earlier and stronger occurrence for higher doses (40 Gy > 30 Gy > 20 Gy). Pial microvessel permeability also increased after 40 Gy, whereas 30 Gy induced moderate changes. Conclusion: Conclusion: Partial-brain irradiation with hfSRT (Novalis trademark System) was successfully adopted for small animals and histopathologic analysis confirmed its repositioning accuracy. The neuropathologic effects correlated with dose and observation time. The approach will be further developed for quality assurance in hfSRT of normal brain tissue, as well as novel treatment modalities in epileptic rats and orthotopic tumor models. (orig.)

  8. WE-F-304-03: Optic Nerve/Chiasm Hypofractionated SRS/SRT Dose Tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Milano, M. [University of Rochester Medical Center (United States)

    2015-06-15

    Stereotactic Body Radiation Therapy (SBRT) was introduced clinically more than twenty years ago, and many subsequent publications have reported safety and efficacy data. The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/SBRT (WGSBRT) extracted published treatment outcomes data from extensive literature searches to summarize and construct tumor control probability (TCP) and normal tissue complication probability (NTCP) models for six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session, we present the WGSBRT’s work for cranial sites, and recurrent head and neck cancer. From literature-based data and associated models, guidelines to aid with safe and effective hypofractionated radiotherapy treatment are being determined. Further, the ability of existing and proposed radiobiological models to fit these data is considered as to the ability to distinguish between the linear-quadratic and alternative radiobiological models such as secondary cell death from vascular damage, immunogenic, or bystander effects. Where appropriate, specific model parameters are estimated. As described in “The lessons of QUANTEC,” (1), lack of adequate reporting standards continues to limit the amount of useful quantitative information that can be extracted from peer-reviewed publications. Recommendations regarding reporting standards are considered, to enable such reviews to achieve more complete characterization of clinical outcomes. 1 Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S155–60. Learning Objectives: Describe the techniques, types of cancer and dose schedules used in treating recurrent H&N cancers with SBRT List the radiobiological models that compete with the linear-quadratic model

  9. WE-F-304-03: Optic Nerve/Chiasm Hypofractionated SRS/SRT Dose Tolerance

    International Nuclear Information System (INIS)

    Milano, M.

    2015-01-01

    Stereotactic Body Radiation Therapy (SBRT) was introduced clinically more than twenty years ago, and many subsequent publications have reported safety and efficacy data. The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/SBRT (WGSBRT) extracted published treatment outcomes data from extensive literature searches to summarize and construct tumor control probability (TCP) and normal tissue complication probability (NTCP) models for six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session, we present the WGSBRT’s work for cranial sites, and recurrent head and neck cancer. From literature-based data and associated models, guidelines to aid with safe and effective hypofractionated radiotherapy treatment are being determined. Further, the ability of existing and proposed radiobiological models to fit these data is considered as to the ability to distinguish between the linear-quadratic and alternative radiobiological models such as secondary cell death from vascular damage, immunogenic, or bystander effects. Where appropriate, specific model parameters are estimated. As described in “The lessons of QUANTEC,” (1), lack of adequate reporting standards continues to limit the amount of useful quantitative information that can be extracted from peer-reviewed publications. Recommendations regarding reporting standards are considered, to enable such reviews to achieve more complete characterization of clinical outcomes. 1 Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S155–60. Learning Objectives: Describe the techniques, types of cancer and dose schedules used in treating recurrent H&N cancers with SBRT List the radiobiological models that compete with the linear-quadratic model

  10. Human tolerance to a single, high dose of D-tagatose.

    Science.gov (United States)

    Buemann, B; Toubro, S; Raben, A; Astrup, A

    1999-04-01

    The addition of 29 g D-tagatose added as a sweetener to a continental breakfast was tested for the appearance of gastrointestinal side effects in a double-blind randomized cross-over study with 29 g sucrose as a control treatment. The subjects reported the side effects during 72 h following the test meal on a questionnaire grading the symptoms on a five-level scale ranging from "none" to "very strong." Although "rumbling in the stomach," "distention," "nausea," "rumbling in the gut," "flatulence, " and "diarrhea" scored significantly higher with D-tagatose, the sugar otherwise was well tolerated in most of the subjects. Two cases of vomiting after D-tagatose were recorded but in one of the cases its relation to the D-tagatose intake was questionable. Only the "distention" score remained higher with D-tagatose for more than 24 h. Nausea, vomiting, and perceived distension may be due to an osmotic effect in the small intestine of unabsorbed D-tagatose. The increased flatus is caused by D-tagatose being fermented in the large intestine. Diarrhea may be explained by osmotic effects in the colon from nondegraded D-tagatose or nonabsorbed short-chain fatty acids produced by the increased fermentation. Copyright 1999 Academic Press.

  11. An increased rectal maximum tolerable volume and long anal canal are associated with poor short-term response to biofeedback therapy for patients with anismus with decreased bowel frequency and normal colonic transit time.

    Science.gov (United States)

    Rhee, P L; Choi, M S; Kim, Y H; Son, H J; Kim, J J; Koh, K C; Paik, S W; Rhee, J C; Choi, K W

    2000-10-01

    Biofeedback is an effective therapy for a majority of patients with anismus. However, a significant proportion of patients still failed to respond to biofeedback, and little has been known about the factors that predict response to biofeedback. We evaluated the factors associated with poor response to biofeedback. Biofeedback therapy was offered to 45 patients with anismus with decreased bowel frequency (less than three times per week) and normal colonic transit time. Any differences in demographics, symptoms, and parameters of anorectal physiologic tests were sought between responders (in whom bowel frequency increased up to three times or more per week after biofeedback) and nonresponders (in whom bowel frequency remained less than three times per week). Thirty-one patients (68.9 percent) responded to biofeedback and 14 patients (31.1 percent) did not. Anal canal length was longer in nonresponders than in responders (4.53 +/- 0.5 vs. 4.08 +/- 0.56 cm; P = 0.02), and rectal maximum tolerable volume was larger in nonresponders than in responders. (361 +/- 87 vs. 302 +/- 69 ml; P = 0.02). Anal canal length and rectal maximum tolerable volume showed significant differences between responders and nonresponders on multivariate analysis (P = 0.027 and P = 0.034, respectively). This study showed that a long anal canal and increased rectal maximum tolerable volume are associated with poor short-term response to biofeedback for patients with anismus with decreased bowel frequency and normal colonic transit time.

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. Radiation-induced rib fracture after stereotactic body radiotherapy with a total dose of 54-56 Gy given in 9-7 fractions for patients with peripheral lung tumor: impact of maximum dose and fraction size.

    Science.gov (United States)

    Aoki, Masahiko; Sato, Mariko; Hirose, Katsumi; Akimoto, Hiroyoshi; Kawaguchi, Hideo; Hatayama, Yoshiomi; Ono, Shuichi; Takai, Yoshihiro

    2015-04-22

    Radiation-induced rib fracture after stereotactic body radiotherapy (SBRT) for lung cancer has been recently reported. However, incidence of radiation-induced rib fracture after SBRT using moderate fraction sizes with a long-term follow-up time are not clarified. We examined incidence and risk factors of radiation-induced rib fracture after SBRT using moderate fraction sizes for the patients with peripherally located lung tumor. During 2003-2008, 41 patients with 42 lung tumors were treated with SBRT to 54-56 Gy in 9-7 fractions. The endpoint in the study was radiation-induced rib fracture detected by CT scan after the treatment. All ribs where the irradiated doses were more than 80% of prescribed dose were selected and contoured to build the dose-volume histograms (DVHs). Comparisons of the several factors obtained from the DVHs and the probabilities of rib fracture calculated by Kaplan-Meier method were performed in the study. Median follow-up time was 68 months. Among 75 contoured ribs, 23 rib fractures were observed in 34% of the patients during 16-48 months after SBRT, however, no patients complained of chest wall pain. The 4-year probabilities of rib fracture for maximum dose of ribs (Dmax) more than and less than 54 Gy were 47.7% and 12.9% (p = 0.0184), and for fraction size of 6, 7 and 8 Gy were 19.5%, 31.2% and 55.7% (p = 0.0458), respectively. Other factors, such as D2cc, mean dose of ribs, V10-55, age, sex, and planning target volume were not significantly different. The doses and fractionations used in this study resulted in no clinically significant rib fractures for this population, but that higher Dmax and dose per fraction treatments resulted in an increase in asymptomatic grade 1 rib fractures.

  17. Radiation-induced rib fracture after stereotactic body radiotherapy with a total dose of 54–56 Gy given in 9–7 fractions for patients with peripheral lung tumor: impact of maximum dose and fraction size

    International Nuclear Information System (INIS)

    Aoki, Masahiko; Sato, Mariko; Hirose, Katsumi; Akimoto, Hiroyoshi; Kawaguchi, Hideo; Hatayama, Yoshiomi; Ono, Shuichi; Takai, Yoshihiro

    2015-01-01

    Radiation-induced rib fracture after stereotactic body radiotherapy (SBRT) for lung cancer has been recently reported. However, incidence of radiation-induced rib fracture after SBRT using moderate fraction sizes with a long-term follow-up time are not clarified. We examined incidence and risk factors of radiation-induced rib fracture after SBRT using moderate fraction sizes for the patients with peripherally located lung tumor. During 2003–2008, 41 patients with 42 lung tumors were treated with SBRT to 54–56 Gy in 9–7 fractions. The endpoint in the study was radiation-induced rib fracture detected by CT scan after the treatment. All ribs where the irradiated doses were more than 80% of prescribed dose were selected and contoured to build the dose-volume histograms (DVHs). Comparisons of the several factors obtained from the DVHs and the probabilities of rib fracture calculated by Kaplan-Meier method were performed in the study. Median follow-up time was 68 months. Among 75 contoured ribs, 23 rib fractures were observed in 34% of the patients during 16–48 months after SBRT, however, no patients complained of chest wall pain. The 4-year probabilities of rib fracture for maximum dose of ribs (Dmax) more than and less than 54 Gy were 47.7% and 12.9% (p = 0.0184), and for fraction size of 6, 7 and 8 Gy were 19.5%, 31.2% and 55.7% (p = 0.0458), respectively. Other factors, such as D2cc, mean dose of ribs, V10–55, age, sex, and planning target volume were not significantly different. The doses and fractionations used in this study resulted in no clinically significant rib fractures for this population, but that higher Dmax and dose per fraction treatments resulted in an increase in asymptomatic grade 1 rib fractures

  18. 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.

  19. 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.

  20. 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.

  1. Production and bromatologic composition of grass-mombaça (Panicum maximum Jacq., submitted to different sources and doses of acidity corrective / Produção e composição bromatológica da forragem do capim-mombaça (Panicum maximum Jacq., submetidos a diferentes fontes e doses de corretivo de acidez

    Directory of Open Access Journals (Sweden)

    Francisco Maximino Fernandes

    2010-04-01

    Full Text Available The experiment was carried in protected (greenhouse atmosphere, in University of Engineering, UNESP of Ilha Solteira-SP, with the objective of evaluating sources (limestone and calcium silicate slag and doses (0,0 – 0,5 – 1,0 – 1,5 – 2,0 times the recommended dose of corrective in the bromatologic composition, tillering and production of dry matter of the grass mombaça (Panicum maximum Jacq.. The lineation was completely randomized design, with four repetitions. It was evaluated the tiller number, the production of dry matter, the gross protein, neutral detergent fiber (NDF and acid detergent fiber (ADF. The corrective influenced the tillering in almost all of the countings. The limestone provided larger production of dry matter in the doses of 1,5 and 2,0 times the recommended dose. The bromatologic composition of the forage was not influenced by the corrective and doses.O experimento foi conduzido em ambiente protegido (estufa, na Faculdade de Engenharia, UNESP de Ilha Solteira, com o objetivo de avaliar fontes (calcário e escória silicatada e doses (0,0 – 0,5 – 1,0 – 1,5 – 2,0 vezes a dose recomendada de corretivos na composição bromatológica, perfilhamento e produção de matéria seca do capim-mombaça (Panicum maximum Jacq.. O delineamento experimental utilizado foi inteiramente casualizado, com quatro repetições. Avaliou-se o número de perfilhos, a produção de matéria seca e os teores de proteína bruta (PB, fibra em detergente neutro (FDN e fibra em detergente ácido (FDA. Os corretivos influenciaram o perfilhamento em quase todas as contagens. O calcário proporcionou maior produção de matéria seca nas doses de 1,5 e 2,0 vezes a dose recomendada. A composição bromatológica da forragem não foi influenciada pelos corretivos e doses utilizadas.

  2. 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

  3. 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.

  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

    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

  5. Tissue persistence of fumonisin B1 in ducks and after exposure to a diet containing the maximum European tolerance for fumonisins in avian feeds.

    Science.gov (United States)

    Tardieu, Didier; Bailly, Jean-Denis; Benlashehr, Imad; Auby, Alienor; Jouglar, Jean-Yves; Guerre, Philippe

    2009-12-10

    Toxicity and persistence of fumonisin B1 (FB1) in liver, kidney and muscle were investigated in ducks fed 5, 10 and 20mg FB1+FB2/kg feed during force-feeding. Mortality and signs of toxicity were only obtained with 20mg/kg, whereas an increased Sa/So ratio was observed from 5mg/kg on. Persistence of FB1 was only found in liver (16 and 20 microg FB1/kg liver in ducks fed 10 and 20 mg FB1+FB2/kg feed, respectively). Toxicokinetic studies were conducted by the intravenous route (IV, single dose: 10mg FB1/kg body weight) and the oral route (single dose: 100mg FB1/kg body weight), in growing ducks and in ducks during force-feeding. After IV administration, serum concentration-time curves were described by a two-compartment open model. Elimination half-life and mean residence time of FB1 were 26 and 24 min, respectively, clearance was 19.3 ml/min/kg. After oral administration, bioavailability, elimination half-life, mean residence time and clearance varied during force-feeding and growth from 2-2.3%, 71-80 min, 200-188 min, 16.7-17 ml/min/kg, respectively. Taken together these results demonstrate that the risk of persistence of FB1 in ducks after force-feeding is very low, Sa/So being a good biomarker which increases before signs of toxicity and risk of persistence of FB1 in tissue (limit of detection 13 microg/kg).

  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. 2004 list of MAK (maximum work place concentration) and BAT (biological workplace tolerance) values; MAK- und BAT-Werte-Liste 2004

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2004-07-01

    The MAK value (maximum workplace concentration) is the highest permissible concentration of a working material occurring in the ambient air of the workplace as a gas or vapour or in suspended form which according to the present state of knowledge does not, in general, impair the health of or pose an unreasonable molestation (for example through repulsive odour) to employees even in the case of repeated, long-term exposure, that is as a rule 8 hours daily, assuming an average working week of no more than 40 hours. As a rule, MAK values are quoted as average values over a time period of up to one working day or shift. They are primarily defined in consideration of effect characteristics of the substances in question, but also - as far as possible - of the practical conditions attending the work processes or the exposure patterns which they entail. This is done on the basis of scientifically founded criteria of health protection, not on whether providing such protection is technically or economically feasible. In addition, substances are assessed in terms of carcinogenicity, sensitising effects, any contribution to systemic toxicity following cutaneous resorption, hazards for pregnancy and germ cell mutagenicity and are classified or marked accordingly. The Commission's procedures in assessing substances with respect to these criteria are described in corresponding sections of the MAK and BAT list of values, in the ''Toxicological and occupational medical explanations of MAK values'' and in scientific journals.

  8. Normal tissue tolerance to external beam radiation therapy: Testicles; Dose de tolerance a l'irradiation des tissus sain: les testicules

    Energy Technology Data Exchange (ETDEWEB)

    Champetier, C.; Gross, E.; Zaccariotto, A.; Duberge, T.; Guerder, C. [Service de radiotherapie, hopital de la Timone, 13 - Marseille (France); Pointreau, Y. [Pole Henry-S.-Kaplan, CHU Bretonneau, 37 - Tours (France); Ortholan, C. [Centre Antoine-Lacassagne, 06 - Nice (France); Chauvet, B. [Institut Sainte-Catherine, 84 - Avignon (France)

    2010-07-15

    Although there is very little evidence for direct irradiation of the testes, they may receive significant doses, especially in the treatment of pelvic tumors in adults and in pediatrics. The exocrine function of the testis seems to be more sensitive to radiotherapy. There is a risk of sterility, even after low doses of radiation. In the adult or the child who has reached puberty, we should propose a self-preservation of semen prior to radiotherapy. In pre-pubescent children, the problem is more delicate. In all cases, it is necessary to limit the dose to the testicles without affecting the coverage of tumour volume. Patients and/or their care-givers should be systematically informed of the risk of infertility related to irradiation. (authors)

  9. 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)

  10. 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)

  11. 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.

  12. 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.

  13. Normal tissue tolerance to external beam radiation therapy: Rectum; Dose de tolerance a l'irradiation des tissus sains: le rectum

    Energy Technology Data Exchange (ETDEWEB)

    Blanchard, P. [Departement de radiotherapie, institut Gustave-Roussy, 94 - Villejuif (France); Chapet, O. [Service d' oncologie-radiotherapie, centre hospitalier Lyon-Sud, 69 - Pierre-Benite (France)

    2010-07-15

    Radiation proctitis is among the most frequent radiation-induced toxicities. This is related to the high frequency of pelvic tumours and the key role of radiotherapy in the treatment of these tumours. Late rectal toxicity usually occurs within the first two years after the completion of a radiotherapy course. Rectal bleeding and a rectal syndrome are the main symptoms, and can be associated to fistulas or rectal ulcers. Clinical factors, such as diabetes mellitus, a severe acute radiation toxicity, small rectal volume or radiation hypersensitivity, are associated with late rectal toxicity. Dosimetric factors derived from the analysis of dose-volume histograms can also predict the occurrence of radiation proctitis, and help to adapt the prescribed dose and the ballistic of irradiation. (authors)

  14. 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)

  15. 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

  16. MAK- and BAT values list 2003. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2003. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2003-07-01

    The importance, application and derivation of the maximum concentrations at the workplace is explained. A material's list contains the presently valid maximum concentration values supplemented by a list of materials for which no such values were determined as yet. Furthermore there is a list of working materials clearly identified as carcinogenic, and of working materials with a sensitizing effect, aerosols and some specific working materials are discussed. Finally, the importance and the application of biological tolerance values is explained, supplemented by a materials list. (orig.) [German] In der vorliegenden neuesten Ausgabe werden erneut Bedeutung, Benutzung und Ableitung der MAK-Werte (maximale Arbeitsplatzkonzentrationen) erlaeutert. Eine Stoffliste enthaelt die derzeit gueltigen MAK-Werte, ergaenzt durch eine Aufzaehlung von Stoffen, fuer die noch keine MAK-Werte aufgestellt werden koennen. Es folgt eine Auflistung der Arbeitsstoffe, die bereits eindeutig als krebserregend ausgewiesen wurden, sowie der sensibilisierenden Arbeitsstoffe, Aerosole und einige besondere Arbeitsstoffe. Abschliessend wird die Bedeutung und Benutzung der BAT-Werte erlaeutert, ergaenzt durch eine Stoffliste. (orig.)

  17. 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.

  18. [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.

  19. Approach to calculating upper bounds on maximum individual doses from the use of contaminated well water following a WIPP repository breach. Report EEG-9

    International Nuclear Information System (INIS)

    Spiegler, P.

    1981-09-01

    As part of the assessment of the potential radiological consequences of the proposed Waste Isolation Pilot Plant (WIPP), this report evaluates the post-closure radiation dose commitments associated with a possible breach event which involves dissolution of the repository by groundwaters and subsequent transport of the nuclear waste through an aquifer to a well assumed to exist at a point 3 miles downstream from the repository. The concentrations of uranium and plutonium isotopes at the well are based on the nuclear waste inventory presently proposed for WIPP and basic assumptions concerning the transport of waste as well as treatment to reduce the salinity of the water. The concentrations of U-233, Pu-239, and Pu-240, all radionuclides originally emplaced as waste in the repository, would exceed current EPA drinking water limits. The concentrations of U-234, U-235, and U-236, all decay products of plutonium isotopes originally emplaced as waste, would be well below current EPA drinking water limits. The 50-year dose commitments from one year of drinking treated water contaminated with U-233 or Pu-239 and Pu-240 were found to be comparable to a one-year dose from natural background. The 50-year dose commitments from one year of drinking milk would be no more than about 1/5 the dose obtained from ingestion of treated water. These doses are considered upper bounds because of several very conservative assumptions which are discussed in the report

  20. 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...

  1. Sustained platelet-sparing effect of weekly low dose paclitaxel allows effective, tolerable delivery of extended dose dense weekly carboplatin in platinum resistant/refractory epithelial ovarian cancer

    Directory of Open Access Journals (Sweden)

    Blagden Sarah

    2011-07-01

    Full Text Available Abstract Background Platinum agents have shown demonstrable activity in the treatment of patients with platinum resistant, recurrent ovarian cancer when delivered in a "dose-dense" fashion. However, the development of thrombocytopenia limits the weekly administration of carboplatin to no greater than AUC 2. Paclitaxel has a well-described platelet sparing effect however its use to explicitly provide thromboprotection in the context of dose dense carboplatin has not been explored. Methods We treated seven patients with platinum resistant ovarian cancer who had previously received paclitaxel or who had developed significant peripheral neuropathy precluding the use of further full dose weekly paclitaxel. Results We were able to deliver carboplatin AUC 3 and paclitaxel 20 mg/m2 with no thrombocytopenia or worsening of neuropathic side-effects, and with good activity. Conclusions We conclude that this regimen may be feasible and active, and could be formally developed as a "platinum-focussed dose-dense scaffold" into which targeted therapies that reverse platinum resistance can be incorporated, and merits further evaluation.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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.

  8. Antihypertensive effects of double the maximum dose of valsartan in African-American patients with type 2 diabetes mellitus and albuminuria

    DEFF Research Database (Denmark)

    Weir, Matthew R; Hollenberg, Norman K; Zappe, Dion H

    2010-01-01

    The blood pressure (BP)-lowering response to renin-angiotensin-aldosterone system blockade in hypertensive African-Americans is typically less than in whites. To determine whether higher than conventional doses of renin-angiotensin-aldosterone system blockade can improve BP reduction in African-A...

  9. Safety, tolerability, and immunogenicity after 1 and 2 doses of zoster vaccine in healthy adults >= 60 years of age

    NARCIS (Netherlands)

    Vermeulen, Joost N.; Lange, Joep M. A.; Tyring, Stephen K.; Peters, Patrick H.; Nunez, Margaret; Poland, Gregory; Levin, Myron J.; Freeman, Carrie; Chalikonda, Ira; Li, Jianjun; Smith, Jeffrey G.; Caulfield, Michael J.; Stek, Jon E.; Chan, Ivan S. F.; Vessey, Rupert; Schödel, Florian P.; Annunziato, Paula W.; Schlienger, Katia; Silber, Jeffrey L.

    2012-01-01

    Background: Incidence and severity of herpes zoster (HZ) and postherpetic neuralgia increase with age, associated with age-related decrease in immunity to varicella-zoster virus (VZV). One dose of zoster vaccine (ZV) has demonstrated substantial protection against HZ; this study examined impact of a

  10. Open-label parallel dose tolerability study of three subcutaneous immunotherapy regimens in house dust mite allergic patients

    NARCIS (Netherlands)

    Rieker-Schwienbacher, Juliane; Nell, Marja J.; Diamant, Zuzana; van Ree, Ronald; Distler, Andreas; Boot, Johan D.; Kleine-Tebbe, Jörg

    2013-01-01

    BACKGROUND: The current maintenance dose (10,000 AUeq/monthly) of a subcutaneous allergoid for house dust mite (HDM) immunotherapy has previously shown significant clinical efficacy in patients with HDM induced allergic rhinitis or rhinoconjunctivitis. In order to comply with the 2009 EMA guidelines

  11. 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.

  12. 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

  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. Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women.

    Science.gov (United States)

    Hughes, T E; Kim, D D; Marjason, J; Proietto, J; Whitehead, J P; Vath, J E

    2013-09-01

    Evaluate the safety and tolerability of beloranib, a fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor, in obese women over 4 weeks. Thirty-one obese (mean BMI 38 kg/m2) women were randomized to intravenous 0.1, 0.3, or 0.9 mg/m2 beloranib or placebo twice weekly for 4 weeks (N = 7, 6, 9, and 9). The most frequent AEs were headache, infusion site injury, nausea, and diarrhea. Nausea and infusion site injury occurred more with beloranib than placebo. The most common reason for discontinuation was loss of venous access. There were no clinically significant abnormal laboratory findings. In subjects completing 4 weeks, median weight loss with 0.9 mg/m2 beloranib was -3.8 kg (95% CI -5.1, -0.9; N = 8) versus -0.6 kg with placebo (-4.5, -0.1; N = 6). Weight change for 0.1 and 0.3 mg/m2 beloranib was similar to placebo. Beloranib (0.9 mg/m2) was associated with a significant 42 and 18% reduction in triglycerides and LDL-cholesterol, as well as improvement in C-reactive protein and reduced sense of hunger. Changes in β-hydroxybutyrate, adiponectin, leptin, and fibroblast growth factor-21 were consistent with the putative mechanism of MetAP2 inhibition. Glucose and blood pressure were unchanged. Beloranib treatment was well tolerated and associated with rapid weight loss and improvements in lipids, C-reactive protein, and adiponectin. Copyright © 2013 The Obesity Society.

  15. Intramural Injection with Botulinum Toxin Type A in Piglet Esophagus. The Influencer on Maximum Load and Elongation: A Dose Response Study.

    Science.gov (United States)

    Ellebæk, Mark Bremholm; Qvist, Niels; Schrøder, Henrik Daa; Rasmussen, Lars

    2016-06-01

    Introduction The treatment of esophageal atresia (OA) is challenging. The main goal is to achieve primary anastomosis. We have previously demonstrated in a pig model that intramural injection of botulinum toxin type A (BTX-A) resulted in significant elongation of the esophagus during tensioning until bursting point. The objectives of the present study were to investigate the influence of different amounts of intramural BTX-A on the stretch-tension characteristics and histological changes of the esophagus in piglets. Materials and Methods A total of 52 piglets were randomized to four groups receiving 2, 4, or 8 units/kg of BTX-A or isotonic saline (placebo). After a 1-hour of rest the esophagus was harvested and subjected to a stretch-tension test and histological examination to assess changes in the density of presynaptic vesicles in the nerve cells. Results Overall, 9 of the 52 animals were excluded from analysis due to problems with the stretch-tension test or death from anesthesia. The maximum loads were higher in the BTX-A groups (2 units/kg: +2.1 N; 4 units/kg: +1.3 N; 8 units/kg: +1.9 N) than the placebo (p = 0.046). There were no significant differences in percentage elongation, or histology. Conclusions This study demonstrated that injection of 2 units/kg BTX-A into a nonanastomosed esophageal wall resulted in a modest increase in the maximum load achieved before bursting; this may be due to the muscle-relaxant effect of BTX-A. BTX-A injection produced no significant effects on elongation or esophageal histology. The clinical usefulness of BTX-A in treatment of OA is still unclear. Georg Thieme Verlag KG Stuttgart · New York.

  16. 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)

  17. Functional genomics indicates yeast requires Golgi/ER transport, chromatin remodeling, and DNA repair for low dose DMSO tolerance

    Directory of Open Access Journals (Sweden)

    Brandon David Gaytán

    2013-08-01

    Full Text Available Dimethyl sulfoxide (DMSO is frequently utilized as a solvent in toxicological and pharmaceutical investigations. It is therefore important to establish the cellular and molecular targets of DMSO in order to differentiate its intrinsic effects from those elicited by a compound of interest. We performed a genome-wide functional screen in Saccharomyces cerevisiae to identify deletion mutants exhibiting sensitivity to 1% DMSO, a concentration standard to yeast chemical profiling studies. We report that mutants defective in Golgi/ER transport are sensitive to DMSO, including those lacking components of the conserved oligomeric Golgi (COG complex. Moreover, strains deleted for members of the SWR1 histone exchange complex are hypersensitive to DMSO, with additional chromatin remodeling mutants displaying a range of growth defects. We also identify DNA repair genes important for DMSO tolerance. Finally, we demonstrate that overexpression of histone H2A.Z, which replaces chromatin-associated histone H2A in a SWR1-catalyzed reaction, confers resistance to DMSO. Many yeast genes described in this study have homologs in more complex organisms, and the data provided is applicable to future investigations into the cellular and molecular mechanisms of DMSO toxicity.

  18. Vaginal tolerance of CT based image-guided high-dose rate interstitial brachytherapy for gynecological malignancies

    International Nuclear Information System (INIS)

    Murakami, Naoya; Inaba, Koji; Morota, Madoka; Ito, Yoshinori; Itami, Jun; Kasamatsu, Takahiro; Sumi, Minako; Yoshimura, Ryoichi; Harada, Ken; Kitaguchi, Mayuka; Sekii, Shuhei; Takahashi, Kana; Yoshio, Kotaro

    2014-01-01

    Purpose of this study was to identify predictors of vaginal ulcer after CT based three-dimensional image-guided high-dose-rate interstitial brachytherapy (HDR-ISBT) for gynecologic malignancies. Records were reviewed for 44 female (14 with primary disease and 30 with recurrence) with gynecological malignancies treated with HDR-ISBT with or without external beam radiation therapy. The HDR-ISBT applicator insertion was performed with image guidance by trans-rectal ultrasound and CT. The median clinical target volume was 35.5 ml (2.4-142.1 ml) and the median delivered dose in equivalent dose in 2 Gy fractions (EQD 2 ) for target volume D 90 was 67.7 Gy (48.8-94.2 Gy, doses of external-beam radiation therapy and brachytherapy were combined). For re-irradiation patients, median EQD 2 of D 2cc for rectum and bladder, D 0.5cc , D 1cc , D 2cc , D 4cc , D 6cc and D 8cc for vaginal wall was 91.1 Gy, 100.9 Gy, 260.3 Gy, 212.3 Gy, 170.1 Gy, 117.1 Gy, 105.2 Gy, and 94.7 Gy, respectively. For those without prior radiation therapy, median EQD 2 of D 2cc for rectum and bladder, D 0.5cc , D 1cc , D 2cc , D 4cc , D 6cc and D 8cc for vaginal wall was 56.3 Gy, 54.3 Gy, 147.4 Gy, 126.2 Gy, 108.0 Gy, 103.5 Gy, 94.7 Gy, and 80.7 Gy, respectively. Among five patients with vaginal ulcer, three had prior pelvic radiation therapy in their initial treatment and three consequently suffered from fistula formation. On univariate analysis, re-irradiation and vaginal wall D 2cc in EQD 2 was the clinical predictors of vaginal ulcer (p = 0.035 and p = 0.025, respectively). The ROC analysis revealed that vaginal wall D 2cc is the best predictor of vaginal ulcer. The 2-year incidence rates of vaginal ulcer in the patients with vaginal wall D 2cc in EQD 2 equal to or less than 145 Gy and over 145 Gy were 3.7% and 23.5%, respectively, with a statistically significant difference (p = 0.026). Re-irradiation and vaginal D 2cc is a significant predictor of vaginal ulcer after HDR-ISBT for gynecologic

  19. Epithelial tissue hyperplasia induced by the RAF inhibitor PF-04880594 is attenuated by a clinically well-tolerated dose of the MEK inhibitor PD-0325901.

    Science.gov (United States)

    Torti, Vince R; Wojciechowicz, Donald; Hu, Wenyue; John-Baptiste, Annette; Evering, Winston; Troche, Gabriel; Marroquin, Lisa D; Smeal, Tod; Yamazaki, Shinji; Palmer, Cynthia L; Burns-Naas, Leigh Ann; Bagrodia, Shubha

    2012-10-01

    Clinical trials of selective RAF inhibitors in patients with melanoma tumors harboring activated BRAFV600E have produced very promising results, and a RAF inhibitor has been approved for treatment of advanced melanoma. However, about a third of patients developed resectable skin tumors during the course of trials. This is likely related to observations that RAF inhibitors activate extracellular signal-regulated kinase (ERK) signaling, stimulate proliferation, and induce epithelial hyperplasia in preclinical models. Because these findings raise safety concerns about RAF inhibitor development, we further investigated the underlying mechanisms. We showed that the RAF inhibitor PF-04880594 induces ERK phosphorylation and RAF dimerization in those epithelial tissues that undergo hyperplasia. Hyperplasia and ERK hyperphosphorylation are prevented by treatment with the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD-0325901 at exposures that extrapolate to clinically well-tolerated doses. To facilitate mechanistic and toxicologic studies, we developed a three-dimensional cell culture model of epithelial layering that recapitulated the RAF inhibitor-induced hyperplasia and reversal by MEK inhibitor in vitro. We also showed that PF-04880594 stimulates production of the inflammatory cytokine interleukin 8 in HL-60 cells, suggesting a possible mechanism for the skin flushing observed in dogs. The complete inhibition of hyperplasia by MEK inhibitor in epithelial tissues does not seem to reduce RAF inhibitor efficacy and, in fact, allows doubling of the PF-04880594 dose without toxicity usually associated with such doses. These findings indicated that combination treatment with MEK inhibitors might greatly increase the safety and therapeutic index of RAF inhibitors for the treatment of melanoma and other cancers. ©2012 AACR.

  20. Efficacy and tolerability of treatment with single doses of diethylcarbamazine (DEC) and DEC plus albendazole (ABZ) for three consecutive years in lymphatic filariasis: a field study in India.

    Science.gov (United States)

    Kshirsagar, Nilima A; Gogtay, N J; Garg, B S; Deshmukh, P R; Rajgor, D D; Kadam, V S; Thakur, P A; Gupta, A; Ingole, N S; Lazdins-Helds, J K

    2017-10-01

    Lymphatic filariasis (LF) affects 73 countries, causes morbidity and impedes socioeconomic development. We had found no difference in safety and micro (Mf) and macro filarial action of single-dose diethylcarbamazine (DEC) and DEC + albendazole (ABZ) in an F01 study done in India (year 2000). There was a programmatic need to evaluate safety and efficacy of multiple annual treatments (F02). Subjects (155) from the F01 study, meeting inclusion-exclusion criteria, were enrolled in F02 and treated with further two annual doses of DEC or DEC + ABZ. Efficacy was evaluated for Mf positivity by peripheral smear (PS) and nucleopore (NP) filter, circulating filarial antigen (CFA) and filarial dance sign (FDS) positivity and Mf count at yearly follow-up. Safety was assessed for 5 days after drug administration. Total of 139 subjects evaluated for efficacy (69 DEC and 70 DEC + ABZ group). Mf positivity prevalence declined progressively by 95% (PS), 66% (NP), and 95% (PS) and 86% (NP); CFA positivity prevalence declined by 15% and 9%; FDS by 100% each; Mf count declined by 75.5 and 76.9% with three annual treatment of DEC and DEC + ABZ, respectively. Addition of ABZ did not show any advantage over DEC given as three annual rounds for LF. DEC and DEC + ABZ were well tolerated. There was no correlation between result of CFA and FDS, (both claimed to be indicative of adult worm). Analysis of published studies and our data indicate that macrofilaricidal effect of DEC/DEC + ABZ may be seen in children and not adults, with three or more annual dosing.

  1. Enhanced Glucose Tolerance and Pancreatic Beta Cell Function by Low Dose Aspirin in Hyperglycemic Insulin-Resistant Type 2 Diabetic Goto-Kakizaki (GK Rats

    Directory of Open Access Journals (Sweden)

    Layla Amiri

    2015-07-01

    Full Text Available Background/Aim: Type 2 diabetes is the most common metabolic disorder, characterized by insulin resistance and pancreatic islet beta-cell failure. The most common complications associated with type 2 diabetes are hyperinsulinemia, hyperglycemia, hyperlipidemia, increased inflammatory and reduced insulin response. Aspirin (ASA and other non-steroidal anti-inflammatory drugs (NSAIDs have been associated with the prevention of diabetes, obesity and related cardiovascular disorders. Aspirin has been used in many clinical and experimental trials for the prevention of diabetes and associated complications. Methods: In this study, five month old Goto-Kakizaki (GK rats, which showed signs of mild hyperglycemia (fasting blood glucose 80-95 mg/dl vs 55-60 mg/dl Wistar control rats were used. Two subgroups of GK and Wistar control rats were injected intraperitoneally with 100 mg aspirin/kg body weight/ day for 5 weeks. Animals were sacrificed and blood and tissues were collected after performing glucose tolerance (2 h post 2g IP glucose ingestion tests in experimental and control groups. Results: Aspirin caused a moderate decrease in hyperglycemia. However, we observed a significant improvement in glucose tolerance after ASA treatment in GK rats compared to the nondiabetic Wistar rats. Also, the ASA treated GK rats exhibited a significant decrease in insulinemia. ASA treatment also caused a marked reduction in the pro-inflammatory prostaglandin, PGE2, which was significantly higher in GK rats. On the other hand, no significant organ toxicity was observed after ASA treatment at this dose and time period. However, the total cholesterol and lipoprotein levels were significantly increased in GK rats, which decreased after ASA treatment. Immunofluorescence staining for insulin/glucagon secreting pancreatic cells showed improved beta-cell structural and functional integrity in ASA-treated rats which was also confirmed by SDS-PAGE and Western blot analysis

  2. 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.

  3. An open pilot study of zonisamide augmentation in major depressive patients not responding to a low dose trial with duloxetine: preliminary results on tolerability and clinical effects

    Directory of Open Access Journals (Sweden)

    Benvenuti Marzia

    2011-09-01

    Full Text Available Abstract Background Despite multiple antidepressant options, major depressive disorder (MDD still faces high non-response rates, eventually requiring anticonvulsant augmentation strategies too. The aim of this study was to explore such a potential role for zonisamide. Methods A total of 40 MDD outpatients diagnosed using the Diagnostic and Statistical Manual for Mental Disorders, fourth edition criteria entered a 24 week open trial receiving duloxetine 60 mg/day for the first 12 weeks and subsequently (weeks 12 to 24 augmentation with zonisamide 75 mg/day if they did not respond to the initial monotherapy. Efficacy and tolerability were assessed using the Hamilton Scales for Anxiety and Depression (a 12 week score ≥50% vs baseline defined 'non-response', the Arizona Sexual Experience Scale, the Patient Rated Inventory of Side Effects and the Young Mania Rating Scale. Results At week 12, 15 patients out of 39 (38.5% were responders, and 1 had dropped out; remarkably, 14 patients out of 24 (58.3% had achieved response by week 24. Poor concentration and general malaise were associated with non-response both at week 12 and 24 (P = 0.001, while loss of libido and reduced energy were prominent among final timepoint non-responders. Patients receiving zonisamide also experienced weight reduction (2.09 ± 12.14 kg; P = 0.001 independently of the outcome. Conclusions Although only a preliminary study due to strong methodological limitations, and thus requiring confirmation by further controlled investigations, the current results indicate zonisamide may be a potential augmentation option for some depressed patients receiving low doses of duloxetine.

  4. Tolerability and efficacy of single dose albendazole, diethylcarbamazine citrate (DEC) or co-administration of albendazole with DEC in the clearance of Wuchereria bancrofti in asymptomatic microfilaraemic volunteers in Pondicherry, South India: a hospital-based study

    OpenAIRE

    Pani, SP; Subramanyam Reddy, G; Das, LK; Vanamail, P; Hoti, SL; Ramesh, J; Das, PK

    2002-01-01

    Background The tolerability and efficacy of single dose albendazole (400 mg), diethylcarbamazine citrate (DEC) (6 mg/kg bodyweight) or co-administration of albendazole (400 mg) + DEC (6 mg/kg bodyweight) was studied in 54 asymptomatic Wuchereria bancrofti microfilaraemic volunteers in a double blind hospital-based clinical study. Results There was no significant difference in the overall incidence of adverse reactions between the three drug groups [42.1% (albendazole), 52.9% (DEC) and 61.1% (...

  5. Safety, tolerability, and efficacy of a fixed-dose combination of olmesartan 40 mg and hydrochlorothiazide 12.5/25 mg in daily practice

    Directory of Open Access Journals (Sweden)

    Bramlage P

    2013-08-01

    Full Text Available Peter Bramlage,1 Claudia Zemmrich,1 Reinhard Ketelhut,2 Wolf-Peter Wolf,3 Eva-Maria Fronk,4 Roland E Schmieder5 1Institut für Pharmakologie und Präventive Medizin, Mahlow, Germany; 2Institut für Sportmedizin, Universitätsklinikum Charité, Humboldt Universität zu Berlin, Berlin, Germany; 3Daiichi Sankyo Deutschland GmbH, Munich, Germany; 4Daiichi Sankyo Europe GmbH, Munich, Germany; 5Universitätsklinikum Erlangen, Klinik für Nephrologie und Hypertensiologie, Erlangen, Germany Background: The safety and efficacy of olmesartan 40 mg and hydrochlorothiazide (HCTZ as a fixed-dose combination has been investigated in clinical trials leading to its approval. The aims of the present study were to confirm these data in an unselected patient population in daily practice and to determine the impact of physical activity on blood pressure control. Methods: In a multicenter, noninterventional study, 3,333 patients with either insufficient blood pressure control on olmesartan 40 mg alone or on a fixed/free combination of olmesartan 40 mg and HCTZ 12.5/25 mg were primarily assessed for safety and tolerability of the fixed-dose combination of olmesartan 40 mg and HCTZ 12.5/25 mg at 24 ± 2 weeks. Secondary objectives were blood pressure reduction, treatment compliance, and impact of physical activity as measured by the sum of weekly energy costs. Results: The mean patient age was 63.2 ± 11.46 years, mean baseline blood pressure was 159.6 ± 15.28/93.5 ± 9.52 mmHg, and 70.9% had at least one additional cardiovascular risk factor. Adverse drug reactions were rare (n = 19, and no serious adverse drug reactions occurred. Compliance with drug therapy was at least sufficient in more than 99% of patients at the end of the study. Blood pressure at the last available visit was reduced by 26.1 ± 15.5/13.0 ± 10.1 mmHg versus baseline (P < 0.0001, but had reduced effectiveness in patients ≥75 years with diabetes or impaired renal function. In 69% of patients

  6. Phase I dose escalation, pharmacokinetic and pharmacodynamic study of naptumomab estafenatox alone in patients with advanced cancer and with docetaxel in patients with advanced non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Borghaei, Hossein; Alpaugh, Katherine; Hedlund, Gunnar

    2009-01-01

    recognizing the tumor-associated antigen 5T4. PATIENTS AND METHODS: Patients with non-small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose...

  7. 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

  8. 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

  9. Normal tissue tolerance to external beam radiation therapy: Peripheral nerves

    International Nuclear Information System (INIS)

    Henriques de Figueiredo, B.; Dejean, C.; Sargos, P.; Kantor, G.; Huchet, A.; Mamou, N.; Loiseau, H.

    2010-01-01

    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)

  10. Approximate maximum parsimony and ancestral maximum likelihood.

    Science.gov (United States)

    Alon, Noga; Chor, Benny; Pardi, Fabio; Rapoport, Anat

    2010-01-01

    We explore the maximum parsimony (MP) and ancestral maximum likelihood (AML) criteria in phylogenetic tree reconstruction. Both problems are NP-hard, so we seek approximate solutions. We formulate the two problems as Steiner tree problems under appropriate distances. The gist of our approach is the succinct characterization of Steiner trees for a small number of leaves for the two distances. This enables the use of known Steiner tree approximation algorithms. The approach leads to a 16/9 approximation ratio for AML and asymptotically to a 1.55 approximation ratio for MP.

  11. 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

  12. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells.

    Science.gov (United States)

    Zent, Clive S; Taylor, Ronald P; Lindorfer, Margaret A; Beum, Paul V; LaPlant, Betsy; Wu, Wenting; Call, Timothy G; Bowen, Deborah A; Conte, Michael J; Frederick, Lori A; Link, Brian K; Blackwell, Sue E; Veeramani, Suresh; Baig, Nisar A; Viswanatha, David S; Weiner, George J; Witzig, Thomas E

    2014-07-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. © 2014 Wiley Periodicals, Inc.

  13. 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.

  14. 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...

  15. 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

  16. Decree of the Ministry of Health about conditions of irradiation of food, permissible additional substances or other food components, which can be subjected to ionizing radiation action, their specification, maximum irradiation doses as well as about requirements for marking and introducing into turnover

    International Nuclear Information System (INIS)

    Lipinski, M.

    2003-01-01

    The decree refers to conditions of irradiation of food and its components for radappertization and radurization using gamma radiation from cobalt 60 or cesium 137, X radiation or electron beam up to maximum total medium absorbed dose 10 kGy

  17. Inefficacy of high-dose transdermal fentanyl in a patient with neuropathic pain, a case report.

    NARCIS (Netherlands)

    Bleeker, C.P.; Bremer, R.; Dongelmans, D.A.; Dongen, R.T.M. van; Crul, B.J.P.

    2001-01-01

    Pain partially responsive to opioids can lead to rapid escalating dosages due to tolerance development. In this report the case of a 58-year-old female with neuropathic pain using increasing transdermal (TTS) fentanyl dosages to a maximum dose of 3400 microg/h resulting in fentanyl plasma levels of

  18. Evaluation of the Efficacy, Safety, and Tolerability of 3 Dose Regimens of Topical Sodium Nitrite With Citric Acid in Patients With Anogenital Warts: A Randomized Clinical Trial.

    Science.gov (United States)

    Ormerod, Anthony D; van Voorst Vader, Pieter C; Majewski, Slovomir; Vanscheidt, Wolfgang; Benjamin, Nigel; van der Meijden, Willem

    2015-08-01

    Anogenital warts are a common disorder associated with significant physical and mental distress and a substantial cause of health care costs. To assess the efficacy of the topical application of nitric oxide delivered using acidified nitrite. A multicenter, randomized, controlled, dose-ranging clinical trial was conducted in European genitourinary medicine clinics between December 20, 2001, and January 14, 2003. Analysis was by intent to treat for all individuals initiating therapy. Participants included male and female volunteers older than 18 years with between 2 and 50 external anogenital warts. A total of 299 individuals from 40 centers were randomized to a control arm and a treatment arm that received 3 doses of acidified nitrite applied topically for 12 weeks with an additional 12 weeks of follow-up, with the final follow-up visit on January 14, 2003. Placebo nitrite cream and placebo citric acid cream were applied twice daily. Active treatment was divided as low dose (sodium nitrite, 3%, with citric acid, 4.5%, creams applied twice daily), middle dose (sodium nitrite, 6%, with citric acid, 9%, creams applied once daily at night, with placebo applied in the morning), and high dose (sodium nitrite, 6%, with citric acid, 9%, creams applied twice daily). The primary outcome was proportion of patients with complete clinical clearance of target warts; secondary outcomes were reduction in target wart area and safety. Complete clinical clearance at 12 weeks occurred in 10 of 74 patients (14%; 95% CI, 6%-21%) with placebo; 11 of 72 (15%; 95% CI, 7%-24%) with low-dose treatment; 17 of 74 (23%; 95% CI, 13%-33%) with middle-dose treatment; and 22 of 70 (31%; 95% CI, 21%-42%) with high-dose treatment (P = .01). Reduction in target wart area, time to clearance, and patient and investigator assessments supported the superiority of the high-dose therapy vs placebo. There were no systemic or serious adverse events associated with treatment. However, there was a dose

  19. Predictors of Rectal Tolerance Observed in a Dose-Escalated Phase 1-2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, D.W. Nathan [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Cho, L. Chinsoo [Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota (United States); Straka, Christopher [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Christie, Alana [Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Lotan, Yair [Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Pistenmaa, David [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Kavanagh, Brian D. [Department of Radiation Oncology, University of Colorado, Denver, Colorado (United States); Nanda, Akash [Department of Radiation Oncology, University of Florida Health Cancer Center at Orlando Health, Orlando, Florida (United States); Kueplian, Patrick [Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California (United States); Brindle, Jeffrey [Prairie Lakes Hospital, Watertown, South Dakota (United States); Cooley, Susan; Perkins, Alida [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Raben, David [Department of Radiation Oncology, University of Colorado, Denver, Colorado (United States); Xie, Xian-Jin [Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Timmerman, Robert D., E-mail: robert.timmerman@utsouthwestern.edu [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)

    2014-07-01

    Purpose: To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury. Methods and Materials: Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer. Results: At the highest dose level, 6.6% of patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm{sup 3} (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010). Conclusion: Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.

  20. 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...

  1. 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.

  2. In vitro mutants identification of banana (Musa sp.) with tolerance to toxin from Fusarium oxysporum f. sp cubense, treating buds with several gamma radiation doses

    International Nuclear Information System (INIS)

    Moura, Adriana Muniz Mendes de; Houllou-Kido, Laureen Michelle; Franca, Jose Geraldo Eugenio de; Colaco, Waldeciro

    1999-01-01

    Mutants of banana, obtained through treatment with different level of gamma-radiation (0; 10; 20; 30; 40 Gy), were initially cultivated in vitro in medium for rapid clonal propagation during 30 days. These treatment affected the shoot tips development ratio. Some plants developed necrosis and died, but some of the shoot tips emitted new gems. These material were cultivated in medium 20% of the toxin of Fusarium oxysporum cubense. During the selection period, the necrosis occurrence and death of susceptible shoot tips were observed. Whereas the tolerant shoot tips kept themselves green during the entire selection process. At the end of the selection process, eight shoot tips were obtained. (author)

  3. 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.

  4. Chemoimmunotherapy for Relapsed/Refractory and Progressive 17p13 Deleted Chronic Lymphocytic Leukemia (CLL) Combining Pentostatin, Alemtuzumab, and Low Dose Rituximab is Effective and Tolerable and Limits Loss of CD20 Expression by Circulating CLL Cells

    Science.gov (United States)

    Zent, Clive S.; Taylor, Ronald P.; Lindorfer, Margaret A.; Beum, Paul V.; LaPlant, Betsy; Wu, Wenting; Call, Timothy G.; Bowen, Deborah A.; Conte, Michael J.; Frederick, Lori A.; Link, Brian K.; Blackwell, Sue E.; Veeramani, Suresh; Baig, Nisar A.; Viswanatha, David S.; Weiner, George J.; Witzig, Thomas E.

    2014-01-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analogue refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a phase II trial testing the efficacy and tolerability of a short duration regimen combining pentostatin, alemtuzumab, and low dose high frequency rituximab (PAR) designed to decrease the risk of treatment associated infections and limit loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n=36) or previously untreated with 17p13 deletion (17p13-)(n=3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional and eight patients had purine analogue refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy with only five (13%) patients having treatment limiting toxicity, and no treatment related deaths. Twenty-two (56%) patients responded to treatment with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression free survival was 7.2 months, time to next treatment 9.1 months, and overall survival 34.1 months. The majority of deaths (82%) were caused by progressive disease including transformed diffuse large B cell lymphoma (n=6). Correlative studies showed that low dose rituximab activates complement and NK cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that PAR is a tolerable and effective therapy for CLL and that low dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

  5. 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...

  6. 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)

  7. 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)

  8. 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

  9. Crafting tolerance

    DEFF Research Database (Denmark)

    Kirchner, Antje; Freitag, Markus; Rapp, Carolin

    2011-01-01

    Ongoing changes in social structures, orientation, and value systems confront us with the growing necessity to address and understand transforming patterns of tolerance as well as specific aspects, such as social tolerance. Based on hierarchical analyses of the latest World Values Survey (2005......–08) and national statistics for 28 countries, we assess both individual and contextual aspects that influence an individual's perception of different social groupings. Using a social tolerance index that captures personal attitudes toward these groupings, we present an institutional theory of social tolerance. Our...

  10. 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.

  11. Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials.

    Science.gov (United States)

    Krauss, Gregory; Biton, Victor; Harvey, Jay H; Elger, Christian; Trinka, Eugen; Soares da Silva, Patrício; Gama, Helena; Cheng, Hailong; Grinnell, Todd; Blum, David

    2018-01-01

    To examine the influence of titration schedule and maintenance dose on the incidence and type of treatment-emergent adverse events (TEAEs) associated with adjunctive eslicarbazepine acetate (ESL). Data from three randomized, double-blind, placebo-controlled trials were analyzed. Patients with refractory partial-onset seizures were randomized to maintenance doses of ESL 400, 800, or 1200mg QD (dosing was initiated at 400 or 800mg QD) or placebo. The incidence of TEAEs was analyzed during the double-blind period (2-week titration phase; 12-week maintenance phase), according to the randomized maintenance dose and the titration schedule. 1447 patients were included in the analysis. During the first week of treatment, 62% of patients taking ESL 800mg QD had ≥1 TEAE, vs 35% of those taking 400mg QD and 32% of the placebo group; dizziness, somnolence, nausea, and headache were numerically more frequent in patients taking ESL 800mg than those taking ESL 400mg QD. During the double-blind period, the incidences of common TEAEs were lower in patients who initiated ESL at 400mg vs 800mg QD. For the 800 and 1200mg QD maintenance doses, rates of TEAEs leading to discontinuation were lower in patients who began treatment with 400mg than in those who began taking ESL 800mg QD. Initiation of ESL at 800mg QD is feasible. However, initiating treatment with ESL 400mg QD for 1 or 2 weeks is recommended, being associated with a lower incidence of TEAEs, and related discontinuations. For some patients, treatment may be initiated at 800mg QD, if the need for more immediate seizure reduction outweighs concerns about increased risk of adverse reactions during initiation. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  12. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial.

    Science.gov (United States)

    Younes, Anas; Berdeja, Jesus G; Patel, Manish R; Flinn, Ian; Gerecitano, John F; Neelapu, Sattva S; Kelly, Kevin R; Copeland, Amanda R; Akins, Amy; Clancy, Myles S; Gong, Lucy; Wang, Jing; Ma, Anna; Viner, Jaye L; Oki, Yasuhiro

    2016-05-01

    Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and PI3K enzymes, which are members of common oncogenic pathways in haematological malignancies. We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy in patients with relapsed or refractory lymphoma and multiple myeloma. This open-label, first-in-man, phase 1 trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres. CUDC-907 was orally administered in a standard 3 + 3 dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for 5 days followed by a 2-day break (5/2), in 21-day cycles. Dosing started at 30 mg for the once-daily schedule and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66% of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. We assessed safety in all patients who received at least one dose of study drug. This ongoing trial is registered at ClinicalTrials.gov, number NCT01742988. Between Jan 23, 2013, and July 27, 2015, we enrolled 44 patients, of whom ten were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to three-times-weekly (MTD 150 mg), and seven to the 5/2 dosing schedule (MTD 60 mg). 37

  13. Maximum Acceleration Recording Circuit

    Science.gov (United States)

    Bozeman, Richard J., Jr.

    1995-01-01

    Coarsely digitized maximum levels recorded in blown fuses. Circuit feeds power to accelerometer and makes nonvolatile record of maximum level to which output of accelerometer rises during measurement interval. In comparison with inertia-type single-preset-trip-point mechanical maximum-acceleration-recording devices, circuit weighs less, occupies less space, and records accelerations within narrower bands of uncertainty. In comparison with prior electronic data-acquisition systems designed for same purpose, circuit simpler, less bulky, consumes less power, costs and analysis of data recorded in magnetic or electronic memory devices. Circuit used, for example, to record accelerations to which commodities subjected during transportation on trucks.

  14. 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.

  15. Dose-tailoring of FEC adjuvant chemotherapy based on leukopenia is feasible and well tolerated. Toxicity and dose intensity in the Scandinavian Breast Group phase 3 adjuvant Trial SBG 2000-1

    DEFF Research Database (Denmark)

    Edlund, Per; Ahlgren, Johan; Bjerre, Karsten

    2011-01-01

    The SBG 2000-1 trial is a randomised study that investigates if dose-tailored adjuvant FEC therapy based on the individual's leukocyte nadir value can improve outcome. The study has included 1535 women with medium and high-risk breast cancer.......The SBG 2000-1 trial is a randomised study that investigates if dose-tailored adjuvant FEC therapy based on the individual's leukocyte nadir value can improve outcome. The study has included 1535 women with medium and high-risk breast cancer....

  16. 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

  17. Efficacy and tolerability of high dose "ethinylestradiol" in post-menopausal advanced breast cancer patients heavily pre-treated with endocrine agents

    OpenAIRE

    Agrawal, Amit; Robertson, John FR; Cheung, KL

    2006-01-01

    Abstract Background High dose estrogens (HDEs) were frequently used as endocrine agents prior to the introduction of tamoxifen which carries fewer side effects. Due to the development of resistance to available endocrine agents in almost all women with metastatic breast cancer, interest has renewed in the use of HDEs as yet another endocrine option that may have activity. We report our experience with one of the HDEs ("ethinylestradiol" 1 mg daily) in advanced breast cancer (locally advanced ...

  18. Maximum Quantum Entropy Method

    OpenAIRE

    Sim, Jae-Hoon; Han, Myung Joon

    2018-01-01

    Maximum entropy method for analytic continuation is extended by introducing quantum relative entropy. This new method is formulated in terms of matrix-valued functions and therefore invariant under arbitrary unitary transformation of input matrix. As a result, the continuation of off-diagonal elements becomes straightforward. Without introducing any further ambiguity, the Bayesian probabilistic interpretation is maintained just as in the conventional maximum entropy method. The applications o...

  19. Maximum power demand cost

    International Nuclear Information System (INIS)

    Biondi, L.

    1998-01-01

    The charging for a service is a supplier's remuneration for the expenses incurred in providing it. There are currently two charges for electricity: consumption and maximum demand. While no problem arises about the former, the issue is more complicated for the latter and the analysis in this article tends to show that the annual charge for maximum demand arbitrarily discriminates among consumer groups, to the disadvantage of some [it

  20. 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...

  1. Om tolerance

    DEFF Research Database (Denmark)

    Huggler, Jørgen

    2007-01-01

    Begrebet tolerance og dets betydninger diskuteres med henblik på en tydeliggørelse af begrebets forbindelse med stat, religion, ytringsfrihed, skeptisk erkendelsesteori, antropologi og pædagogik.......Begrebet tolerance og dets betydninger diskuteres med henblik på en tydeliggørelse af begrebets forbindelse med stat, religion, ytringsfrihed, skeptisk erkendelsesteori, antropologi og pædagogik....

  2. Postoperative irradiation of carcinoma of the head of the pancreas area: Short-time tolerance and results to precision high-dose technique in 18 patients

    International Nuclear Information System (INIS)

    Nguyen, T.D.; Bugat, R.; Combes, P.F.

    1982-01-01

    During the period from January 1977-August 1979, 18 patients with biopsy-proven pancreas duct or ampullary adenocarcinoma with no distant or liver metastases underwent external beam radiation therapy following laparotomy. With the use of a 25 MEV photon beam and a four field ''box'' technique, the dose delivered to the target volume identified with radio-opaque clips at laparotomy was 6000 rad in six weeks, while largely sparing the spinal cord, kidney, liver and gut. All patients subjected to low fat, gluten free diet completed treatment as planned without any acute reaction. Three patients developed delayed pancreatic insufficiency. According to actuarial survival analysis and low morbidity such an approach may lead to increased survival in patients with pancreatic cancer

  3. Efficacy and tolerability of high dose "ethinylestradiol" in post-menopausal advanced breast cancer patients heavily pre-treated with endocrine agents.

    Science.gov (United States)

    Agrawal, Amit; Robertson, John F R; Cheung, K L

    2006-07-11

    High dose estrogens (HDEs) were frequently used as endocrine agents prior to the introduction of tamoxifen which carries fewer side effects. Due to the development of resistance to available endocrine agents in almost all women with metastatic breast cancer, interest has renewed in the use of HDEs as yet another endocrine option that may have activity. We report our experience with one of the HDEs ("ethinylestradiol" 1 mg daily) in advanced breast cancer (locally advanced and metastatic) in post-menopausal women who had progressed on multiple endocrine agents. According to a database of advanced breast cancer patients seen in our Unit since 1998, those who had complete set of information and fulfilled the following criteria were studied: (1) patients in whom further endocrine therapy was deemed appropriate i.e., patients who have had clinical benefit with previous endocrine agents or were not fit or unwilling to receive chemotherapy in the presence of potentially life-threatening visceral metastases; (2) disease was assessable by UICC criteria; (3) were treated with "ethinylestradiol" until they were withdrawn from treatment due to adverse events or disease progression. Twelve patients with a median age of 75.1 years (49.1-85 years) were identified. Majority (N = 8) had bony disease. They had ethinylestradiol as 3rd to 7th line endocrine therapy. One patient (8%) came off treatment early due to hepato-renal syndrome. Clinical benefit (objective response or durable stable disease for > or = 6 months) was seen in 4 patients (33.3%) with a median duration of response of 10+ (7-36) months. The time to treatment failure was 4 (0.5-36) months. Yet unreported, high dose "ethinylestradiol" is another viable therapeutic strategy in heavily pre-treated patients when further endocrine therapy is deemed appropriate. Although it tends to carry more side effects, they may not be comparable to those of other HDEs (such as diethylstilbestrol) or chemotherapy.

  4. Maximum likely scale estimation

    DEFF Research Database (Denmark)

    Loog, Marco; Pedersen, Kim Steenstrup; Markussen, Bo

    2005-01-01

    A maximum likelihood local scale estimation principle is presented. An actual implementation of the estimation principle uses second order moments of multiple measurements at a fixed location in the image. These measurements consist of Gaussian derivatives possibly taken at several scales and/or ...

  5. Robust Maximum Association Estimators

    NARCIS (Netherlands)

    A. Alfons (Andreas); C. Croux (Christophe); P. Filzmoser (Peter)

    2017-01-01

    textabstractThe maximum association between two multivariate variables X and Y is defined as the maximal value that a bivariate association measure between one-dimensional projections αX and αY can attain. Taking the Pearson correlation as projection index results in the first canonical correlation

  6. Deconstructing tolerance with clobazam

    Science.gov (United States)

    Wechsler, Robert T.; Sankar, Raman; Montouris, Georgia D.; White, H. Steve; Cloyd, James C.; Kane, Mary Clare; Peng, Guangbin; Tworek, David M.; Shen, Vivienne; Isojarvi, Jouko

    2016-01-01

    Objective: To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome. Methods: Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg−1·d−1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg−1·d−1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ≥40% and increasing seizure rates. Results: Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ≥75% responders demonstrated a consistent response over time. Few patients had a dosage increase ≥40% associated with an increase in seizure rates. Conclusions: Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated. ClinicalTrials.gov identifier: NCT00518713 and NCT01160770. Classification of evidence: This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment. PMID:27683846

  7. Dose prescription in boron neutron capture therapy

    International Nuclear Information System (INIS)

    Gupta, N.M.S.; Gahbauer, R.A.; Blue, T.E.; Wambersie, A.

    1994-01-01

    The purpose of this paper is to address some aspects of the many considerations that need to go into a dose prescription in boron neutron capture therapy (BNCT) for brain tumors; and to describe some methods to incorporate knowledge from animal studies and other experiments into the process of dose prescription. Previously, an algorithm to estimate the normal tissue tolerance to mixed high and low linear energy transfer radiations in BNCT was proposed. The authors have developed mathematical formulations and computational methods to represent this algorithm. Generalized models to fit the central axis dose rate components for an epithermal neutron field were also developed. These formulations and beam fitting models were programmed into spreadsheets to simulate two treatment techniques which are expected to be used in BNCT: a two-field bilateral scheme and a single-field treatment scheme. Parameters in these spreadsheets can be varied to represent the fractionation scheme used, the 10 B microdistribution in normal tissue, and the ratio of 10 B in tumor to normal tissue. Most of these factors have to be determined for a given neutron field and 10 B compound combination from large animal studies. The spreadsheets have been programmed to integrate all of the treatment-related information and calculate the location along the central axis where the normal tissue tolerance is exceeded first. This information is then used to compute the maximum treatment time allowable and the maximum tumor dose that may be delivered for a given BNCT treatment. The effect of different treatment variables on the treatment time and tumor dose has been shown to be very significant. It has also been shown that the location of D max shifts significantly, depending on some of the treatment variables-mainly the fractionation scheme used. These results further emphasize the fact that dose prescription in BNCT is very complicated and nonintuitive. 11 refs., 6 figs., 3 tabs

  8. Efficacy and tolerability of high dose "ethinylestradiol" in post-menopausal advanced breast cancer patients heavily pre-treated with endocrine agents

    Directory of Open Access Journals (Sweden)

    Robertson John FR

    2006-07-01

    Full Text Available Abstract Background High dose estrogens (HDEs were frequently used as endocrine agents prior to the introduction of tamoxifen which carries fewer side effects. Due to the development of resistance to available endocrine agents in almost all women with metastatic breast cancer, interest has renewed in the use of HDEs as yet another endocrine option that may have activity. We report our experience with one of the HDEs ("ethinylestradiol" 1 mg daily in advanced breast cancer (locally advanced and metastatic in post-menopausal women who had progressed on multiple endocrine agents. Patients and methods According to a database of advanced breast cancer patients seen in our Unit since 1998, those who had complete set of information and fulfilled the following criteria were studied: (1 patients in whom further endocrine therapy was deemed appropriate i.e., patients who have had clinical benefit with previous endocrine agents or were not fit or unwilling to receive chemotherapy in the presence of potentially life-threatening visceral metastases; (2 disease was assessable by UICC criteria; (3 were treated with "ethinylestradiol" until they were withdrawn from treatment due to adverse events or disease progression. Results Twelve patients with a median age of 75.1 years (49.1 – 85 years were identified. Majority (N = 8 had bony disease. They had ethinylestradiol as 3rd to 7th line endocrine therapy. One patient (8% came off treatment early due to hepato-renal syndrome. Clinical benefit (objective response or durable stable disease for ≥ 6 months was seen in 4 patients (33.3% with a median duration of response of 10+ (7–36 months. The time to treatment failure was 4 (0.5–36 months. Conclusion Yet unreported, high dose "ethinylestradiol" is another viable therapeutic strategy in heavily pre-treated patients when further endocrine therapy is deemed appropriate. Although it tends to carry more side effects, they may not be comparable to those of other

  9. Volume correction factor in time dose relationships in brachytherapy

    International Nuclear Information System (INIS)

    Supe, S.J.; Sasane, J.B.

    1987-01-01

    Paterson's clinical data about the maximum tolerance doses for various volumes of interstitial implants with Ra-226 delivered in seven days was made use of in deriving volume correction factors for TDF and CRE concepts respectively for brachytherapy. The derived volume correction factors for TDF and for CRE differ fromthe one assumed for CRE by Kirk et al. and implied for TDF by Goitein. A normalising volume of 70 cc has been suggested for both CRE and TDF concepts for brachytherapy. A table showing the volume corrected TDF is presented for various volumes and dose rates for continuous irradiation. The use of this table is illustrated with examples. (orig.) [de

  10. Neo-adjuvant radiotherapy focused by Cyberknife in the breast cancer: phase one test of Cyberneo dose escalation; Radiotherapie neoadjuvante focalisee par Cyberknife dans le cancer du sein: essai de phase I d'escalade de dose Cyberneo

    Energy Technology Data Exchange (ETDEWEB)

    Bondiau, P.Y.; Courdi, A.; Lallemand, M.; Peyrote, I.; Chapellier, C.; Ferrero, J.M

    2007-11-15

    The principal evaluation criterion is the maximum tolerated dose ( limiting dose if toxicity {>=} grade 3, recommended if toxicity {<=} 2). The deep cutaneous toxicity is evaluated by two independent observers by colorimetry, macro photographs and video capillaroscopy. The secondary evaluation criteria are the easiness of surgery, the therapeutical effect evaluated on the surgery piece (Sataloff classification) and the measurement of the quality of life. (N.C.)

  11. Maximum power point tracking

    International Nuclear Information System (INIS)

    Enslin, J.H.R.

    1990-01-01

    A well engineered renewable remote energy system, utilizing the principal of Maximum Power Point Tracking can be m ore cost effective, has a higher reliability and can improve the quality of life in remote areas. This paper reports that a high-efficient power electronic converter, for converting the output voltage of a solar panel, or wind generator, to the required DC battery bus voltage has been realized. The converter is controlled to track the maximum power point of the input source under varying input and output parameters. Maximum power point tracking for relative small systems is achieved by maximization of the output current in a battery charging regulator, using an optimized hill-climbing, inexpensive microprocessor based algorithm. Through practical field measurements it is shown that a minimum input source saving of 15% on 3-5 kWh/day systems can easily be achieved. A total cost saving of at least 10-15% on the capital cost of these systems are achievable for relative small rating Remote Area Power Supply systems. The advantages at larger temperature variations and larger power rated systems are much higher. Other advantages include optimal sizing and system monitor and control

  12. 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

  13. SU-F-T-113: Inherent Functional Dependence of Spinal Cord Doses of Variable Irradiated Volumes in Spine SBRT

    Energy Technology Data Exchange (ETDEWEB)

    Ma, L; Braunstein, S; Chiu, J [University of California San Francisco, San Francisco, CA (United States); Sahgal, A [Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario (Canada)

    2016-06-15

    Purpose: Spinal cord tolerance for SBRT has been recommended for the maximum point dose level or at irradiated volumes such as 0.35 mL or 10% of contoured volumes. In this study, we investigated an inherent functional relationship that associates these dose surrogates for irradiated spinal cord volumes of up to 3.0 mL. Methods: A hidden variable termed as Effective Dose Radius (EDR) was formulated based on a dose fall-off model to correlate dose at irradiated spinal cord volumes ranging from 0 mL (point maximum) to 3.0 mL. A cohort of 15 spine SBRT cases was randomly selected to derive an EDR-parameterized formula. The mean prescription dose for the studied cases was 21.0±8.0 Gy (range, 10–40Gy) delivered in 3±1 fractions with target volumes of 39.1 ± 70.6 mL. Linear regression and variance analysis were performed for the fitting parameters of variable EDR values. Results: No direct correlation was found between the dose at maximum point and doses at variable spinal cord volumes. For example, Pearson R{sup 2} = 0.643 and R{sup 2}= 0.491 were obtained when correlating the point maximum dose with the spinal cord dose at 1 mL and 3 mL, respectively. However, near perfect correlation (R{sup 2} ≥0.99) was obtained when corresponding parameterized EDRs. Specifically, Pearson R{sup 2}= 0.996 and R{sup 2} = 0.990 were obtained when correlating EDR (maximum point dose) with EDR (dose at 1 mL) and EDR(dose at 3 mL), respectively. As a result, high confidence level look-up tables were established to correlate spinal cord doses at the maximum point to any finite irradiated volumes. Conclusion: An inherent functional relationship was demonstrated for spine SBRT. Such a relationship unifies dose surrogates at variable cord volumes and proves that a single dose surrogate (e.g. point maximum dose) is mathematically sufficient in constraining the overall spinal cord dose tolerance for SBRT.

  14. 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.

  15. Maximum entropy methods

    International Nuclear Information System (INIS)

    Ponman, T.J.

    1984-01-01

    For some years now two different expressions have been in use for maximum entropy image restoration and there has been some controversy over which one is appropriate for a given problem. Here two further entropies are presented and it is argued that there is no single correct algorithm. The properties of the four different methods are compared using simple 1D simulations with a view to showing how they can be used together to gain as much information as possible about the original object. (orig.)

  16. Towards Tolerance

    NARCIS (Netherlands)

    Lisette Kuyper; Jurjen Iedema; Saskia Keuzenkamp

    2013-01-01

    Across Europe, public attitudes towards lesbian, gay and bisexual (LGB) individuals range from broad tolerance to widespread rejection. Attitudes towards homosexuality are more than mere individual opinions, but form part of the social and political structures which foster or hinder the equality

  17. Intolerant tolerance.

    Science.gov (United States)

    Khushf, G

    1994-04-01

    The Hyde Amendment and Roman Catholic attempts to put restrictions on Title X funding have been criticized for being intolerant. However, such criticism fails to appreciate that there are two competing notions of tolerance, one focusing on the limits of state force and accepting pluralism as unavoidable, and the other focusing on the limits of knowledge and advancing pluralism as a good. These two types of tolerance, illustrated in the writings of John Locke and J.S. Mill, each involve an intolerance. In a pluralistic context where the free exercise of religion is respected, John Locke's account of tolerance is preferable. However, it (in a reconstructed form) leads to a minimal state. Positive entitlements to benefits like artificial contraception or nontherapeutic abortions can legitimately be resisted, because an intolerance has already been shown with respect to those that consider the benefit immoral, since their resources have been coopted by taxation to advance an end that is contrary to their own. There is a sliding scale from tolerance (viewed as forbearance) to the affirmation of communal integrity, and this scale maps on to the continuum from negative to positive rights.

  18. The last glacial maximum

    Science.gov (United States)

    Clark, P.U.; Dyke, A.S.; Shakun, J.D.; Carlson, A.E.; Clark, J.; Wohlfarth, B.; Mitrovica, J.X.; Hostetler, S.W.; McCabe, A.M.

    2009-01-01

    We used 5704 14C, 10Be, and 3He ages that span the interval from 10,000 to 50,000 years ago (10 to 50 ka) to constrain the timing of the Last Glacial Maximum (LGM) in terms of global ice-sheet and mountain-glacier extent. Growth of the ice sheets to their maximum positions occurred between 33.0 and 26.5 ka in response to climate forcing from decreases in northern summer insolation, tropical Pacific sea surface temperatures, and atmospheric CO2. Nearly all ice sheets were at their LGM positions from 26.5 ka to 19 to 20 ka, corresponding to minima in these forcings. The onset of Northern Hemisphere deglaciation 19 to 20 ka was induced by an increase in northern summer insolation, providing the source for an abrupt rise in sea level. The onset of deglaciation of the West Antarctic Ice Sheet occurred between 14 and 15 ka, consistent with evidence that this was the primary source for an abrupt rise in sea level ???14.5 ka.

  19. Heat tolerance in wheat

    DEFF Research Database (Denmark)

    Sharma, Dew Kumari

    As a consequence of global climate change, heat stress together with other abiotic stresses will remain an important determinant of future food security. Wheat (Triticum aestivum L.) is the third most important crop of the world feeding one third of the world population. Being a crop of temperate...... climate, wheat is sensitive to heat stress. We need to understand how our crops will perform in these changing climatic conditions and how we can develop varieties, which are more tolerant. The PhD study focussed on understanding heat tolerance in wheat with a combined approach of plant physiology...... and quantitative genetics in particular, plant phenotyping based quantitative trait loci (QTL) discovery for a physiological trait under heat stress. Chlorophyll a fluorescence trait, Fv/Fm was used as a phenotyping tool, as it reflects the effect of heat stress on maximum photochemical efficiency of photosystem...

  20. 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

  1. Phase 2, Randomized, Double-Blind, Dose-Ranging Study Evaluating the Safety, Tolerability, Population Pharmacokinetics, and Efficacy of Oral Torezolid Phosphate in Patients with Complicated Skin and Skin Structure Infections▿ † ‡

    Science.gov (United States)

    Prokocimer, P.; Bien, P.; Surber, J.; Mehra, P.; DeAnda, C.; Bulitta, J. B.; Corey, G. R.

    2011-01-01

    Torezolid (TR-700) is the active moiety of the prodrug torezolid phosphate ([TP] TR-701), a second-generation oxazolidinone with 4- to 16-fold greater potency than linezolid against Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind phase 2 study evaluated three levels (200, 300, or 400 mg) of oral, once-daily TP over 5 to 7 days for complicated skin and skin structure infections (cSSSI). Patients 18 to 75 years old with cSSSI caused by suspected or confirmed Gram-positive pathogens were randomized 1:1:1. Of 188 treated patients, 76.6% had abscesses, 17.6% had extensive cellulitis, and 5.9% had wound infections. S. aureus, the most common pathogen, was isolated in 90.3% of patients (139/154) with a baseline pathogen; 80.6% were MRSA. Cure rates in clinically evaluable patients were 98.2% at 200 mg, 94.4% at 300 mg, and 94.4% at 400 mg. Cure rates were consistent across diagnoses, regardless of lesion size or the presence of systemic signs of infection. Clinical cure rates in patients with S. aureus isolated at baseline were 96.6% overall and 96.8% for MRSA. TP was safe and well tolerated at all dose levels. No patients discontinued treatment due to an adverse event. Three-stage hierarchical population pharmacokinetic modeling yielded a geometric mean clearance of 8.28 liters/h (between-patient variability, 32.3%), a volume of the central compartment of 71.4 liters (24.0%), and a volume of the peripheral compartment of 27.9 liters (35.7%). Results of this study show a high degree of efficacy at all three dose levels without significant differences in the safety profile and support the continued evaluation of TP for the treatment of cSSSI in phase 3 trials. PMID:21115795

  2. 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.

  3. 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

  4. Maximum Entropy Fundamentals

    Directory of Open Access Journals (Sweden)

    F. Topsøe

    2001-09-01

    Full Text Available Abstract: In its modern formulation, the Maximum Entropy Principle was promoted by E.T. Jaynes, starting in the mid-fifties. The principle dictates that one should look for a distribution, consistent with available information, which maximizes the entropy. However, this principle focuses only on distributions and it appears advantageous to bring information theoretical thinking more prominently into play by also focusing on the "observer" and on coding. This view was brought forward by the second named author in the late seventies and is the view we will follow-up on here. It leads to the consideration of a certain game, the Code Length Game and, via standard game theoretical thinking, to a principle of Game Theoretical Equilibrium. This principle is more basic than the Maximum Entropy Principle in the sense that the search for one type of optimal strategies in the Code Length Game translates directly into the search for distributions with maximum entropy. In the present paper we offer a self-contained and comprehensive treatment of fundamentals of both principles mentioned, based on a study of the Code Length Game. Though new concepts and results are presented, the reading should be instructional and accessible to a rather wide audience, at least if certain mathematical details are left aside at a rst reading. The most frequently studied instance of entropy maximization pertains to the Mean Energy Model which involves a moment constraint related to a given function, here taken to represent "energy". This type of application is very well known from the literature with hundreds of applications pertaining to several different elds and will also here serve as important illustration of the theory. But our approach reaches further, especially regarding the study of continuity properties of the entropy function, and this leads to new results which allow a discussion of models with so-called entropy loss. These results have tempted us to speculate over

  5. A prospective, parallel group, open-labeled, comparative, multi-centric, active controlled study to evaluate the safety, tolerability and benefits of fixed dose combination of acarbose and metformin versus metformin alone in type 2 diabetes.

    Science.gov (United States)

    Jayaram, S; Hariharan, R S; Madhavan, R; Periyandavar, I; Samra, S S

    2010-11-01

    The present study was a prospective, parallel group, open-labeled, comparative, multicentric, active controlled study to evaluate the safety, tolerability and benefits of fixed dose combination of acarbose and metformin versus metformin alone in type 2 diabetic patients. A total of 229 patients with type 2 diabetes were enrolled at 5 medical centers across India. They received either acarbose (50 mg) + metformin (500 mg) bid/tid (n=115) or metformin monotherapy (500 mg) bid/ tid (n=114) for 12 weeks. Primary objective was to evaluate safety and tolerability based on the adverse events reported. Secondary objective was efficacy assessment based on changes in fasting, post prandial blood glucose and HbA1c values. In the acarbose + metformin group 10 patients reported 14 adverse events while in metformin group 9 patients reported 10 adverse events. No patient reported any serious adverse event or was withdraw from study because of adverse events. In the acarbose plus metformin group fasting blood glucose (FBG) decreased from a baseline of 158.85 +/- 18.14 mg/dl to 113.55 +/- 19.38 mg/dl (p fasting blood glucose decreased from a baseline of 158.31 +/- 26.53 mg/dl to 130.55 +/- 28.31 mg/dl (p < 0.0001) (decrease of 27.76 +/- 22.91 mg/dl) at 12 weeks. In the acarbose plus metformin group postprandial blood glucose (PPBG) decreased from a baseline of 264.65 +/- 34.03 mg/dl to 173.22 +/- 31.40 mg/dl (p < 0.0001) (decrease of 91.43 +/- 28.65 mg/dl) at 12 weeks, while in the metformin group PPBG decreased from a baseline of 253.56 +/- 36.28 mg/dl to 205.36 +/- 39.49 mg/dl (p < 0.0001) (decrease of 48.20 +/- 32.72 mg/dl) at 12 weeks. In the acarbose plus metformin group glycosylated haemoglobin (HbA1c) decreased from a baseline of 9.47 +/- 0.69% to 7.71 +/- 0.85% (p < 0.0001) (% decrease of 1.76 +/- 1.11) at 12 weeks, while in the metformin group HbAlc decreased from a baseline of 9.32 +/- 0.65% to 8.26 +/- 0.68% (p < 0.0001) (% decrease of 1.06 +/- 0.66) at 12 weeks. The

  6. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Herman, Gary A; Bergman, Arthur; Stevens, Catherine

    2006-01-01

    CONTEXT: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglyce......CONTEXT: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral...... antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated. OBJECTIVE: The objective of the study was to examine...... concentrations; and sitagliptin pharmacokinetics. RESULTS: Sitagliptin dose-dependently inhibited plasma DPP-4 activity over 24 h, enhanced active GLP-1 and GIP levels, increased insulin/C-peptide, decreased glucagon, and reduced glycemic excursion after OGTTs administered at 2 and 24 h after single oral 25...

  7. 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

  8. Probable maximum flood control

    International Nuclear Information System (INIS)

    DeGabriele, C.E.; Wu, C.L.

    1991-11-01

    This study proposes preliminary design concepts to protect the waste-handling facilities and all shaft and ramp entries to the underground from the probable maximum flood (PMF) in the current design configuration for the proposed Nevada Nuclear Waste Storage Investigation (NNWSI) repository protection provisions were furnished by the United States Bureau of Reclamation (USSR) or developed from USSR data. Proposed flood protection provisions include site grading, drainage channels, and diversion dikes. Figures are provided to show these proposed flood protection provisions at each area investigated. These areas are the central surface facilities (including the waste-handling building and waste treatment building), tuff ramp portal, waste ramp portal, men-and-materials shaft, emplacement exhaust shaft, and exploratory shafts facility

  9. Introduction to maximum entropy

    International Nuclear Information System (INIS)

    Sivia, D.S.

    1988-01-01

    The maximum entropy (MaxEnt) principle has been successfully used in image reconstruction in a wide variety of fields. We review the need for such methods in data analysis and show, by use of a very simple example, why MaxEnt is to be preferred over other regularizing functions. This leads to a more general interpretation of the MaxEnt method, and its use is illustrated with several different examples. Practical difficulties with non-linear problems still remain, this being highlighted by the notorious phase problem in crystallography. We conclude with an example from neutron scattering, using data from a filter difference spectrometer to contrast MaxEnt with a conventional deconvolution. 12 refs., 8 figs., 1 tab

  10. Solar maximum observatory

    International Nuclear Information System (INIS)

    Rust, D.M.

    1984-01-01

    The successful retrieval and repair of the Solar Maximum Mission (SMM) satellite by Shuttle astronauts in April 1984 permitted continuance of solar flare observations that began in 1980. The SMM carries a soft X ray polychromator, gamma ray, UV and hard X ray imaging spectrometers, a coronagraph/polarimeter and particle counters. The data gathered thus far indicated that electrical potentials of 25 MeV develop in flares within 2 sec of onset. X ray data show that flares are composed of compressed magnetic loops that have come too close together. Other data have been taken on mass ejection, impacts of electron beams and conduction fronts with the chromosphere and changes in the solar radiant flux due to sunspots. 13 references

  11. Introduction to maximum entropy

    International Nuclear Information System (INIS)

    Sivia, D.S.

    1989-01-01

    The maximum entropy (MaxEnt) principle has been successfully used in image reconstruction in a wide variety of fields. The author reviews the need for such methods in data analysis and shows, by use of a very simple example, why MaxEnt is to be preferred over other regularizing functions. This leads to a more general interpretation of the MaxEnt method, and its use is illustrated with several different examples. Practical difficulties with non-linear problems still remain, this being highlighted by the notorious phase problem in crystallography. He concludes with an example from neutron scattering, using data from a filter difference spectrometer to contrast MaxEnt with a conventional deconvolution. 12 refs., 8 figs., 1 tab

  12. Functional Maximum Autocorrelation Factors

    DEFF Research Database (Denmark)

    Larsen, Rasmus; Nielsen, Allan Aasbjerg

    2005-01-01

    MAF outperforms the functional PCA in concentrating the interesting' spectra/shape variation in one end of the eigenvalue spectrum and allows for easier interpretation of effects. Conclusions. Functional MAF analysis is a useful methods for extracting low dimensional models of temporally or spatially......Purpose. We aim at data where samples of an underlying function are observed in a spatial or temporal layout. Examples of underlying functions are reflectance spectra and biological shapes. We apply functional models based on smoothing splines and generalize the functional PCA in......\\verb+~+\\$\\backslash\\$cite{ramsay97} to functional maximum autocorrelation factors (MAF)\\verb+~+\\$\\backslash\\$cite{switzer85,larsen2001d}. We apply the method to biological shapes as well as reflectance spectra. {\\$\\backslash\\$bf Methods}. MAF seeks linear combination of the original variables that maximize autocorrelation between...

  13. Regularized maximum correntropy machine

    KAUST Repository

    Wang, Jim Jing-Yan; Wang, Yunji; Jing, Bing-Yi; Gao, Xin

    2015-01-01

    In this paper we investigate the usage of regularized correntropy framework for learning of classifiers from noisy labels. The class label predictors learned by minimizing transitional loss functions are sensitive to the noisy and outlying labels of training samples, because the transitional loss functions are equally applied to all the samples. To solve this problem, we propose to learn the class label predictors by maximizing the correntropy between the predicted labels and the true labels of the training samples, under the regularized Maximum Correntropy Criteria (MCC) framework. Moreover, we regularize the predictor parameter to control the complexity of the predictor. The learning problem is formulated by an objective function considering the parameter regularization and MCC simultaneously. By optimizing the objective function alternately, we develop a novel predictor learning algorithm. The experiments on two challenging pattern classification tasks show that it significantly outperforms the machines with transitional loss functions.

  14. Regularized maximum correntropy machine

    KAUST Repository

    Wang, Jim Jing-Yan

    2015-02-12

    In this paper we investigate the usage of regularized correntropy framework for learning of classifiers from noisy labels. The class label predictors learned by minimizing transitional loss functions are sensitive to the noisy and outlying labels of training samples, because the transitional loss functions are equally applied to all the samples. To solve this problem, we propose to learn the class label predictors by maximizing the correntropy between the predicted labels and the true labels of the training samples, under the regularized Maximum Correntropy Criteria (MCC) framework. Moreover, we regularize the predictor parameter to control the complexity of the predictor. The learning problem is formulated by an objective function considering the parameter regularization and MCC simultaneously. By optimizing the objective function alternately, we develop a novel predictor learning algorithm. The experiments on two challenging pattern classification tasks show that it significantly outperforms the machines with transitional loss functions.

  15. 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

  16. Salt Tolerance

    OpenAIRE

    Xiong, Liming; Zhu, Jian-Kang

    2002-01-01

    Studying salt stress is an important means to the understanding of plant ion homeostasis and osmo-balance. Salt stress research also benefits agriculture because soil salinity significantly limits plant productivity on agricultural lands. Decades of physiological and molecular studies have generated a large body of literature regarding potential salt tolerance determinants. Recent advances in applying molecular genetic analysis and genomics tools in the model plant Arabidopsis thaliana are sh...

  17. Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension: Safe and Tolerable.

    Science.gov (United States)

    El-Kersh, Karim; Ruf, Kathryn M; Smith, J Shaun

    There is no standard protocol for intravenous treprostinil dose escalation. In most cases, slow up-titration is performed in the outpatient setting. However, rapid up-titration in an inpatient setting is an alternative that provides opportunity for aggressive treatment of common side effects experienced during dose escalation. In this study, we describe our experience with inpatient rapid up-titration of intravenous treprostinil. This was a single-center, retrospective study in which we reviewed the data of subjects with pulmonary arterial hypertension treated at our center who underwent inpatient rapid up-titration of intravenous treprostinil. Our treprostinil dose escalation protocol included initiation at 2 ng·kg·min with subsequent up-titration by 1 ng·kg·min every 6 to 8 hours as tolerated by side effects. A total of 16 subjects were identified. Thirteen subjects were treprostinil naive (naive group), and 3 subjects were receiving subcutaneous treprostinil but were hospitalized for further intravenous up-titration of treprostinil dose (nonnaive group). In the naive group, the median maximum dose achieved was 20 ng·kg·min with an interquartile range (IQR) of 20-23 ng·kg·min. The median up-titration interval was 6 days (IQR: 4-9). In the nonnaive group, the median maximum dose achieved was 20 ng·kg·min (range: 17-30). The median up-titration interval was 8.5 days (range: 1.5-11). Overall, the median maximum dose achieved was 20 ng·kg·min (IQR: 20-23.5), and the median up-titration interval was 6 days (IQR: 4.6-9.25), with no reported significant adverse hemodynamic events. In patients with pulmonary arterial hypertension, rapid inpatient titration of intravenous treprostinil is safe and tolerable.

  18. Evaluation of preclinical single and multiple dose toxicity and efficacy of 213 Bi-labeled plasminogen activator inhibitor 2 for breast and prostate cancer

    International Nuclear Information System (INIS)

    Rizvi, S.; Li, Y.; Allen, B.; Littlejohn, T.; Ranson, M.; Links, M.; Irving, D.; Andrews, J.

    2003-01-01

    The aim of the study was to evaluate the single and multiple dose toxicity (maximum tolerated dose or MTD) regimes for 213 Bi-labeled PAI2. Dose range of 2-8 mCi/kg was used for the single dose toxicity studies. It was found that end point (20% weight loss and/or distressed behaviour) was not reached for the highest dose either with single or multiple dose injections. For multiple dose toxicity studies, the dose levels ranged between 0.4 - 2 mCi/kg, and were administered daily for 5 days. The highest level tested (2mCi/kg/day x 5) was the maximum tolerated dose as 3/6 mice succumbed to the endpoints. However, histological examination of major organs showed no adverse morphological changes. From these toxicity studies, we concluded that either a dose of 1.6mCi/kg of 213 Bi-PAI2 per day for 5 days or a single injection of 8 mCi/kg can be administered without reaching the endpoints. These dose levels were used for efficacy trials. The efficacy studies were conducted to examine if the 1.6mCi/kgday x 5 multiple dose schedule (sub-maximum tolerated dose) showed efficacy against established and early stage human breast and prostate tumours in mice. Statistical analyses of the data indicate a significant tumour growth rate delay and increased time to reach tumour size endpoint for alpha-PAI2 treatment compared to control tumours, in both pre-tumour stage and established tumour models

  19. 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...

  20. 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...

  1. Solar maximum mission

    International Nuclear Information System (INIS)

    Ryan, J.

    1981-01-01

    By understanding the sun, astrophysicists hope to expand this knowledge to understanding other stars. To study the sun, NASA launched a satellite on February 14, 1980. The project is named the Solar Maximum Mission (SMM). The satellite conducted detailed observations of the sun in collaboration with other satellites and ground-based optical and radio observations until its failure 10 months into the mission. The main objective of the SMM was to investigate one aspect of solar activity: solar flares. A brief description of the flare mechanism is given. The SMM satellite was valuable in providing information on where and how a solar flare occurs. A sequence of photographs of a solar flare taken from SMM satellite shows how a solar flare develops in a particular layer of the solar atmosphere. Two flares especially suitable for detailed observations by a joint effort occurred on April 30 and May 21 of 1980. These flares and observations of the flares are discussed. Also discussed are significant discoveries made by individual experiments

  2. 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

  3. Zinc dosing and glucose tolerance in humans

    International Nuclear Information System (INIS)

    Greenley, S.; Taylor, M.

    1986-01-01

    Animal data suggest the existence of a physiologic relationship between glucoregulatory hormones and zinc metabolism. In order to investigate this proposed relationship in humans, they examined the effect of moderately elevated plasma zinc levels on blood glucose clearance. Eight women (24-37 yrs) served as subjects for the study. Fasted volunteers were tested under two experimental conditions (a) ingestion of 50 g D-glucose (b) ingestion of 25 mg zinc followed 60 min later by ingestion of 50 g D-glucose. Five ml venous blood was drawn into trace-metal-free, fluoride-containing vacutainer tubes prior to and 15, 30, 45, 60, 90, and 120 min after glucose ingestion. Plasma was analyzed for glucose and zinc; glycemic responses were quantified by computing areas under the curves and times to peak concentration. Their human data indicate varied glycemic responses to the acute elevation of plasma zinc: 4 subjects showed little apparent effect; 3 subjects marginally increased either the area under the curve or time to peak and 1 subject (classified as suspect diabetic in the non-zinc condition) showed marked improvement in glycemic response following zinc ingestion. Their preliminary results suggest that blood glucose clearance may be affected in some individuals by the acute elevation of plasma zinc

  4. Infectious Tolerance

    OpenAIRE

    Jonuleit, Helmut; Schmitt, Edgar; Kakirman, Hacer; Stassen, Michael; Knop, Jürgen; Enk, Alexander H.

    2002-01-01

    Regulatory CD4+CD25+ T cells (Treg) are mandatory for maintaining immunologic self-tolerance. We demonstrate that the cell-cell contact–mediated suppression of conventional CD4+ T cells by human CD25+ Treg cells is fixation resistant, independent from membrane-bound TGF-β but requires activation and protein synthesis of CD25+ Treg cells. Coactivation of CD25+ Treg cells with Treg cell–depleted CD4+ T cells results in anergized CD4+ T cells that in turn inhibit the activation of conventional, ...

  5. Adherence to Treatment, Safety, Tolerance, and Effectiveness of Perindopril/Amlodipine Fixed-Dose Combination in Greek Patients with Hypertension and Stable Coronary Artery Disease: A Pan-Hellenic Prospective Observational Study of Daily Clinical Practice.

    Science.gov (United States)

    Liakos, Charalampos I; Papadopoulos, Dimitrios P; Kotsis, Vasilios T

    2017-10-01

    Initiation of antihypertensive therapy with a two-drug fixed-dose combination (FDC) in a single tablet may be recommended in patients at high risk of cardiovascular events to improve adherence and effectiveness. Preferred combinations include an angiotensin-converting enzyme inhibitor with a dihydropyridine calcium antagonist. This study assessed adherence to and the safety, tolerance, and effectiveness of the perindopril/amlodipine FDC in Greek patients with hypertension and stable coronary artery disease (CAD) over a 4-month period. A total of 1907 patients with hypertension and CAD (59.1% males) who had recently (≤2 weeks) commenced treatment with the perindopril/amlodipine FDC (5/5, 5/10, 10/5, or 10/10 mg) were studied at baseline and at 1 and 4 months. Adherence to treatment was assessed with the Morisky Medication-taking Adherence Scale (MMAS). Seven patients (0.4%) did not attend the scheduled visits. In total, 1607 (84.6%) patients received a constant treatment dose throughout the study. High adherence (MMAS score = 0) was reported by 1592 (83.6%), 1628 (85.7%), and 1477 (77.7%) patients at the second and the third visit and at both visits, respectively. Adverse reactions were reported by only 13 (0.7%) patients, were all minor, and did not result in treatment discontinuation. Office blood pressure (BP) was significantly decreased at the third visit (130.8 ± 8.4/78.2 ± 6.4 mmHg) compared with baseline (156.5 ± 15.0/89.9 ± 9.6 mmHg; p < 0.001), regardless of previous antihypertensive treatment. Patients with grade 1, 2, and 3 hypertension at baseline showed a reduction in BP of 19.3/9.4, 31.5/13.5, and 47.8/22.2 mmHg, respectively (p < 0.001). Uncontrolled hypertension (≥140/90 mmHg) was notably reduced from 90.3% at baseline to 18.5% at the third visit. The perindopril/amlodipine FDC is characterized by high adherence and effectiveness, regardless of previous treatment. Degree of BP reduction was related to baseline BP levels

  6. Infectious Tolerance

    Science.gov (United States)

    Jonuleit, Helmut; Schmitt, Edgar; Kakirman, Hacer; Stassen, Michael; Knop, Jürgen; Enk, Alexander H.

    2002-01-01

    Regulatory CD4+CD25+ T cells (Treg) are mandatory for maintaining immunologic self-tolerance. We demonstrate that the cell-cell contact–mediated suppression of conventional CD4+ T cells by human CD25+ Treg cells is fixation resistant, independent from membrane-bound TGF-β but requires activation and protein synthesis of CD25+ Treg cells. Coactivation of CD25+ Treg cells with Treg cell–depleted CD4+ T cells results in anergized CD4+ T cells that in turn inhibit the activation of conventional, freshly isolated CD4+ T helper (Th) cells. This infectious suppressive activity, transferred from CD25+ Treg cells via cell contact, is cell contact–independent and partially mediated by soluble transforming growth factor (TGF)-β. The induction of suppressive properties in conventional CD4+ Th cells represents a mechanism underlying the phenomenon of infectious tolerance. This explains previously published conflicting data on the role of TGF-β in CD25+ Treg cell–induced immunosuppression. PMID:12119350

  7. Tolerance of cranial nerves of the cavernous sinus to radiosurgery

    International Nuclear Information System (INIS)

    Tishler, R.B.; Loeffler, J.S.; Alexander, E. III; Kooy, H.M.; Lunsford, L.D.; Duma, C.; Flickinger, J.C.

    1993-01-01

    Stereotactic radiosurgery is becoming a more accepted treatment option for benign, deep seated intracranial lesions. However, little is known about the effects of large single fractions of radiation on cranial nerves. This study was undertaken to assess the effect of radiosurgery on the cranial nerves of the cavernous sinus. The authors examined the tolerance of cranial nerves (II-VI) following radiosurgery for 62 patients (42/62 with meningiomas) treated for lesions within or near the cavernous sinus. Twenty-nine patients were treated with a modified 6 MV linear accelerator (Joint Center for Radiation Therapy) and 33 were treated with the Gamma Knife (University of Pittsburgh). Three-dimensional treatment plans were retrospectively reviewed and maximum doses were calculated for the cavernous sinus and the optic nerve and chiasm. Median follow-up was 19 months (range 3-49). New cranial neuropathies developed in 12 patients from 3-41 months following radiosurgery. Four of these complications involved injury to the optic system and 8 (3/8 transient) were the result of injury to the sensory or motor nerves of the cavernous sinus. There was no clear relationship between the maximum dose to the cavernous sinus and the development of complications for cranial nerves III-VI over the dose range used (1000-4000 cGy). For the optic apparatus, there was a significantly increased incidence of complications with dose. Four of 17 patients (24%) receiving greater than 800 cGy to any part of the optic apparatus developed visual complications compared with 0/35 who received less than 800 cGy (p = 0.009). Radiosurgery using tumor-controlling doses of up to 4000 cGy appears to be a relatively safe technique in treating lesions within or near the sensory and motor nerves (III-VI) of the cavernous sinus. The dose to the optic apparatus should be limited to under 800 cGy. 21 refs., 4 tabs

  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. 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

  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. 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.

  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. Repressive Tolerance

    DEFF Research Database (Denmark)

    Pedersen, Morten Jarlbæk

    2017-01-01

    Consultation of organised interests and others when drafting laws is often seen as an important source of both input and output legitimacy. But whereas the input side of the equation stems from the very process of listening to societal actors, output legitimacy can only be strengthened if consult......Consultation of organised interests and others when drafting laws is often seen as an important source of both input and output legitimacy. But whereas the input side of the equation stems from the very process of listening to societal actors, output legitimacy can only be strengthened...... a substantial effect on the substance of laws – shows that there is a great difference in the amenability of different branches of government but that, in general, authorities do not listen much despite a very strong consultation institution and tradition. A suggestion for an explanation could be pointing...... to an administrative culture of repressive tolerance of organised interests: authorities listen but only reacts in a very limited sense. This bears in it the risk of jeopardising the knowledge transfer from societal actors to administrative ditto thus harming the consultation institutions’ potential for strengthening...

  15. 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.

  16. 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

  17. Theoretical considerations for SRAM total-dose hardening

    International Nuclear Information System (INIS)

    Francis, P.; Flandre, D.; Colinge, J.P.

    1995-01-01

    The theoretical hardness against total dose of the six-transistor SRAM cell is investigated in detail. An explicit analytical expression of the maximum tolerable threshold voltage shift is derived for two cross-coupled inverters. A numerical method is used to explore the hardness of the read and write operations. Both N- and P-channel access transistors designs are considered and their respective advantages are compared. The study points out that the radiation hardness mainly relies on the technology. Results obtained with the very robust Gate-All-Around process are finally presented

  18. Influence of Routine MV CBCT Usage on Dose Distribution in Pelvic Radiotherapy

    International Nuclear Information System (INIS)

    Faj, D.; Kasabasic, M.; Ivkovic, A.; Tomas, I.; Jurkovic, S.

    2013-01-01

    The pelvic radiotherapy is a standard treatment for patients with cervical, uterine and rectal carcinomas. During radiation treatment open tabletop device or bellyboard is used to reduce the side effects of healthy surrounding tissue. Patients are continually adjusting to the bellyboard during the treatment which causes geometrical and dosage uncertainties and influences the results of the treatment. Therefore, to reduce these uncertainties, megavoltage cone-beam computed tomography (MV CBCT) system is used. The objective of this research was to evaluate the image acquisition dose delivered to patients from MV CBCT. MV CBCT imaging was simulated on 15 patients using 3D treatment planning software XiO (CMS Inc., St. Louis, MO). The influence of the routine MV CBCT usage on treatment plan was investigated by analyzing the changes in dose volume histograms, mean values and maximum doses in the planning volumes. Simulations have shown that daily usage of MV CBCT causes differences in the dose volume histograms. Moreover, for every patient mean value exceeded prescribed tolerance (±1% of the prescribed dose) and maximum value exceeded recommended maximum of 107% of the prescribed dose. The results have shown that MV CBCT dose to the patient should be a part of the RT plan.(author)

  19. Credal Networks under Maximum Entropy

    OpenAIRE

    Lukasiewicz, Thomas

    2013-01-01

    We apply the principle of maximum entropy to select a unique joint probability distribution from the set of all joint probability distributions specified by a credal network. In detail, we start by showing that the unique joint distribution of a Bayesian tree coincides with the maximum entropy model of its conditional distributions. This result, however, does not hold anymore for general Bayesian networks. We thus present a new kind of maximum entropy models, which are computed sequentially. ...

  20. 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.

  1. 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

  2. Spectroscopic gamma camera for use in high dose environments

    Energy Technology Data Exchange (ETDEWEB)

    Ueno, Yuichiro, E-mail: yuichiro.ueno.bv@hitachi.com [Research and Development Group, Hitachi, Ltd., Hitachi-shi, Ibaraki-ken 319-1221 (Japan); Takahashi, Isao; Ishitsu, Takafumi; Tadokoro, Takahiro; Okada, Koichi; Nagumo, Yasushi [Research and Development Group, Hitachi, Ltd., Hitachi-shi, Ibaraki-ken 319-1221 (Japan); Fujishima, Yasutake; Kometani, Yutaka [Hitachi Works, Hitachi-GE Nuclear Energy, Ltd., Hitachi-shi, Ibaraki-ken (Japan); Suzuki, Yasuhiko [Measuring Systems Engineering Dept., Hitachi Aloka Medical, Ltd., Ome-shi, Tokyo (Japan); Umegaki, Kikuo [Faculty of Engineering, Hokkaido University, Sapporo-shi, Hokkaido (Japan)

    2016-06-21

    We developed a pinhole gamma camera to measure distributions of radioactive material contaminants and to identify radionuclides in extraordinarily high dose regions (1000 mSv/h). The developed gamma camera is characterized by: (1) tolerance for high dose rate environments; (2) high spatial and spectral resolution for identifying unknown contaminating sources; and (3) good usability for being carried on a robot and remotely controlled. These are achieved by using a compact pixelated detector module with CdTe semiconductors, efficient shielding, and a fine resolution pinhole collimator. The gamma camera weighs less than 100 kg, and its field of view is an 8 m square in the case of a distance of 10 m and its image is divided into 256 (16×16) pixels. From the laboratory test, we found the energy resolution at the 662 keV photopeak was 2.3% FWHM, which is enough to identify the radionuclides. We found that the count rate per background dose rate was 220 cps h/mSv and the maximum count rate was 300 kcps, so the maximum dose rate of the environment where the gamma camera can be operated was calculated as 1400 mSv/h. We investigated the reactor building of Unit 1 at the Fukushima Dai-ichi Nuclear Power Plant using the gamma camera and could identify the unknown contaminating source in the dose rate environment that was as high as 659 mSv/h.

  3. 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

  4. IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Landau, David B., E-mail: david.landau@kcl.ac.uk [Guy' s & St. Thomas' NHS Trust, King' s College London, London (United Kingdom); Hughes, Laura [Cancer Research UK and UCL Cancer Trials Centre, London (United Kingdom); Baker, Angela [Clatterbridge Cancer Centre, Bebington (United Kingdom); Bates, Andrew T. [Southampton General Hospital, Southampton (United Kingdom); Bayne, Michael C. [Poole Hospital, Poole (United Kingdom); Counsell, Nicholas [Cancer Research UK and UCL Cancer Trials Centre, London (United Kingdom); Garcia-Alonso, Angel [North Wales Cancer Centre, Rhyl (United Kingdom); Harden, Susan V. [Addenbrookes Hospital, Cambridge (United Kingdom); Hicks, Jonathan D. [Beatson West of Scotland Cancer Centre, Glasgow (United Kingdom); Hughes, Simon R. [Guy' s & St. Thomas' NHS Trust, King' s College London, London (United Kingdom); Illsley, Marianne C. [Royal Surrey County Hospital, Guilford (United Kingdom); Khan, Iftekhar [Cancer Research UK and UCL Cancer Trials Centre, London (United Kingdom); Laurence, Virginia [Poole Hospital, Poole (United Kingdom); Malik, Zafar; Mayles, Helen; Mayles, William Philip M. [Clatterbridge Cancer Centre, Bebington (United Kingdom); Miles, Elizabeth [Mount Vernon Hospital, Middlesex (United Kingdom); Mohammed, Nazia [Beatson West of Scotland Cancer Centre, Glasgow (United Kingdom); Ngai, Yenting [Cancer Research UK and UCL Cancer Trials Centre, London (United Kingdom); Parsons, Emma [Mount Vernon Hospital, Middlesex (United Kingdom); and others

    2016-08-01

    Purpose: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

  5. TOLERANCE SENSITIVITY ANALYSIS: THIRTY YEARS LATER

    Directory of Open Access Journals (Sweden)

    Richard E. Wendell

    2010-12-01

    Full Text Available Tolerance sensitivity analysis was conceived in 1980 as a pragmatic approach to effectively characterize a parametric region over which objective function coefficients and right-hand-side terms in linear programming could vary simultaneously and independently while maintaining the same optimal basis. As originally proposed, the tolerance region corresponds to the maximum percentage by which coefficients or terms could vary from their estimated values. Over the last thirty years the original results have been extended in a number of ways and applied in a variety of applications. This paper is a critical review of tolerance sensitivity analysis, including extensions and applications.

  6. Dose from radiological examinations

    International Nuclear Information System (INIS)

    Imamura, Keiko; Uji, Teruyuki; Sakuyama, Keiko; Fujikawa, Mitsuhiro; Fujii, Masamichi

    1976-01-01

    Relatively high gonad doses, several hundred to one thousand mR, have been observed in case of pelvis, hip-joint, coccyx, lower abdomen and lumber examination. Dose to the ovary is especially high in barium enema and I.V.P. examinations. About 12 per cent of the 4-ray examination are high-dose. The gonad dose is relatively high in examination of abdomen and lower extremities, in infants. The dose to the eyes is especially high, 1.0 to 2.5R per exposure, in temporal bone and nasal sinuses tomography. X-ray doses have been compared with dose limits recommended by ICRP and with the gonad dose from natural radiations. The gonad dose in lumbar examination, barium enema, I.V.P. etc. is as high as the maximum permissible dose per year recommended by ICRP. Several devices have been made for dose reduction in the daily examinations: (1) separating the radiation field from the gonad by one centimeter decreases the gonad dose about one-half. (2) using sensitive screens and films. In pelvimetry and in infant hip-joint examination, the most sensitive screen and film are used. In the I.V.P. examination of adult, use of MS screen in place of FS screen decreases the dose to one-third, in combination with careful setting of radiation field, (3) use of grid increases the dose about 50 percent and the lead rubber protection (0.1mm lead equivalent) decreases the gonad dose to one-thirtieth in the spinal column examination of infant, (4) A lead protector, 1mm thickness and 2.5cm in diameter, on the eyes decreases the dose to about one-eighth in the face and nead examinations. These simple and effective methods for dose reduction. Should be carried out in as many examinations as possible in addition to observing dose limits recommended by ICRP. (Evans, J.)

  7. [Value of early application of different doses of amino acids in parenteral nutrition among preterm infants].

    Science.gov (United States)

    Liu, Zhi-Juan; Liu, Guo-Sheng; Chen, Yong-Ge; Zhang, Hui-Li; Wu, Xue-Fen

    2015-01-01

    To study the short-term response and tolerance of different doses of amino acids in parenteral nutrition among preterm infants. This study included 86 preterm infants who had a birth weight between 1 000 to 2 000 g and were admitted to the hospital within 24 hours of birth between March 2013 and June 2014. According to the early application of different doses of amino acids, they were randomized into low-dose group (n=29, 1.0 g/kg per day with an increase of 1.0 g/kg daily and a maximum of 3.5 g/kg per day), medium-dose group (n=28, 2.0 g/kg per day with an increase of 1.0 g/kg daily and a maximum of 3.7 g/kg per day), and high-dose group (n=29, 3.0 g/kg per day with an increase of 0.5-1.0 g/kg daily and a maximum of 4.0 g/kg per day). Other routine parenteral nutrition and enteral nutrition support were also applied. The maximum weight loss was lower and the growth rate of head circumference was greater in the high-dose group than in the low-dose group (Pnutrition, shorter duration of hospital stay, and less hospital cost than those in the low-dose group (P0.05). Parenteral administration of high-dose amino acids in preterm infants within 24 hours after birth can improve the short-term nutritional status of preterm infants, but there is a transient increase in BUN level.

  8. 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)

  9. 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

  10. Dosimetric Evaluation of High-Dose-Rate Interstitial Brachytherapy Boost Treatments for Localized Prostate Cancer

    International Nuclear Information System (INIS)

    Froehlich, Georgina; Agoston, Peter; Loevey, Jozsef; Somogyi, Andras; Fodor, Janos; Polgar, Csaba; Major, Tibor

    2010-01-01

    Purpose: to quantitatively evaluate the dose distributions of high-dose-rate (HDR) prostate implants regarding target coverage, dose homogeneity, and dose to organs at risk. Material and methods: treatment plans of 174 implants were evaluated using cumulative dose-volume histograms (DVHs). The planning was based on transrectal ultrasound (US) imaging, and the prescribed dose (100%) was 10 Gy. The tolerance doses to rectum and urethra were 80% and 120%, respectively. Dose-volume parameters for target (V90, V100, V150, V200, D90, D min ) and quality indices (DNR [dose nonuniformity ratio], DHI [dose homogeneity index], CI [coverage index], COIN [conformal index]) were calculated. Maximum dose in reference points of rectum (D r ) and urethra (D u ), dose to volume of 2 cm 3 of the rectum (D 2ccm ), and 0.1 cm 3 and 1% of the urethra (D 0.1ccm and D1) were determined. Nonparametric correlation analysis was performed between these parameters. Results: the median number of needles was 16, the mean prostate volume (V p ) was 27.1 cm 3 . The mean V90, V100, V150, and V200 were 90%, 97%, 39% and 13%, respectively. The mean D90 was 109%, and the D min was 87%. The mean doses in rectum and urethra reference points were 75% and 119%, respectively. The mean volumetric doses were D 2ccm = 49% for the rectum, D 0.1ccm = 126%, and D1 = 140% for the urethra. The mean DNR was 0.37, while the DHI was 0.60. The mean COIN was 0.66. The Spearman rank order correlation coefficients for volume doses to rectum and urethra were R(D r , D 2ccm ) = 0.69, R(D u , D 0.1ccm ) = 0.64, R(D u , D1) = 0.23. Conclusion: US-based treatment plans for HDR prostate implants based on the real positions of catheters provided acceptable dose distributions. In the majority of the cases, the doses to urethra and rectum were kept below the defined tolerance levels. For rectum, the dose in reference points correlated well with dose-volume parameters. For urethra dose characterization, the use of D1 volumetric

  11. Dosimetric Evaluation of High-Dose-Rate Interstitial Brachytherapy Boost Treatments for Localized Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Froehlich, Georgina [Semmelweis Univ., Budapest (Hungary); Dept. of Radiotherapy, National Inst. of Oncology, Budapest (Hungary); Agoston, Peter; Loevey, Jozsef; Somogyi, Andras; Fodor, Janos; Polgar, Csaba; Major, Tibor [Dept. of Radiotherapy, National Inst. of Oncology, Budapest (Hungary)

    2010-07-15

    Purpose: to quantitatively evaluate the dose distributions of high-dose-rate (HDR) prostate implants regarding target coverage, dose homogeneity, and dose to organs at risk. Material and methods: treatment plans of 174 implants were evaluated using cumulative dose-volume histograms (DVHs). The planning was based on transrectal ultrasound (US) imaging, and the prescribed dose (100%) was 10 Gy. The tolerance doses to rectum and urethra were 80% and 120%, respectively. Dose-volume parameters for target (V90, V100, V150, V200, D90, D{sub min}) and quality indices (DNR [dose nonuniformity ratio], DHI [dose homogeneity index], CI [coverage index], COIN [conformal index]) were calculated. Maximum dose in reference points of rectum (D{sub r}) and urethra (D{sub u}), dose to volume of 2 cm{sup 3} of the rectum (D{sub 2ccm}), and 0.1 cm{sup 3} and 1% of the urethra (D{sub 0.1ccm} and D1) were determined. Nonparametric correlation analysis was performed between these parameters. Results: the median number of needles was 16, the mean prostate volume (V{sub p}) was 27.1 cm{sup 3}. The mean V90, V100, V150, and V200 were 90%, 97%, 39% and 13%, respectively. The mean D90 was 109%, and the D{sub min} was 87%. The mean doses in rectum and urethra reference points were 75% and 119%, respectively. The mean volumetric doses were D{sub 2ccm} = 49% for the rectum, D{sub 0.1ccm} = 126%, and D1 = 140% for the urethra. The mean DNR was 0.37, while the DHI was 0.60. The mean COIN was 0.66. The Spearman rank order correlation coefficients for volume doses to rectum and urethra were R(D{sub r}, D{sub 2ccm}) = 0.69, R(D{sub u}, D{sub 0.1ccm}) = 0.64, R(D{sub u}, D1) = 0.23. Conclusion: US-based treatment plans for HDR prostate implants based on the real positions of catheters provided acceptable dose distributions. In the majority of the cases, the doses to urethra and rectum were kept below the defined tolerance levels. For rectum, the dose in reference points correlated well with dose

  12. Dosimetric evaluation of high-dose-rate interstitial brachytherapy boost treatments for localized prostate cancer.

    Science.gov (United States)

    Fröhlich, Georgina; Agoston, Péter; Lövey, József; Somogyi, András; Fodor, János; Polgár, Csaba; Major, Tibor

    2010-07-01

    To quantitatively evaluate the dose distributions of high-dose-rate (HDR) prostate implants regarding target coverage, dose homogeneity, and dose to organs at risk. Treatment plans of 174 implants were evaluated using cumulative dose-volume histograms (DVHs). The planning was based on transrectal ultrasound (US) imaging, and the prescribed dose (100%) was 10 Gy. The tolerance doses to rectum and urethra were 80% and 120%, respectively. Dose-volume parameters for target (V90, V100, V150, V200, D90, D(min)) and quality indices (DNR [dose nonuniformity ratio], DHI [dose homogeneity index], CI [coverage index], COIN [conformal index]) were calculated. Maximum dose in reference points of rectum (D(r)) and urethra (D(u)), dose to volume of 2 cm(3) of the rectum (D(2ccm)), and 0.1 cm(3) and 1% of the urethra (D(0.1ccm) and D1) were determined. Nonparametric correlation analysis was performed between these parameters. The median number of needles was 16, the mean prostate volume (V(p)) was 27.1 cm(3). The mean V90, V100, V150, and V200 were 99%, 97%, 39%, and 13%, respectively. The mean D90 was 109%, and the D(min) was 87%. The mean doses in rectum and urethra reference points were 75% and 119%, respectively. The mean volumetric doses were D(2ccm) = 49% for the rectum, D(0.1ccm) = 126%, and D1 = 140% for the urethra. The mean DNR was 0.37, while the DHI was 0.60. The mean COIN was 0.66. The Spearman rank order correlation coefficients for volume doses to rectum and urethra were R(D(r),D(2ccm)) = 0.69, R(D(u),D0.(1ccm)) = 0.64, R(D(u),D1) = 0.23. US-based treatment plans for HDR prostate implants based on the real positions of catheters provided acceptable dose distributions. In the majority of the cases, the doses to urethra and rectum were kept below the defined tolerance levels. For rectum, the dose in reference points correlated well with dose-volume parameters. For urethra dose characterization, the use of D1 volumetric parameter is recommended.

  13. Anthropomorphic chest phantom imaging – The potential for dose creep in computed radiography

    International Nuclear Information System (INIS)

    Ma, W.K.; Hogg, P.; Tootell, A.; Manning, D.; Thomas, N.; Kane, T.; Kelly, J.; McKenzie, M.; Kitching, J.

    2013-01-01

    For film-based radiography the operator had to be exact in the selection of acquisition parameters or the image could easily become under- or over-exposed. By contrast, digital technology allows for a much greater tolerance of acquisition factor selection which would still give an image of acceptable diagnostic quality. In turn this greater tolerance allows for the operator to increase effective dose for little or no penalty in image quality. The purpose of this article is to determine how image quality and lesion visibility vary with effective dose (E) in order to identify how much overexposure could be tolerated within the radiograph. Using an anthropomorphic chest phantom with ground glass lesions we determined how perceptual image quality and E varied over a wide range of acquisition conditions. Perceptual image quality comprised of image quality and lesion visibility. E was calculated using Monte Carlo method; image quality was determined using a two alternative forced choice (2AFC) method and the quality criteria were partly informed from European guidelines. Five clinicians with significant experience in image reading scored the images for quality (intraclass correlation coefficient 0.869). Image quality and lesion visibility had a close correlation (R 2 > 0.8). The tolerance for over-exposure, whilst still acquiring an image of acceptable quality, increases with decreasing kV and increasing source to image distance (SID). The maximum over-exposure factor (ratio of maximum E to minimum E that produce images of acceptable quality) possible was 139 (at 125 cm and 60 kV). Given the phantom had characteristics similar to the human thorax we propose that that potential for overexposure in a human whilst still obtaining an image of acceptable perceptual image quality is very high. Further research into overexposure tolerance and dose creep should be undertaken

  14. Tolerance of snakes to hypergravity

    Science.gov (United States)

    Lillywhite, H. B.; Ballard, R. E.; Hargens, A. R.

    1996-01-01

    Sensitivity of carotid blood flow to increased gravitational force acting in the head-to-tail direction(+Gz) was studied in diverse species of snakes hypothesized to show adaptive variation of response. Tolerance to increased gravity was measured red as the maximum graded acceleration force at which carotid blood flow ceased and was shown to vary according to gravitational adaptation of species defined by their ecology and behavior. Multiple regression analysis showed that gravitational habitat, but not body length, had a significant effect on Gz tolerance. At the extremes, carotid blood flow decreased in response to increasing G force and approached zero near +1 Gz in aquatic and ground-dwelling species, whereas in climbing species carotid flow was maintained at forces in excess of +2 Gz. Tolerant (arboreal) species were able to withstand hypergravic forces of +2 to +3 Gz for periods up to 1 h without cessation of carotid blood flow or loss of body movement and tongue flicking. Data suggest that the relatively tight skin characteristic of tolerant species provides a natural antigravity suit and is of prime importance in counteracting Gz stress on blood circulation.

  15. A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma.

    Science.gov (United States)

    Mark, Tomer M; Guarneri, Danielle; Forsberg, Peter; Rossi, Adriana; Pearse, Roger; Perry, Arthur; Pekle, Karen; Tegnestam, Linda; Greenberg, June; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; Van Besien, Koen; Ely, Scott; Jayabalan, David; Sherbenou, Daniel; Coleman, Morton; Niesvizky, Ruben

    2017-06-01

    Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  16. Maximum Entropy in Drug Discovery

    Directory of Open Access Journals (Sweden)

    Chih-Yuan Tseng

    2014-07-01

    Full Text Available Drug discovery applies multidisciplinary approaches either experimentally, computationally or both ways to identify lead compounds to treat various diseases. While conventional approaches have yielded many US Food and Drug Administration (FDA-approved drugs, researchers continue investigating and designing better approaches to increase the success rate in the discovery process. In this article, we provide an overview of the current strategies and point out where and how the method of maximum entropy has been introduced in this area. The maximum entropy principle has its root in thermodynamics, yet since Jaynes’ pioneering work in the 1950s, the maximum entropy principle has not only been used as a physics law, but also as a reasoning tool that allows us to process information in hand with the least bias. Its applicability in various disciplines has been abundantly demonstrated. We give several examples of applications of maximum entropy in different stages of drug discovery. Finally, we discuss a promising new direction in drug discovery that is likely to hinge on the ways of utilizing maximum entropy.

  17. Dose optimization in simulated permanent interstitial implant of prostate brachytherapy

    International Nuclear Information System (INIS)

    Faria, Fernando Pereira de

    2006-01-01

    Any treatment of cancer that uses some modality of radiotherapy is planned before being executed. In general the goal in radiotherapy is to irradiate the target to be treated minimizing the incidence of radiation in healthy surrounding tissues. The planning differ among themselves according to the modality of radiotherapy, the type of cancer and where it is located. This work approaches the problem of dose optimization for the planning of prostate cancer treatment through the modality of low dose-rate brachytherapy with Iodine 125 or Palladium 103 seeds. An algorithm for dose calculation and optimization was constructed to find the seeds configuration that better fits the relevant clinical criteria such as as the tolerated dose by the urethra and rectum and the desired dose for prostate. The algorithm automatically finds this configuration from the prostate geometry established in two or three dimensions by using images of ultrasound, magnetic resonance or tomography and from the establishment of minimum restrictions to the positions of the seeds in the prostate and needles in a template. Six patterns of seeds distribution based on clinical criteria were suggested and tested in this work. Each one of these patterns generated a space of possible seeds configurations for the prostate tested by the dose calculation and optimization algorithm. The configurations that satisfied the clinical criteria were submitted to a test according to an optimization function suggested in this work. The configuration that produced maximum value for this function was considered the optimized one. (author)

  18. Intercomparison On Depth Dose Measurement

    International Nuclear Information System (INIS)

    Rohmah, N; Akhadi, M

    1996-01-01

    Intercomparation on personal dose evaluation system has been carried out between CSRSR-NAEA of Indonesia toward Standard Laboratory of JAERI (Japan) and ARL (Australia). The intercomparison was in 10 amm depth dose measurement , Hp (10), from the intercomparison result could be stated that personal depth dose measurement conducted by CSRSR was sufficiently good. Deviation of dose measurement result using personal dosemeter of TLD BG-1 type which were used by CSRSR in the intercomparison and routine photon personal dose monitoring was still in internationally agreed limit. Maximum deviation of reported doses by CSRSR compared to delivered doses for dosemeter irradiation by JAERI was -10.0 percent and by ARL was +29 percent. Maximum deviation permitted in personal dose monitoring is ± 50 percent

  19. Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.

    Science.gov (United States)

    Ito, Yoshinori; Suenaga, Mitsukuni; Hatake, Kiyohiko; Takahashi, Shunji; Yokoyama, Masahiro; Onozawa, Yusuke; Yamazaki, Kentaro; Hironaka, Shuichi; Hashigami, Kiyoshi; Hasegawa, Hirotaka; Takenaka, Nobuko; Boku, Narikazu

    2012-04-01

    Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors. Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses. Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose. The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.

  20. Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy

    International Nuclear Information System (INIS)

    Bratland, Åse; Dueland, Svein; Hollywood, Donal; Flatmark, Kjersti; Ree, Anne H

    2011-01-01

    In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT. Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug. When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile.

  1. Teaching Tolerance? Associational Diversity and Tolerance Formation

    DEFF Research Database (Denmark)

    Rapp, Carolin; Freitag, Markus

    2015-01-01

    , a closer look is taken at how associational diversity relates to the formation of tolerance and the importance of associations as schools of tolerance are evaluated. The main theoretical argument follows contact theory, wherein regular and enduring contact in diverse settings reduces prejudice and thereby...

  2. Maximum stellar iron core mass

    Indian Academy of Sciences (India)

    60, No. 3. — journal of. March 2003 physics pp. 415–422. Maximum stellar iron core mass. F W GIACOBBE. Chicago Research Center/American Air Liquide ... iron core compression due to the weight of non-ferrous matter overlying the iron cores within large .... thermal equilibrium velocities will tend to be non-relativistic.

  3. Maximum entropy beam diagnostic tomography

    International Nuclear Information System (INIS)

    Mottershead, C.T.

    1985-01-01

    This paper reviews the formalism of maximum entropy beam diagnostic tomography as applied to the Fusion Materials Irradiation Test (FMIT) prototype accelerator. The same formalism has also been used with streak camera data to produce an ultrahigh speed movie of the beam profile of the Experimental Test Accelerator (ETA) at Livermore. 11 refs., 4 figs

  4. Maximum entropy beam diagnostic tomography

    International Nuclear Information System (INIS)

    Mottershead, C.T.

    1985-01-01

    This paper reviews the formalism of maximum entropy beam diagnostic tomography as applied to the Fusion Materials Irradiation Test (FMIT) prototype accelerator. The same formalism has also been used with streak camera data to produce an ultrahigh speed movie of the beam profile of the Experimental Test Accelerator (ETA) at Livermore

  5. A portable storage maximum thermometer

    International Nuclear Information System (INIS)

    Fayart, Gerard.

    1976-01-01

    A clinical thermometer storing the voltage corresponding to the maximum temperature in an analog memory is described. End of the measurement is shown by a lamp switch out. The measurement time is shortened by means of a low thermal inertia platinum probe. This portable thermometer is fitted with cell test and calibration system [fr

  6. Irradiation of meningioma: a prototype circumscribed tumor for planning high-dose irradiation of the brain

    International Nuclear Information System (INIS)

    Friedman, M.

    1977-01-01

    The purpose of this report is to provide specific data concerning the radiation dose required to destroy meningioma, and to demonstrate that radiation doses much greater than the alleged tolerance dose, can be administered to the brain in some patients. Most meninglomas are not responsive to irradiation, but, some surgically incurable lesions benefit from irradiation with radically high doses to small volumes of tissue. The arrest of 7 of 12 consecutive meningiomas in adults for periods of 2 to 17 years following maximum tumor doses up to 8800 R in 40 days is reported in this paper. All patients, when irradiated, had active tumor in the form of inoperable primary tumor, recurrence, or known postoperative residual tumor. Three of the successful results were achieved with orthovoltage radiation. The incidence of brain damage may be acceptable to the patient when it is related to arrest of tumor growth but he must be forewarned of possible brain damage. The factors influencing the radioresponsiveness of meningioma are: the required tumor lethal dose, histology and vascularity of the tumor, anatomical site in the brain, treatment technique for each tumor site, small size of the treated volume, growth rate of the tumor, displacement of normal brain tissue by tumor, inherent individual variations of tumor and normal tissues, quality of the radiation, and tolerance of normal brain tissues. The role of these factors is discussed in the light of modern radiobiological concepts

  7. Neutron spectra unfolding with maximum entropy and maximum likelihood

    International Nuclear Information System (INIS)

    Itoh, Shikoh; Tsunoda, Toshiharu

    1989-01-01

    A new unfolding theory has been established on the basis of the maximum entropy principle and the maximum likelihood method. This theory correctly embodies the Poisson statistics of neutron detection, and always brings a positive solution over the whole energy range. Moreover, the theory unifies both problems of overdetermined and of underdetermined. For the latter, the ambiguity in assigning a prior probability, i.e. the initial guess in the Bayesian sense, has become extinct by virtue of the principle. An approximate expression of the covariance matrix for the resultant spectra is also presented. An efficient algorithm to solve the nonlinear system, which appears in the present study, has been established. Results of computer simulation showed the effectiveness of the present theory. (author)

  8. Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects

    Directory of Open Access Journals (Sweden)

    Shen Z

    2017-07-01

    Full Text Available Zancong Shen,1 Michael Gillen,2 Jeffrey N Miner,1 Gail Bucci,1 David M Wilson,1 Jesse W Hall1 1Ardea Biosciences, Inc., San Diego, CA, 2AstraZeneca, Gaithersburg, MD, USA Purpose: Verinurad (RDEA3170 is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males.Subjects and methods: This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10–12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE reports, laboratory tests, vital signs, and electrocardiograms (ECGs.Results: A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (Cmax and area under the plasma concentration–time curve (AUC increased in a dose-proportional manner; Cmax occurred at 0.5–0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and Cmax by 37%-53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose and 61% (10 mg, multiple dose. The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported.Conclusion: Single and multiple doses of verinurad were well tolerated

  9. 40 CFR 180.422 - Tralomethrin; tolerances for residues.

    Science.gov (United States)

    2010-07-01

    ...-handling establishments, including food service, manufacturing, and processing establishments, such as... shall be limited to a maximum of 0.06 percent active ingredient. Contamination of food and food-contact...) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Specific Tolerances...

  10. Lactose tolerance tests

    Science.gov (United States)

    Hydrogen breath test for lactose tolerance ... Two common methods include: Lactose tolerance blood test Hydrogen breath test The hydrogen breath test is the preferred method. It measures the amount of hydrogen ...

  11. Relative bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension.

    Science.gov (United States)

    Clemens, Pamela L; Cloyd, James C; Kriel, Robert L; Remmel, Rory P

    2007-01-01

    Maintenance of effective drug concentrations is essential for adequate treatment of epilepsy. Some antiepileptic drugs can be successfully administered rectally when the oral route of administration is temporarily unavailable. Oxcarbazepine is a newer antiepileptic drug that is rapidly converted to a monohydroxy derivative, the active compound. This study aimed to characterise the bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension using a randomised, crossover design in ten healthy volunteers. Two subjects received 300 mg doses of oxcarbazepine suspension via rectal and oral routes and eight received 450 mg doses. A washout period of at least 2 weeks elapsed between doses. The rectal dose was diluted 1:1 with water. Blood samples and urine were collected for 72 hours post-dose. Adverse effects were assessed at each blood collection time-point using a self-administered questionnaire. Plasma was assayed for oxcarbazepine and monohydroxy derivative; urine was assayed for monohydroxy derivative and monohydroxy derivative-glucuronide. Maximum plasma concentration (C(max)) and time to reach C(max) (t(max)) were obtained directly from the plasma concentration-time curves. The areas under the concentration-time curve (AUCs) were determined via non-compartmental analysis. Relative bioavailability was calculated and the C(max) and AUCs were compared using Wilcoxon signed-rank tests. Mean relative bioavailability calculated from plasma AUCs was 8.3% (SD 5.5%) for the monohydroxy derivative and 10.8% (SD 7.3%) for oxcarbazepine. Oxcarbazepine and monohydroxy derivative C(max) and AUC values were significantly lower following rectal administration (p effects were headache and fatigue with no discernible differences between routes. Monohydroxy derivative bioavailability following rectal administration of oxcarbazepine suspension is significantly lower than following oral administration, most likely because of poor oxcarbazepine water

  12. Pesticide tolerant and phosphorus solubilizing Pseudomonas sp. strain SGRAJ09 isolated from pesticides treated Achillea clavennae rhizosphere soil.

    Science.gov (United States)

    Rajasankar, R; Manju Gayathry, G; Sathiavelu, A; Ramalingam, C; Saravanan, V S

    2013-05-01

    In this study, an attempt was made to identify an effective phosphate solubilizing bacteria from pesticide polluted field soil. Based on the formation of solubilization halo on Pikovskaya's agar, six isolates were selected and screened for pesticide tolerance and phosphate (P) solubilization ability through liquid assay. The results showed that only one strain (SGRAJ09) obtained from Achillea clavennae was found to tolerate maximum level of the pesticides tested and it was phylogenetically identified as Pseudomonas sp. It possessed a wide range of pesticide tolerance, ranging from 117 μg mL(-1) for alphamethrin to 2,600 μg mL(-1) for endosulfan. The available P concentrations increased with the maximum and double the maximum dose of monocrotophos and imidacloprid, respectively. On subjected to FT-IR and HPLC analysis, the presence of organic acids functional group in the culture broth and the production of gluconic acid as dominant acid aiding the P solubilization were identified. On comparison with control broth, monocrotophos and imidacloprid added culture broth showed quantitatively high organic acids production. In addition to gluconic acid production, citric and acetic acids were also observed in the pesticide amended broth. Furthermore, the Pseudomonas sp. strain SGRAJ09 possessed all the plant growth promoting traits tested. In presence of monocrotophos and imidacloprid, its plant growth promoting activities were lower than that of the pesticides unamended treatment.

  13. Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours

    International Nuclear Information System (INIS)

    Fumoleau, Pierre; Trigo, Jose Manuel; Isambert, Nicolas; Sémiond, Dorothée; Gupta, Sunil; Campone, Mario

    2013-01-01

    Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5–12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m 2 , which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in C max and AUC 0–t were dose proportional for the 6–12 mg/m 2 doses. The MTD of weekly cabazitaxel was 12 mg/m 2 and the recommended weekly dose was 10 mg/m 2 . The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens. The study was registered with ClinicalTrials.gov as http://www.clinicaltrials.gov/ct2/show/NCT01755390

  14. 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

  15. Enjebi Island dose assessment

    International Nuclear Information System (INIS)

    Robison, W.L.; Conrado, C.L.; Phillips, W.A.

    1987-07-01

    We have updeated the radiological dose assessment for Enjebi Island at Enewetak Atoll using data derived from analysis of food crops grown on Enjebi. This is a much more precise assessment of potential doses to people resettling Enjebi Island than the 1980 assessment in which there were no data available from food crops on Enjebi. Details of the methods and data used to evaluate each exposure pathway are presented. The terrestrial food chain is the most significant potential exposure pathway and 137 Cs is the radionuclide responsible for most of the estimated dose over the next 50 y. The doses are calculated assuming a resettlement date of 1990. The average wholebody maximum annual estimated dose equivalent derived using our diet model is 166 mremy;the effective dose equivalent is 169 mremy. The estimated 30-, 50-, and 70-y integral whole-body dose equivalents are 3.5 rem, 5.1 rem, and 6.2 rem, respectively. Bone-marrow dose equivalents are only slightly higher than the whole-body estimates in each case. The bone-surface cells (endosteal cells) receive the highest dose, but they are a less sensitive cell population and are less sensitive to fatal cancer induction than whole body and bone marrow. The effective dose equivalents for 30, 50, and 70 y are 3.6 rem, 5.3 rem, and 6.6 rem, respectively. 79 refs., 17 figs., 24 tabs

  16. A phase I study of amrubicin and fixed dose of irinotecan (CPT-11) in relapsed small cell lung cancer: Japan multinational trial organization LC0303.

    Science.gov (United States)

    Kawahara, Masaaki; Kubo, Akihito; Komuta, Kiyoshi; Fujita, Yuka; Sasaki, Yoshiaki; Fukushima, Masanori; Daimon, Takashi; Furuse, Kiyoyuki; Mishima, Michiaki; Mio, Tadashi

    2012-12-01

    To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11). Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m2, level 2: 90 mg/m2, and level 3: 100 mg/m2. Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed. Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m2. Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate. This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

  17. 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

  18. On Maximum Entropy and Inference

    Directory of Open Access Journals (Sweden)

    Luigi Gresele

    2017-11-01

    Full Text Available Maximum entropy is a powerful concept that entails a sharp separation between relevant and irrelevant variables. It is typically invoked in inference, once an assumption is made on what the relevant variables are, in order to estimate a model from data, that affords predictions on all other (dependent variables. Conversely, maximum entropy can be invoked to retrieve the relevant variables (sufficient statistics directly from the data, once a model is identified by Bayesian model selection. We explore this approach in the case of spin models with interactions of arbitrary order, and we discuss how relevant interactions can be inferred. In this perspective, the dimensionality of the inference problem is not set by the number of parameters in the model, but by the frequency distribution of the data. We illustrate the method showing its ability to recover the correct model in a few prototype cases and discuss its application on a real dataset.

  19. Maximum Water Hammer Sensitivity Analysis

    OpenAIRE

    Jalil Emadi; Abbas Solemani

    2011-01-01

    Pressure waves and Water Hammer occur in a pumping system when valves are closed or opened suddenly or in the case of sudden failure of pumps. Determination of maximum water hammer is considered one of the most important technical and economical items of which engineers and designers of pumping stations and conveyance pipelines should take care. Hammer Software is a recent application used to simulate water hammer. The present study focuses on determining significance of ...

  20. Maximum Gene-Support Tree

    Directory of Open Access Journals (Sweden)

    Yunfeng Shan

    2008-01-01

    Full Text Available Genomes and genes diversify during evolution; however, it is unclear to what extent genes still retain the relationship among species. Model species for molecular phylogenetic studies include yeasts and viruses whose genomes were sequenced as well as plants that have the fossil-supported true phylogenetic trees available. In this study, we generated single gene trees of seven yeast species as well as single gene trees of nine baculovirus species using all the orthologous genes among the species compared. Homologous genes among seven known plants were used for validation of the finding. Four algorithms—maximum parsimony (MP, minimum evolution (ME, maximum likelihood (ML, and neighbor-joining (NJ—were used. Trees were reconstructed before and after weighting the DNA and protein sequence lengths among genes. Rarely a gene can always generate the “true tree” by all the four algorithms. However, the most frequent gene tree, termed “maximum gene-support tree” (MGS tree, or WMGS tree for the weighted one, in yeasts, baculoviruses, or plants was consistently found to be the “true tree” among the species. The results provide insights into the overall degree of divergence of orthologous genes of the genomes analyzed and suggest the following: 1 The true tree relationship among the species studied is still maintained by the largest group of orthologous genes; 2 There are usually more orthologous genes with higher similarities between genetically closer species than between genetically more distant ones; and 3 The maximum gene-support tree reflects the phylogenetic relationship among species in comparison.

  1. 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)

  2. 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...

  3. 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...

  4. 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...

  5. 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...

  6. 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...

  7. LCLS Maximum Credible Beam Power

    International Nuclear Information System (INIS)

    Clendenin, J.

    2005-01-01

    The maximum credible beam power is defined as the highest credible average beam power that the accelerator can deliver to the point in question, given the laws of physics, the beam line design, and assuming all protection devices have failed. For a new accelerator project, the official maximum credible beam power is determined by project staff in consultation with the Radiation Physics Department, after examining the arguments and evidence presented by the appropriate accelerator physicist(s) and beam line engineers. The definitive parameter becomes part of the project's safety envelope. This technical note will first review the studies that were done for the Gun Test Facility (GTF) at SSRL, where a photoinjector similar to the one proposed for the LCLS is being tested. In Section 3 the maximum charge out of the gun for a single rf pulse is calculated. In Section 4, PARMELA simulations are used to track the beam from the gun to the end of the photoinjector. Finally in Section 5 the beam through the matching section and injected into Linac-1 is discussed

  8. 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

  9. 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)

  10. 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

  11. Recognition and Toleration

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2010-01-01

    Recognition and toleration are ways of relating to the diversity characteristic of multicultural societies. The article concerns the possible meanings of toleration and recognition, and the conflict that is often claimed to exist between these two approaches to diversity. Different forms...... or interpretations of recognition and toleration are considered, confusing and problematic uses of the terms are noted, and the compatibility of toleration and recognition is discussed. The article argues that there is a range of legitimate and importantly different conceptions of both toleration and recognition...

  12. Fault Tolerant Feedback Control

    DEFF Research Database (Denmark)

    Stoustrup, Jakob; Niemann, H.

    2001-01-01

    An architecture for fault tolerant feedback controllers based on the Youla parameterization is suggested. It is shown that the Youla parameterization will give a residual vector directly in connection with the fault diagnosis part of the fault tolerant feedback controller. It turns out...... that there is a separation be-tween the feedback controller and the fault tolerant part. The closed loop feedback properties are handled by the nominal feedback controller and the fault tolerant part is handled by the design of the Youla parameter. The design of the fault tolerant part will not affect the design...... of the nominal feedback con-troller....

  13. 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.

  14. 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.

  15. Mechanical tolerance stackup and analysis

    CERN Document Server

    Fischer, Bryan R

    2004-01-01

    BackgroundDimensioning and TolerancingTolerance Format and Decimal PlacesConverting Plus/Minus Dimensions and Tolerances into Equal Bilaterally Toleranced DimensionsVariation and Sources of VariationTolerance AnalysisWorst-case Tolerance StackupsStatistical Tolerance StackupsGeometric Dimensioning and Tolerancing (GD&T)Converting Plus/Minus Tolerancing to Positional Tolerancing and Projected Tolerance ZonesDiametral and Radial Tolerance StackupsSpecifying Material Condition Modifiers and Their Effect on Tolerance Stackups The Tolerance Stackup SketchThe Tolerance Stackup Report FormTolerance S

  16. 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

  17. 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.

  18. Maximum likelihood as a common computational framework in tomotherapy

    International Nuclear Information System (INIS)

    Olivera, G.H.; Shepard, D.M.; Reckwerdt, P.J.; Ruchala, K.; Zachman, J.; Fitchard, E.E.; Mackie, T.R.

    1998-01-01

    Tomotherapy is a dose delivery technique using helical or axial intensity modulated beams. One of the strengths of the tomotherapy concept is that it can incorporate a number of processes into a single piece of equipment. These processes include treatment optimization planning, dose reconstruction and kilovoltage/megavoltage image reconstruction. A common computational technique that could be used for all of these processes would be very appealing. The maximum likelihood estimator, originally developed for emission tomography, can serve as a useful tool in imaging and radiotherapy. We believe that this approach can play an important role in the processes of optimization planning, dose reconstruction and kilovoltage and/or megavoltage image reconstruction. These processes involve computations that require comparable physical methods. They are also based on equivalent assumptions, and they have similar mathematical solutions. As a result, the maximum likelihood approach is able to provide a common framework for all three of these computational problems. We will demonstrate how maximum likelihood methods can be applied to optimization planning, dose reconstruction and megavoltage image reconstruction in tomotherapy. Results for planning optimization, dose reconstruction and megavoltage image reconstruction will be presented. Strengths and weaknesses of the methodology are analysed. Future directions for this work are also suggested. (author)

  19. Tolerance of Snakes to Hypergravity

    Science.gov (United States)

    Lillywhite, H. B.; Ballard, R. E.; Hargens, A. R.

    1994-01-01

    Sensitivity of carotid blood flow to +Gz (head-to-tail) acceleration was studied in six species of snakes hypothesized to show varied adaptive cardiovascular responses to gravity. Blood flow in the proximal carotid artery was measured in 15 snakes before, during and following stepwise increments of +0.25Gz force produced on a 2.4 m diameter centrifuge. During centrifugation each snake was confined to a straight position within an individually- fitted acrylic tube with the head facing the center of rotation. We measured the centrifugal force at the tail of the snake in order to quantify the maximum intensity of force gradient promoting antero-posterior pooling of blood. Tolerance to increased gravity was quantified as the acceleration force at which carotid blood flow ceased. This parameter varied according to the gravitational adaptation of species defined by their ecology and behavior. At the extremes, carotid blood flow decreased in response to increasing gravity and approached zero near +1Gz in aquatic and ground-dwelling species, whereas in climbing species carotid flow was maintained at forces in excess of +2Gz. Surprisingly, tolerant (arboreal) species withstood hypergravic forces of +2 to +3 G. for periods up to 1 h without cessation of carotid blood flow or apparent loss of consciousness. Data suggest that relatively tight skin of the tolerant species provides a natural antigravity suit which is of prime importance in counteracting Gz stress on blood circulation.

  20. Generic maximum likely scale selection

    DEFF Research Database (Denmark)

    Pedersen, Kim Steenstrup; Loog, Marco; Markussen, Bo

    2007-01-01

    in this work is on applying this selection principle under a Brownian image model. This image model provides a simple scale invariant prior for natural images and we provide illustrative examples of the behavior of our scale estimation on such images. In these illustrative examples, estimation is based......The fundamental problem of local scale selection is addressed by means of a novel principle, which is based on maximum likelihood estimation. The principle is generally applicable to a broad variety of image models and descriptors, and provides a generic scale estimation methodology. The focus...

  1. 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)

  2. 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)

  3. Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer

    OpenAIRE

    Shitara, Kohei; Kim, Tae Min; Yokota, Tomoya; Goto, Masahiro; Satoh, Taroh; Ahn, Jin-Hee; Kim, Hyo Song; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hamauchi, Satoshi; Kudo, Toshihiro; Doi, Toshihido; Bang, Yung-Jue

    2017-01-01

    SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260–570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety...

  4. Effective dose and dose to crystalline lens during angiographic procedures

    International Nuclear Information System (INIS)

    Pages, J.

    1998-01-01

    The highest radiation doses levels received by radiologists are observed during interventional procedures. Doses to forehead and neck received by a radiologist executing angiographic examinations at the department of radiology at the academic hospital (AZ-VUB) have been measured for a group of 34 examinations. The doses to crystalline lens and the effective doses for a period of one year have been estimated. For the crystalline lens the maximum dose approaches the ICRP limit, that indicates the necessity for the radiologist to use leaded glasses. (N.C.)

  5. Extreme Maximum Land Surface Temperatures.

    Science.gov (United States)

    Garratt, J. R.

    1992-09-01

    There are numerous reports in the literature of observations of land surface temperatures. Some of these, almost all made in situ, reveal maximum values in the 50°-70°C range, with a few, made in desert regions, near 80°C. Consideration of a simplified form of the surface energy balance equation, utilizing likely upper values of absorbed shortwave flux (1000 W m2) and screen air temperature (55°C), that surface temperatures in the vicinity of 90°-100°C may occur for dry, darkish soils of low thermal conductivity (0.1-0.2 W m1 K1). Numerical simulations confirm this and suggest that temperature gradients in the first few centimeters of soil may reach 0.5°-1°C mm1 under these extreme conditions. The study bears upon the intrinsic interest of identifying extreme maximum temperatures and yields interesting information regarding the comfort zone of animals (including man).

  6. The true bladder dose: on average thrice higher than the ICRU reference

    International Nuclear Information System (INIS)

    Barillot, I.; Horiot, J.C.; Maingon, P.; Bone-Lepinoy, M.C.; D'Hombres, A.; Comte, J.; Delignette, A.; Feutray, S.; Vaillant, D.

    1996-01-01

    The aim of this study is to compare ICRU dose to doses at the bladder base located from ultrasonography measurements. Since 1990, the dose delivered to the bladder during utero-vaginal brachytherapy was systematically calculated at 3 or 4 points representative of bladder base determined with ultrasonography. The ICRU Reference Dose (IRD) from films, the Maximum Dose (Dmax), the Mean Dose (Dmean) representative of the dose received by a large area of bladder mucosa, the Reference Dose Rate (RDR) and the Mean Dose Rate (MDR) were recorded. Material: from 1990 to 1994, 198 measurements were performed in 152 patients. 98 patients were treated for cervix carcinomas, 54 for endometrial carcinomas. Methods: Bladder complications were classified using French Italian Syllabus. The influence of doses and dose rates on complications were tested using non parametric t test. Results: On average IRD is 21 Gy +/- 12 Gy, Dmax is 51Gy +/- 21Gy, Dmean is 40 Gy +/16 Gy. On average Dmax is thrice higher than IRD and Dmean twice higher than IRD. The same results are obtained for cervix and endometrium. Comparisons on dose rates were also performed: MDR is on average twice higher than RDR (RDR 48 cGy/h vs MDR 88 cGy/h). The five observed complications consist of incontinence only (3 G1, 1G2, 1G3). They are only statistically correlated with RDR p=0.01 (46 cGy/h in patients without complications vs 74 cGy/h in patients with complications). However the full responsibility of RT remains doubtful and should be shared with surgery in all cases. In summary: Bladder mucosa seems to tolerate well much higher doses than previous recorded without increased risk of severe sequelae. However this finding is probably explained by our efforts to spare most of bladder mucosa by 1 deg. ) customised external irradiation therapy (4 fields, full bladder) 2 deg. ) reproduction of physiologic bladder filling during brachytherapy by intermittent clamping of the Foley catheter

  7. Chronic administration of the HNO donor Angeli's salt does not lead to tolerance, cross-tolerance, or endothelial dysfunction: comparison with GTN and DEA/NO.

    Science.gov (United States)

    Irvine, Jennifer C; Kemp-Harper, Barbara K; Widdop, Robert E

    2011-05-01

    Nitroxyl (HNO) displays distinct pharmacology to its redox congener nitric oxide (NO(•)) with therapeutic potential in the treatment of heart failure. It remains unknown if HNO donors are resistant to tolerance development following chronic in vivo administration. Wistar-Kyoto rats received a 3-day subcutaneous infusion of one of the NO(•) donors, glyceryl trinitrate (GTN) or diethylamine/NONOate (DEA/NO), or the HNO donor Angeli's salt (AS). GTN infusion (10 μg/kg/min) resulted in significantly blunted depressor responses to intravenous bolus doses of GTN, demonstrating tolerance development. By contrast, infusion with AS (20 μg/kg/min) or DEA/NO (2 μg/kg/min) did not alter their subsequent depressor responses. Similarly, ex vivo vasorelaxation responses in isolated aortae revealed that GTN infusion elicited a significant 6-fold decrease in the sensitivity to GTN and reduction in the maximum response to acetylcholine (ACh). Chronic infusion of AS or DEA/NO had no effect on subsequent vasorelaxation responses to themselves or to ACh. No functional cross-tolerance between nitrovasodilators was evident, either in vivo or ex vivo, although an impaired ability of a nitrovasodilator to increase tissue cGMP content was not necessarily indicative of a reduced functional response. In conclusion, HNO donors may represent novel therapies for cardiovascular disease with therapeutic potential over clinically used organic nitrates.

  8. Dose escalation of cisplatin with 5-fluorouracil in concurrent chemoradiotherapy for esophageal carcinoma

    International Nuclear Information System (INIS)

    Lin Qiang; Gao Xianshu; Qiao Xueying; Zhou Zhiguo; Zhang Jun; Yang Xiangran; Wan Xin

    2006-01-01

    Objective: To define the maximum-tolerated dose (MTD) and observe the side effect of escalating cisplatin with 5-fluorouracil in concurrent chemoradiotherapy for esophageal carcinoma in Chinese, with toxicity studied. Methods: Previously untreated fifteen Chinese patients suffering from esophageal carcinoma received conventional fractionation radiotherapy, with 5 daily fractions of 2.0 Gy per week. The total radiation dose was 60 Gy. Concurrent chemotherapy dose escalation was given by the relatively safe and kidney-sparing modified Fibonacci sequence. The starting dose was cisplatin 37.5 mg/m 2 D1 and 5-fluorouracil 500 mg/m 2 D1-5, respectively. This regimen was repeated 4 times every 28 days. Escalation dose was cisplatin 7.5 mg/m 2 and 5- fluorouracil 100 mg/m 2 . Every. cohort contained at least 3 patients. If no dose-limiting toxicity(DLT) was observed, the next dose level was opened for entry. These courses were repeated until DLT appeared. MTD was declared as one dose level below which DLT appeared. Results: DLT was defined as grade 3 radiation-induced esophagitis at the level of cisplatin 60 mg/m2, 5-fluorouracil 700 mg/m 2 . MTD was defined as cisplatin 52.5 mg/m 2 , 5- fiuorouracil 700 mg/m 2 . The major side effect were radiation-induced esophagitis, leucopenia, nausea, vomiting and anorexia. Conclusion: Maximun tolerated dose of cisplatin with 5-fiuorouracil in concurrent ehemoradiotherapy in the Chinese people with esophageal carcinoma were eisplatin 52.5 mg/m2 D1,5-fluorouracil 700 mg/m 2 D1-5, repeated 4 times every 28 days. (authors)

  9. High lenticular tolerance to ultraviolet radiation-B by pigmented guinea-pig; application of a safety limit strategy for UVR-induced cataract.

    Science.gov (United States)

    Mody, Vino C; Kakar, Manoj; Söderberg, Per G; Löfgren, Stefan

    2012-05-01

    The purpose of this study was to determine a threshold measure, maximum tolerable dose (MTD), for avoidance of UVR-B-induced cataract in the pigmented guinea-pig. Thirty pupil-dilated anesthetized young female guinea-pigs, divided into five equal groups, received between 0 and 84.9 kJ/m(2) unilateral UVR-B. Lens extraction and in vitro lens photography occurred 24 hr after exposure. Measurement of intensity of lens light scattering served as quantifying tool for the degree of cataract. Data analysis included regression, using a second order polynomial model. The applied MTD concept was based on the UVR-B dose-response curve obtained for the pigmented guinea-pig. A smaller number of pigmented guinea-pigs, pigmented rats and albino rats underwent morphometric analysis of the anterior segment geometry. All eyes exposed to UVR-B developed cataract in the anterior subcapsular region. MTD for avoidance of UVR-B-induced cataract was 69.0 kJ/m(2) in the pigmented guinea-pig. Iris was considerably thicker in the guinea-pig than in the rats. Lens blockage by the dilated iris was lowest in the guinea-pig. Maximum tolerable dose for avoidance of UVR-B-induced cataract in the pigmented guinea-pig was 69.0 kJ/m(2), over 10-fold higher than the threshold 5 kJ/m(2) obtained by Pitts et al. in the pigmented rabbit. Maximum tolerable dose is an appropriate method for estimation of toxicity for UVR-B-induced cataract in the guinea-pig. The pigmented guinea-pig is significantly less sensitive to UVR-B exposure than the pigmented rabbit and pigmented rat. © 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.

  10. Toleration out of respect?

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2013-01-01

    Under conditions of pluralism different cultures, interests or values can come into conflict, which raises the problem of how to secure peaceful co-existence. The idea of toleration historically emerged as an answer to this problem. Recently Rainer Forst has argued that toleration should not just...... be based on a modus vivendi designed to secure peaceful co-existence, but should be based on moral reasons. Forst therefore advances what he calls the ‘respect conception’ of toleration as an in itself morally desirable type of relationship, which is furthermore the only conception of toleration...... that avoids various so-called ‘paradoxes of toleration’. The paper first examines whether Forst’s respect conception can be applied descriptively to distinguish between actual patterns of behaviour and classify different acts of toleration. Then the focus is shifted to toleration out of respect as a normative...

  11. Tolerance in Drosophila

    OpenAIRE

    Atkinson, Nigel S.

    2009-01-01

    The set of genes that underlie ethanol tolerance (inducible resistance) are likely to overlap with the set of genes responsible for ethanol addiction. Whereas addiction is difficult to recognize in simple model systems, behavioral tolerance is readily identifiable and can be induced in large populations of animals. Thus, tolerance lends itself to analysis in model systems with powerful genetics. Drosophila melanogaster has been used by a variety of laboratories for the identification of genes...

  12. 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

  13. System for memorizing maximum values

    Science.gov (United States)

    Bozeman, Richard J., Jr.

    1992-08-01

    The invention discloses a system capable of memorizing maximum sensed values. The system includes conditioning circuitry which receives the analog output signal from a sensor transducer. The conditioning circuitry rectifies and filters the analog signal and provides an input signal to a digital driver, which may be either linear or logarithmic. The driver converts the analog signal to discrete digital values, which in turn triggers an output signal on one of a plurality of driver output lines n. The particular output lines selected is dependent on the converted digital value. A microfuse memory device connects across the driver output lines, with n segments. Each segment is associated with one driver output line, and includes a microfuse that is blown when a signal appears on the associated driver output line.

  14. Remarks on the maximum luminosity

    Science.gov (United States)

    Cardoso, Vitor; Ikeda, Taishi; Moore, Christopher J.; Yoo, Chul-Moon

    2018-04-01

    The quest for fundamental limitations on physical processes is old and venerable. Here, we investigate the maximum possible power, or luminosity, that any event can produce. We show, via full nonlinear simulations of Einstein's equations, that there exist initial conditions which give rise to arbitrarily large luminosities. However, the requirement that there is no past horizon in the spacetime seems to limit the luminosity to below the Planck value, LP=c5/G . Numerical relativity simulations of critical collapse yield the largest luminosities observed to date, ≈ 0.2 LP . We also present an analytic solution to the Einstein equations which seems to give an unboundedly large luminosity; this will guide future numerical efforts to investigate super-Planckian luminosities.

  15. Maximum mutual information regularized classification

    KAUST Repository

    Wang, Jim Jing-Yan

    2014-09-07

    In this paper, a novel pattern classification approach is proposed by regularizing the classifier learning to maximize mutual information between the classification response and the true class label. We argue that, with the learned classifier, the uncertainty of the true class label of a data sample should be reduced by knowing its classification response as much as possible. The reduced uncertainty is measured by the mutual information between the classification response and the true class label. To this end, when learning a linear classifier, we propose to maximize the mutual information between classification responses and true class labels of training samples, besides minimizing the classification error and reducing the classifier complexity. An objective function is constructed by modeling mutual information with entropy estimation, and it is optimized by a gradient descend method in an iterative algorithm. Experiments on two real world pattern classification problems show the significant improvements achieved by maximum mutual information regularization.

  16. Scintillation counter, maximum gamma aspect

    International Nuclear Information System (INIS)

    Thumim, A.D.

    1975-01-01

    A scintillation counter, particularly for counting gamma ray photons, includes a massive lead radiation shield surrounding a sample-receiving zone. The shield is disassembleable into a plurality of segments to allow facile installation and removal of a photomultiplier tube assembly, the segments being so constructed as to prevent straight-line access of external radiation through the shield into radiation-responsive areas. Provisions are made for accurately aligning the photomultiplier tube with respect to one or more sample-transmitting bores extending through the shield to the sample receiving zone. A sample elevator, used in transporting samples into the zone, is designed to provide a maximum gamma-receiving aspect to maximize the gamma detecting efficiency. (U.S.)

  17. Maximum mutual information regularized classification

    KAUST Repository

    Wang, Jim Jing-Yan; Wang, Yi; Zhao, Shiguang; Gao, Xin

    2014-01-01

    In this paper, a novel pattern classification approach is proposed by regularizing the classifier learning to maximize mutual information between the classification response and the true class label. We argue that, with the learned classifier, the uncertainty of the true class label of a data sample should be reduced by knowing its classification response as much as possible. The reduced uncertainty is measured by the mutual information between the classification response and the true class label. To this end, when learning a linear classifier, we propose to maximize the mutual information between classification responses and true class labels of training samples, besides minimizing the classification error and reducing the classifier complexity. An objective function is constructed by modeling mutual information with entropy estimation, and it is optimized by a gradient descend method in an iterative algorithm. Experiments on two real world pattern classification problems show the significant improvements achieved by maximum mutual information regularization.

  18. 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.)

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. Liposomal bupivacaine as a single-injection peripheral nerve block: a dose-response study.

    Science.gov (United States)

    Ilfeld, Brian M; Malhotra, Nisha; Furnish, Timothy J; Donohue, Michael C; Madison, Sarah J

    2013-11-01

    Currently available local anesthetics approved for single-injection peripheral nerve blocks have a maximum duration of fashion. The end points included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current in the femoral nerve distribution. Measurements were performed from baseline until quadriceps MVIC returned to 80% of baseline bilaterally. There were statistically significant dose responses in MVIC (0.09%/mg, SE = 0.03, 95% confidence interval [CI], 0.04-0.14, P = 0.002) and tolerance to cutaneous current (-0.03 mA/mg, SE = 0.01, 95% CI, -0.04 to -0.02, P 40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 hours in 100% of subjects (95% CI, 56%-100%). MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI, 54%-100%). Motor block duration was not correlated with bupivacaine dose (0.06 hour/mg, SE = 0.14, 95% CI, -0.27 to 0.39, P = 0.707). The results of this investigation suggest that deposition of a liposomal bupivacaine formulation adjacent to the femoral nerve results in a partial sensory and motor block of >24 hours for the highest doses examined. However, the high variability of block magnitude among subjects and inverse relationship of dose and response magnitude attests to the need for a phase 3 study with a far larger sample size, and that these results should be viewed as suggestive, requiring confirmation in a future trial.

  5. Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kelsey, Chris R., E-mail: christopher.kelsey@duke.edu [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Das, Shiva [Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (United States); Gu, Lin [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina (United States); Dunphy, Frank R.; Ready, Neal E. [Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Marks, Lawrence B. [Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (United States)

    2015-12-01

    Purpose: To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT. Methods and Materials: Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standard 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT. Results: A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6). Conclusions: Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade ≥3 acute esophageal reactions.

  6. Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer

    International Nuclear Information System (INIS)

    Minsky, B.D.; Cohen, A.M.; Kemeny, N.; Enker, W.E.; Kelsen, D.P.; Schwartz, G.; Saltz, L.; Dougherty, J.; Frankel, J.; Wiseberg, J.

    1993-01-01

    The authors performed a Phase 1 trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily x 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer. Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy was not dose escalated; 5-FU: 425 mg/m2 and LV: 20 mg/m2. The median follow-up was 14 months (7--16 months). Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2. Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, the authors do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate they remain encouraged with this approach. 31 refs., 1 fig., 2 tabs

  7. Efficacy and tolerability of chemotherapy with modified dose-dense TCF regimen (TCF-dd) in locally advanced or metastatic gastric cancer: final results of a phase II trial.

    Science.gov (United States)

    Tomasello, Gianluca; Liguigli, Wanda; Poli, Rossana; Lazzarelli, Silvia; Brighenti, Matteo; Negri, Federica; Curti, Alessandra; Martinotti, Mario; Olivetti, Lucio; Rovatti, Massimo; Donati, Gianvito; Passalacqua, Rodolfo

    2014-10-01

    We previously studied a dose-dense TCF (TCF-dd) regimen demonstrating its feasibility and an activity comparable to epirubicin-based chemotherapy and TCF q3w in terms of overall survival and time to progression (TTP). We report here the final results of a phase II study of chemotherapy with a modified TCF-dd regimen in locally advanced or metastatic gastric cancer (MGC). Patients with histologically confirmed measurable MGC, not previously treated for advanced disease, received docetaxel 70 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, l-folinic acid 100 mg/m(2) days 1 and 2, followed by 5-fluorouracil (5-FU) 400 mg/m(2) bolus days 1 and 2, and then 600 mg/m(2) as a 22-h continuous infusion days 1 and 2, every 14 days, plus pegfilgrastim 6 mg on day 3. Patients aged ≥65 years received the same schedule with a dose reduction of 30 %. Study duration: December 2007-November 2010. Forty-six consecutive patients were enrolled (78 % male, 22 % female; median age, 66 years, range, 38-76 years; ECOG PS: 0, 48 %, 1, 46 %). Primary endpoint was overall response rate (ORR). A median of four cycles (range, one to six) was administered. Forty-three patients were evaluated for response (93.5 %) and all for toxicity: 3 complete response (CR), 25 partial response (PR), 10 stable disease (SD), and 5 progressive disease (PD) were observed, for an ORR by intention to treat (ITT) of 61 % (95 % CI 47-75). Median overall survival (OS) was 17.63 months (95 % CI, 13.67-20.67); median progression-free survival was 8.9 months (95 % CI, 6.5-13.4). Twenty-one patients (46.0 %) were treated at full doses without any delay, thus respecting the dose-dense criterion. Most frequent grade 3-4 toxicities were neutropenia (20 %), leukopenia (4 %), thrombocytopenia (2 %), anemia (2 %), febrile neutropenia (6 %), asthenia (22 %), diarrhea (4 %), nausea/vomiting (11 %), and hypokalemia (6 %). Overall, TCF-dd was shown to be safe. The TCF-dd regimen in locally advanced or MGC

  8. 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

  9. 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)

  10. Maximum entropy technique in the doublet structure analysis

    International Nuclear Information System (INIS)

    Belashev, B.Z.; Panebrattsev, Yu.A.; Shakhaliev, Eh.I.; Soroko, L.M.

    1998-01-01

    The Maximum Entropy Technique (MENT) for solution of the inverse problems is explained. The effective computer program for resolution of the nonlinear equations system encountered in the MENT has been developed and tested. The possibilities of the MENT have been demonstrated on the example of the MENT in the doublet structure analysis of noisy experimental data. The comparison of the MENT results with results of the Fourier algorithm technique without regularization is presented. The tolerant noise level is equal to 30% for MENT and only 0.1% for the Fourier algorithm

  11. 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

  12. Maximum entropy and Bayesian methods

    International Nuclear Information System (INIS)

    Smith, C.R.; Erickson, G.J.; Neudorfer, P.O.

    1992-01-01

    Bayesian probability theory and Maximum Entropy methods are at the core of a new view of scientific inference. These 'new' ideas, along with the revolution in computational methods afforded by modern computers allow astronomers, electrical engineers, image processors of any type, NMR chemists and physicists, and anyone at all who has to deal with incomplete and noisy data, to take advantage of methods that, in the past, have been applied only in some areas of theoretical physics. The title workshops have been the focus of a group of researchers from many different fields, and this diversity is evident in this book. There are tutorial and theoretical papers, and applications in a very wide variety of fields. Almost any instance of dealing with incomplete and noisy data can be usefully treated by these methods, and many areas of theoretical research are being enhanced by the thoughtful application of Bayes' theorem. Contributions contained in this volume present a state-of-the-art overview that will be influential and useful for many years to come

  13. Compromise and Toleration

    DEFF Research Database (Denmark)

    Rostbøll, Christian F.

    Political compromise is akin to toleration, since both consist of an "agreement to disagree." Compromise and toleration also share a predicament of being regarded as ambiguous virtues that require of us to accept something we actually regard as wrong. However, we misunderstand the nature, justifi...... in compromise are more stringent than those for being tolerated. Still, the limits of compromise cannot be drawn to narrowly if it is to remain its value as a form of agreement that respects and embodies the differences of opinion in society.......Political compromise is akin to toleration, since both consist of an "agreement to disagree." Compromise and toleration also share a predicament of being regarded as ambiguous virtues that require of us to accept something we actually regard as wrong. However, we misunderstand the nature......, justification, and limits of compromise if we see it merely as a matter of toleration. While toleration is mainly a matter of accepting citizens' equal right to co-existence as subjects to law, political compromise includes the parties in making law – it makes them co-authors of law. Toleration entails...

  14. Tolerances in micro manufacturing

    DEFF Research Database (Denmark)

    Hansen, Hans Nørgaard; Zhang, Yang; Islam, Aminul

    This paper describes a method for analysis of tolerances in micro manufacturing. It proposes a mapping oftolerances to dimensions and compares this with current available international standards. The analysisdocuments that tolerances are not scaled down as the absolute dimension. In practice...

  15. Fault tolerant computing systems

    International Nuclear Information System (INIS)

    Randell, B.

    1981-01-01

    Fault tolerance involves the provision of strategies for error detection damage assessment, fault treatment and error recovery. A survey is given of the different sorts of strategies used in highly reliable computing systems, together with an outline of recent research on the problems of providing fault tolerance in parallel and distributed computing systems. (orig.)

  16. Toleration out of respect?

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2014-01-01

    be based on a modus vivendi designed to secure peaceful co-existence, but should be based on moral reasons. Forst therefore advances what he calls the ‘respect conception’ of toleration as an in itself morally desirable type of relationship, which is furthermore the only conception of toleration...

  17. Recognition and Toleration

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2010-01-01

    Recognition and toleration are ways of relating to the diversity characteristic of multicultural societies. The article concerns the possible meanings of toleration and recognition, and the conflict that is often claimed to exist between these two approaches to diversity. Different forms or inter...

  18. Is the maximum permissible radiation burden for the population indeed permissible

    International Nuclear Information System (INIS)

    Renesse, R.L. van.

    1975-01-01

    It is argued that legislation based on the ICRP doses will, under economical influences, lead to a situation where the population is exposed to radiation doses near the maximum permissible dose. Due to cumulative radiation effects, this will introduce unacceptable health risks. Therefore, it will be necessary to lower the legal dose limit of 170 millrem per year per person by a factor 10 to 20

  19. Remember Tolerance Differently

    DEFF Research Database (Denmark)

    Tønder, Lars

    2012-01-01

    This essay questions the linear conception of history which often accompanies the way contemporary democratic theory tends to disavow tolerance's discontinuities and remainders. In the spirit of Foucault's genealogy of descent, the idea is to develop a new sense of tolerance's history, not by inv......This essay questions the linear conception of history which often accompanies the way contemporary democratic theory tends to disavow tolerance's discontinuities and remainders. In the spirit of Foucault's genealogy of descent, the idea is to develop a new sense of tolerance's history......, not by invoking a critique external to contemporary democratic theory, but by witnessing the history of tolerance paraliptically, with an eye to what it obscures and yet presupposes....

  20. Sensitivity of dose-finding studies to observation errors.

    Science.gov (United States)

    Zohar, Sarah; O'Quigley, John

    2009-11-01

    The purpose of Phase I designs is to estimate the MTD (maximum tolerated dose, in practice a dose with some given acceptable rate of toxicity) while, at the same time, minimizing the number of patients treated at doses too far removed from the MTD. Our purpose here is to investigate the sensitivity of conclusions from dose-finding designs to recording or observation errors. Certain toxicities may go undetected and, conversely, certain non-toxicities may be incorrectly recorded as dose-limiting toxicities. Recording inaccuracies would be expected to have an influence on final and within trial recommendations and, in this paper, we study in greater depth this question. We focus, in particular on three designs used currently; the standard '3+3' design, the grouped up-and-down design [M. Gezmu, N. Flournoy, Group up-and-down designs for dose finding. Journal of Statistical Planning and Inference 2006; 136 (6): 1749-1764.] and the continual reassessment method (CRM, [J. O'Quigley, M. Pepe, L. Fisher, Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 1990; 46 (1): 33-48.]). A non-toxicity incorrectly recorded as a toxicity (error of first kind) has a greater influence in general than the converse (error of second kind). These results are illustrated via figures which suggest that the standard '3+3' design in particular is sensitive to errors of the second kind. Such errors can have a very important impact on drug development in that, if carried through to the Phase 2 and Phase 3 studies, we can significantly increase the probability of failure to detect efficacy as a result of having delivered an inadequate dose.

  1. Retention, dosing, tolerability and patient reported seizure outcome of Zonisamide as only add-on treatment under real-life conditions in adult patients with partial onset seizures: Results of the observational study ZOOM.

    Science.gov (United States)

    Hamer, Hajo; Baulac, Michel; McMurray, Rob; Kockelmann, Edgar

    2016-01-01

    Zonisamide is licensed for adjunctive therapy for partial-onset seizures with or without secondary generalisation in patients 6 years and older and as monotherapy for the treatment of partial seizures in adult patients with newly diagnosed epilepsy, and shows a favourable pharmacokinetic profile with low interaction potential with other drugs. The aim of the present study was to gather real-life data on retention and modalities of zonisamide use when administered as only add-on treatment to a current AED monotherapy in adult patients with partial-onset seizures. This multicenter observational study was performed in 4 European countries and comprised three visits: baseline, and after 3 and 6 months. Data on patients' retention, reported efficacy, tolerability and safety, and quality of life was collected. Of 100 included patients, 93 could be evaluated. After 6 months, the retention rate of zonisamide add-on therapy was 82.8%. At this time, a reduction of seizure frequency of at least 50% was observed in 79.7% of patients, with 43.6% reporting seizure freedom over the last 3 months of the study period. Adverse events were reported by 19.4% of patients, with fatigue, agitation, dizziness, and headache being most frequent. Approximately 25% of patients were older than 60 years, many of whom suffered from late-onset epilepsy. Compared to younger patients, these patients showed considerable differences with regard to their antiepileptic drug regimen at baseline, and slightly higher responder and retention rates at 6 months. Despite limitations due to the non-interventional open-label design and the low sample size, the results show that zonisamide as only add-on therapy is well retained, indicating effectiveness in the majority of patients under real-life conditions. Copyright © 2015. Published by Elsevier Ltd.

  2. Maximum entropy principal for transportation

    International Nuclear Information System (INIS)

    Bilich, F.; Da Silva, R.

    2008-01-01

    In this work we deal with modeling of the transportation phenomenon for use in the transportation planning process and policy-impact studies. The model developed is based on the dependence concept, i.e., the notion that the probability of a trip starting at origin i is dependent on the probability of a trip ending at destination j given that the factors (such as travel time, cost, etc.) which affect travel between origin i and destination j assume some specific values. The derivation of the solution of the model employs the maximum entropy principle combining a priori multinomial distribution with a trip utility concept. This model is utilized to forecast trip distributions under a variety of policy changes and scenarios. The dependence coefficients are obtained from a regression equation where the functional form is derived based on conditional probability and perception of factors from experimental psychology. The dependence coefficients encode all the information that was previously encoded in the form of constraints. In addition, the dependence coefficients encode information that cannot be expressed in the form of constraints for practical reasons, namely, computational tractability. The equivalence between the standard formulation (i.e., objective function with constraints) and the dependence formulation (i.e., without constraints) is demonstrated. The parameters of the dependence-based trip-distribution model are estimated, and the model is also validated using commercial air travel data in the U.S. In addition, policy impact analyses (such as allowance of supersonic flights inside the U.S. and user surcharge at noise-impacted airports) on air travel are performed.

  3. HDR- and LDR-interstitial irradiation (IRT) in rat spinal cord: the effect of decreasing the dose rate and the impact of a rapid dose fall off over the spinal cord

    International Nuclear Information System (INIS)

    Pop, L.A.M.; Plas, M. van der; Hanssen, A.E.J.; Kogel, A.J. van der

    1996-01-01

    Introduction: Detailed knowledge of radiobiological parameters of the different tissues involved are warranted before HDR- and recently PDR-brachytherapy can be successfully introduced in clinical practice as an alternative to LDR- brachytherapy. The purpose of this study is to determine the α/β ratio and half time of repair of rat spinal cord during continuous 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 are inserted on each side of the vertebral bodies from the level of Th 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. Serial experiments have been carried out to obtain complete dose response curves at 5 different dose rates, resp. 0.5, 0.9, 1.6, 2.6 and 120 Gy/h. Paralysis of the hindlegs after 5-6 months and histopathological examination of the spinal cord of each animal are used as experimental endpoints. Dose-volume histograms of each irradiated rat have been analysed to evaluate the correlation between dose distribution and biological response and the histopathological damage seen. 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. Estimates of the repair parameters using different types of analysis revealed an α/β ratio of 2.44 Gy and a (mono- exponential) half time of repair (=t (1(2)) ) of 1.43 hours; for the maximum of 150 % of the prescribed dose these values were 3.67 Gy and 1.43 hours respectively. Conclusions: Spinal cord radiation tolerance is

  4. Center of cancer systems biology second annual workshop--tumor metronomics: timing and dose level dynamics.

    Science.gov (United States)

    Hahnfeldt, Philip; Hlatky, Lynn; Klement, Giannoula Lakka

    2013-05-15

    Metronomic chemotherapy, the delivery of doses in a low, regular manner so as to avoid toxic side effects, was introduced over 12 years ago in the face of substantial clinical and preclinical evidence supporting its tumor-suppressive capability. It constituted a marked departure from the classic maximum-tolerated dose (MTD) strategy, which, given its goal of rapid eradication, uses dosing sufficiently intense to require rest periods between cycles to limit toxicity. Even so, upfront tumor eradication is frequently not achieved with MTD, whereupon a de facto goal of longer-term tumor control is often pursued. As metronomic dosing has shown tumor control capability, even for cancers that have become resistant to the same drug delivered under MTD, the question arises whether it may be a preferable alternative dosing approach from the outset. To date, however, our knowledge of the coupled dynamics underlying metronomic dosing is neither sufficiently well developed nor widely enough disseminated to establish its actual potential. Meeting organizers thus felt the time was right, armed with new quantitative approaches, to call a workshop on "Tumor Metronomics: Timing and Dose Level Dynamics" to explore prospects for gaining a deeper, systems-level appreciation of the metronomics concept. The workshop proved to be a forum in which experts from the clinical, biologic, mathematical, and computational realms could work together to clarify the principles and underpinnings of metronomics. Among other things, the need for significant shifts in thinking regarding endpoints to be used as clinical standards of therapeutic progress was recognized. ©2013 AACR.

  5. Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Mukai, Hirofumi; Takahashi, Shunji; Nozawa, Masahiro; Onozawa, Yusuke; Miyazaki, Jun; Ohno, Keiji; Suzuki, Kazuhiro

    2014-04-01

    The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.

  6. Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial.

    Directory of Open Access Journals (Sweden)

    Moeko Noguchi-Shinohara

    Full Text Available The aim of this study was to evaluate the safety, tolerability and pharmacokinetics of single dose of Melissa officinalis extract which contained rosmarinic acid, including food-effects in healthy individuals. A total of eleven healthy individuals were randomly assigned to treatment arms in the two studies [Study 1 (fasted state and Study 2 (fed state]. Rosmarinic acid in serum was measured by a coulometric detection method using High-Performance Liquid Chromatography electrochemical detector. The serum concentration of total rosmarinic acid peaked at 1 hour after administration of Melissa officinalis extract containing 500mg rosmarinic acid in fasted state, with a maximum serum concentration 162.20 nmol/ L. The area under the curve for intact rosmarinic acid was calculated from the serum concentration-time profile to be 832.13 nmol • hour/ L. Food intake increases area under the curve and delayed time at which the maximum serum concentration. Rosmarinic acid supplementation did not affect liver, kidney, or blood cell function parameters. No adverse event was reported by any of the participants due to the study treatment. Single dose of Melissa officinalis extract containing 500 mg rosmarinic acid appears to be safe and tolerable in healthy individuals. Food intake increased the exposure of rosmarinic acid and delayed absorption of rosmarinic acid in healthy individuals.

  7. Last Glacial Maximum Salinity Reconstruction

    Science.gov (United States)

    Homola, K.; Spivack, A. J.

    2016-12-01

    It has been previously demonstrated that salinity can be reconstructed from sediment porewater. The goal of our study is to reconstruct high precision salinity during the Last Glacial Maximum (LGM). Salinity is usually determined at high precision via conductivity, which requires a larger volume of water than can be extracted from a sediment core, or via chloride titration, which yields lower than ideal precision. It has been demonstrated for water column samples that high precision density measurements can be used to determine salinity at the precision of a conductivity measurement using the equation of state of seawater. However, water column seawater has a relatively constant composition, in contrast to porewater, where variations from standard seawater composition occur. These deviations, which affect the equation of state, must be corrected for through precise measurements of each ion's concentration and knowledge of apparent partial molar density in seawater. We have developed a density-based method for determining porewater salinity that requires only 5 mL of sample, achieving density precisions of 10-6 g/mL. We have applied this method to porewater samples extracted from long cores collected along a N-S transect across the western North Atlantic (R/V Knorr cruise KN223). Density was determined to a precision of 2.3x10-6 g/mL, which translates to salinity uncertainty of 0.002 gms/kg if the effect of differences in composition is well constrained. Concentrations of anions (Cl-, and SO4-2) and cations (Na+, Mg+, Ca+2, and K+) were measured. To correct salinities at the precision required to unravel LGM Meridional Overturning Circulation, our ion precisions must be better than 0.1% for SO4-/Cl- and Mg+/Na+, and 0.4% for Ca+/Na+, and K+/Na+. Alkalinity, pH and Dissolved Inorganic Carbon of the porewater were determined to precisions better than 4% when ratioed to Cl-, and used to calculate HCO3-, and CO3-2. Apparent partial molar densities in seawater were

  8. Maximum Parsimony on Phylogenetic networks

    Science.gov (United States)

    2012-01-01

    Background Phylogenetic networks are generalizations of phylogenetic trees, that are used to model evolutionary events in various contexts. Several different methods and criteria have been introduced for reconstructing phylogenetic trees. Maximum Parsimony is a character-based approach that infers a phylogenetic tree by minimizing the total number of evolutionary steps required to explain a given set of data assigned on the leaves. Exact solutions for optimizing parsimony scores on phylogenetic trees have been introduced in the past. Results In this paper, we define the parsimony score on networks as the sum of the substitution costs along all the edges of the network; and show that certain well-known algorithms that calculate the optimum parsimony score on trees, such as Sankoff and Fitch algorithms extend naturally for networks, barring conflicting assignments at the reticulate vertices. We provide heuristics for finding the optimum parsimony scores on networks. Our algorithms can be applied for any cost matrix that may contain unequal substitution costs of transforming between different characters along different edges of the network. We analyzed this for experimental data on 10 leaves or fewer with at most 2 reticulations and found that for almost all networks, the bounds returned by the heuristics matched with the exhaustively determined optimum parsimony scores. Conclusion The parsimony score we define here does not directly reflect the cost of the best tree in the network that displays the evolution of the character. However, when searching for the most parsimonious network that describes a collection of characters, it becomes necessary to add additional cost considerations to prefer simpler structures, such as trees over networks. The parsimony score on a network that we describe here takes into account the substitution costs along the additional edges incident on each reticulate vertex, in addition to the substitution costs along the other edges which are

  9. Implementation of spot scanning dose optimization and dose calculation for helium ions in Hyperion

    Energy Technology Data Exchange (ETDEWEB)

    Fuchs, Hermann, E-mail: hermann.fuchs@meduniwien.ac.at [Department of Radiation Oncology, Division of Medical Radiation Physics, Medical University of Vienna/AKH Vienna, Vienna 1090, Austria and Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Vienna 1090 (Austria); Alber, Markus [Department for Oncology, Aarhus University Hospital, Aarhus 8000 (Denmark); Schreiner, Thomas [PEG MedAustron, Wiener Neustadt 2700 (Austria); Georg, Dietmar [Department of Radiation Oncology, Division of Medical Radiation Physics, Medical University of Vienna/AKH Vienna, Vienna 1090 (Austria); Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Vienna 1090 (Austria); Comprehensive Cancer Center, Medical University of Vienna/AKH Vienna, Vienna 1090 (Austria)

    2015-09-15

    Purpose: Helium ions ({sup 4}He) may supplement current particle beam therapy strategies as they possess advantages in physical dose distribution over protons. To assess potential clinical advantages, a dose calculation module accounting for relative biological effectiveness (RBE) was developed and integrated into the treatment planning system Hyperion. Methods: Current knowledge on RBE of {sup 4}He together with linear energy transfer considerations motivated an empirical depth-dependent “zonal” RBE model. In the plateau region, a RBE of 1.0 was assumed, followed by an increasing RBE up to 2.8 at the Bragg-peak region, which was then kept constant over the fragmentation tail. To account for a variable proton RBE, the same model concept was also applied to protons with a maximum RBE of 1.6. Both RBE models were added to a previously developed pencil beam algorithm for physical dose calculation and included into the treatment planning system Hyperion. The implementation was validated against Monte Carlo simulations within a water phantom using γ-index evaluation. The potential benefits of {sup 4}He based treatment plans were explored in a preliminary treatment planning comparison (against protons) for four treatment sites, i.e., a prostate, a base-of-skull, a pediatric, and a head-and-neck tumor case. Separate treatment plans taking into account physical dose calculation only or using biological modeling were created for protons and {sup 4}He. Results: Comparison of Monte Carlo and Hyperion calculated doses resulted in a γ{sub mean} of 0.3, with 3.4% of the values above 1 and γ{sub 1%} of 1.5 and better. Treatment plan evaluation showed comparable planning target volume coverage for both particles, with slightly increased coverage for {sup 4}He. Organ at risk (OAR) doses were generally reduced using {sup 4}He, some by more than to 30%. Improvements of {sup 4}He over protons were more pronounced for treatment plans taking biological effects into account. All

  10. A Multirelational Account of Toleration

    DEFF Research Database (Denmark)

    Ferretti, Maria Paola; Lægaard, Sune

    2013-01-01

    Toleration classically denotes a relation between two agents that is characterised by three components: objection, power, and acceptance overriding the objection. Against recent claims that classical toleration is not applicable in liberal democracies and that toleration must therefore either be ...

  11. Maximum credible accident analysis for TR-2 reactor conceptual design

    International Nuclear Information System (INIS)

    Manopulo, E.

    1981-01-01

    A new reactor, TR-2, of 5 MW, designed in cooperation with CEN/GRENOBLE is under construction in the open pool of TR-1 reactor of 1 MW set up by AMF atomics at the Cekmece Nuclear Research and Training Center. In this report the fission product inventory and doses released after the maximum credible accident have been studied. The diffusion of the gaseous fission products to the environment and the potential radiation risks to the population have been evaluated

  12. In vitro mutants identification of banana (Musa sp.) with tolerance to toxin from Fusarium oxysporum f. sp cubense, treating buds with several gamma radiation doses; Identificacao in vitro de mutantes de banana maca (Musa sp.) tolerantes a toxina do Fusarium oxysporum f. sp. cubense, a partir de gemas tratadas com diferentes doses de radiacao gama

    Energy Technology Data Exchange (ETDEWEB)

    Moura, Adriana Muniz Mendes de; Houllou-Kido, Laureen Michelle; Franca, Jose Geraldo Eugenio de [Empresa Pernambucana de Pesquisa Agropecuaria, Recife, PE (Brazil); Colaco, Waldeciro [Pernambuco Univ., Recife, PE (Brazil). Dept. de Energia Nuclear

    1999-11-01

    Mutants of banana, obtained through treatment with different level of gamma-radiation (0; 10; 20; 30; 40 Gy), were initially cultivated in vitro in medium for rapid clonal propagation during 30 days. These treatment affected the shoot tips development ratio. Some plants developed necrosis and died, but some of the shoot tips emitted new gems. These material were cultivated in medium 20% of the toxin of Fusarium oxysporum cubense. During the selection period, the necrosis occurrence and death of susceptible shoot tips were observed. Whereas the tolerant shoot tips kept themselves green during the entire selection process. At the end of the selection process, eight shoot tips were obtained. (author) 7 refs.

  13. Optimization of dose distributions for adjuvant locoregional radiotherapy of gastric cancer by IMRT

    International Nuclear Information System (INIS)

    Lohr, F.; Dobler, B.; Mai, S.; Hermann, B.; Tiefenbacher, U.; Wieland, P.; Steil, V.; Wenz, F.

    2003-01-01

    Background and Purpose: Locoregional relapse is a problem frequently encountered with advanced gastric cancer. Data from the randomized Intergroup trial 116 suggest effectiveness of adjuvant radiochemotherapy, albeit with significant toxicity. The potential of intensity-modulated radiotherapy (IMRT) to reduce toxicity by significantly reducing maximum and median doses to organs at risk while still applying sufficient dose to the target volume in the upper abdomen was studied. Patient and Methods: For a typical configuration of target volumes and organs, a step-and-shoot IMRT plan (eight beam orientations), developed as a class solution for treatment of tumors in the upper abdomen (Figures 1 to 3), a conventional plan, a combination of the conventional plan with a kidney-sparing boost plan, and a conventional plan with noncoplanar ap and pa fields for improved kidney sparing were compared with respect to coverage of target volume and dose to organs at risk with a dose of 45 Gy delivered as the median dose to the target volume. Results: When using the conventional three-dimensionally planned box techniques, the right kidney could be kept below tolerance, but median dose to the left kidney amounted to between 14.8 and 26.9 Gy, depending on the plan. IMRT reduced the median dose to the left kidney to 10.5 Gy, while still keeping the dose to the right kidney 90% of prescription dose were delivered to > 90% of target volume with IMRT (Table 1). Conclusion: IMRT has the potential to deliver efficient doses to target volumes in the upper abdomen, while delivering dose to organs at risk in a more advantageous fashion than a conventional technique. For clinical implementation, the possibility of extensive organ motion in the upper abdomen has to be taken into account for treatment planning and patient positioning. The multitude of potential risks related to its application has to be the subject of thorough follow-up and further studies. (orig.)

  14. 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

  15. Dose mapping role in gamma irradiation industry

    International Nuclear Information System (INIS)

    Noriah Mod Ali; John Konsoh Sangau; Mazni Abd Latif

    2002-01-01

    In this studies, the role of dosimetry activity in gamma irradiator was discussed. Dose distribution in the irradiator, which is a main needs in irradiator or chamber commissioning. This distribution data were used to confirm the dosimetry parameters i.e. exposure time, maximum and minimum dose map/points, and dose distribution - in which were used as guidelines for optimum product irradiation. (Author)

  16. Evaluation of robustness of maximum likelihood cone-beam CT reconstruction with total variation regularization

    International Nuclear Information System (INIS)

    Stsepankou, D; Arns, A; Hesser, J; Ng, S K; Zygmanski, P

    2012-01-01

    The objective of this paper is to evaluate an iterative maximum likelihood (ML) cone–beam computed tomography (CBCT) reconstruction with total variation (TV) regularization with respect to the robustness of the algorithm due to data inconsistencies. Three different and (for clinical application) typical classes of errors are considered for simulated phantom and measured projection data: quantum noise, defect detector pixels and projection matrix errors. To quantify those errors we apply error measures like mean square error, signal-to-noise ratio, contrast-to-noise ratio and streak indicator. These measures are derived from linear signal theory and generalized and applied for nonlinear signal reconstruction. For quality check, we focus on resolution and CT-number linearity based on a Catphan phantom. All comparisons are made versus the clinical standard, the filtered backprojection algorithm (FBP). In our results, we confirm and substantially extend previous results on iterative reconstruction such as massive undersampling of the number of projections. Errors of projection matrix parameters of up to 1° projection angle deviations are still in the tolerance level. Single defect pixels exhibit ring artifacts for each method. However using defect pixel compensation, allows up to 40% of defect pixels for passing the standard clinical quality check. Further, the iterative algorithm is extraordinarily robust in the low photon regime (down to 0.05 mAs) when compared to FPB, allowing for extremely low-dose image acquisitions, a substantial issue when considering daily CBCT imaging for position correction in radiotherapy. We conclude that the ML method studied herein is robust under clinical quality assurance conditions. Consequently, low-dose regime imaging, especially for daily patient localization in radiation therapy is possible without change of the current hardware of the imaging system. (paper)

  17. Collective dose, conceptual basis and practical applications

    International Nuclear Information System (INIS)

    Bonka, H.

    1985-01-01

    In the ICRP Publications no. 22(1973) and no. 26(1977), the ICRP recommends that the maximum permissible whole-body dose by kept below the dose limits corresponding to the sum of all effective dose equivalents of the persons concerned, i.e. the collective dose. The effective dose equivalent is recommended by the ICRP for use as a new quantity for evaluating the stochastic radiation dose for individual persons. Examples are given by the author explaining cost-benefit analyses according to ICRP recommendations, especially discussing the definition of optimum local dose limits with regard to shielding design in nuclear installations. (DG) [de

  18. State, religion and toleration

    DEFF Research Database (Denmark)

    Huggler, Jørgen

    2009-01-01

    Contribution to Religion and State - From separation to cooperation? Legal-philosophical reflections for a de-secularized world. (IVR Cracow Special Workshop). Eds. Bart. C. Labuschagne & Ari M. Solon. Abstract: Toleration is indeed a complex phenomenon. A discussion of the concept will have...... to underline not only the broadmindedness and liberty of individuals or of groups, but also the relevant distinctions and arguments in political philosophy, epistemology, philosophy of religion and philosophical anthropology and their connection with educational issues. Through a discussion of these relations......, the essay argues three theses: (1) Toleration is not reducible to an ethics of spiritual freedom. (2) Toleration is not neutral to fanatism. (3) Toleration involves esteem for the person....

  19. Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study.

    Science.gov (United States)

    Phuphanich, Surasak; Baker, Sharyn D; Grossman, Stuart A; Carson, Kathryn A; Gilbert, Mark R; Fisher, Joy D; Carducci, Michael A

    2005-04-01

    We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.

  20. Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study1

    Science.gov (United States)

    Phuphanich, Surasak; Baker, Sharyn D.; Grossman, Stuart A.; Carson, Kathryn A.; Gilbert, Mark R.; Fisher, Joy D.; Carducci, Michael A.

    2005-01-01

    We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 μM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme–inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants. PMID:15831235

  1. Phase I/II Study Evaluating Early Tolerance in Breast Cancer Patients Undergoing Accelerated Partial Breast Irradiation Treated With the MammoSite Balloon Breast Brachytherapy Catheter Using a 2-Day Dose Schedule

    International Nuclear Information System (INIS)

    Wallace, Michelle; Martinez, Alvaro; Mitchell, Christina; Chen, Peter Y.; Ghilezan, Mihai; Benitez, Pamela; Brown, Eric; Vicini, Frank

    2010-01-01

    Purpose: Initial Phase I/II results using balloon brachytherapy to deliver accelerated partial breast irradiation (APBI) in 2 days in patients with early-stage breast cancer are presented. Materials and Methods: Between March 2004 and August 2007, 45 patients received adjuvant radiation therapy after lumpectomy with balloon brachytherapy in a Phase I/II trial delivering 2800 cGy in four fractions of 700 cGy. Toxicities were evaluated using the National Cancer Institute Common Toxicity Criteria for Adverse Events v3.0 scale and cosmesis was documented at ≥6 months. Results: The median age was 66 years (range, 48-83) and median skin spacing was 12 mm (range, 8-24). The median follow-up was 11.4 months (5.4-48 months) with 21 patients (47%) followed ≥1 year, 11 (24%) ≥2 years, and 7 (16%) ≥3 years. At <6 months (n = 45), Grade II toxicity rates were 9% radiation dermatitis, 13% breast pain, 2% edema, and 2% hyperpigmentation. Grade III breast pain was reported in 13% (n = 6). At ≥6 months (n = 43), Grade II toxicity rates were: 2% radiation dermatitis, 2% induration, and 2% hypopigmentation. Grade III breast pain was reported in 2%. Infection was 13% (n = 6) at <6 months and 5% (n = 2) at ≥6 months. Persistent seroma ≥6 months was 30% (n = 13). Fat necrosis developed in 4 cases (2 symptomatic). Rib fractures were seen in 4% (n = 2). Cosmesis was good/excellent in 96% of cases. Conclusions: Treatment with balloon brachytherapy using a 2-day dose schedule resulted acceptable rates of Grade II/III chronic toxicity rates and similar cosmetic results observed with a standard 5-day accelerated partial breast irradiation schedule.

  2. Maximum power point tracker based on fuzzy logic

    International Nuclear Information System (INIS)

    Daoud, A.; Midoun, A.

    2006-01-01

    The solar energy is used as power source in photovoltaic power systems and the need for an intelligent power management system is important to obtain the maximum power from the limited solar panels. With the changing of the sun illumination due to variation of angle of incidence of sun radiation and of the temperature of the panels, Maximum Power Point Tracker (MPPT) enables optimization of solar power generation. The MPPT is a sub-system designed to extract the maximum power from a power source. In the case of solar panels power source. the maximum power point varies as a result of changes in its electrical characteristics which in turn are functions of radiation dose, temperature, ageing and other effects. The MPPT maximum the power output from panels for a given set of conditions by detecting the best working point of the power characteristic and then controls the current through the panels or the voltage across them. Many MPPT methods have been reported in literature. These techniques of MPPT can be classified into three main categories that include: lookup table methods, hill climbing methods and computational methods. The techniques vary according to the degree of sophistication, processing time and memory requirements. The perturbation and observation algorithm (hill climbing technique) is commonly used due to its ease of implementation, and relative tracking efficiency. However, it has been shown that when the insolation changes rapidly, the perturbation and observation method is slow to track the maximum power point. In recent years, the fuzzy controllers are used for maximum power point tracking. This method only requires the linguistic control rules for maximum power point, the mathematical model is not required and therefore the implementation of this control method is easy to real control system. In this paper, we we present a simple robust MPPT using fuzzy set theory where the hardware consists of the microchip's microcontroller unit control card and

  3. Skin dose variation: influence of energy

    International Nuclear Information System (INIS)

    Cheung, T.; Yu, P.K.N.; Butson, M.J.; Cancer Services, Wollongong, NSW

    2004-01-01

    Full text: This research aimed to quantitatively evaluate the differences in percentage dose of maximum for 6MV and 18MV x-ray beams within the first lcm of interactions. Thus provide quantitative information regarding the basal, dermal and subcutaneous dose differences achievable with these two types of high-energy x-ray beams. Percentage dose of maximum build up curves are measured for most clinical field sizes using 6MV and 18MV x-ray beams. Calculations are performed to produce quantitative results highlighting the percentage dose of maximum differences delivered to various depths within the skin and subcutaneous tissue region by these two beams Results have shown that basal cell layer doses are not significantly different for 6MV and 18Mv x-ray beams At depths beyond the surface and basal cell layer there is a measurable and significant difference in delivered dose. This variation increases to 20% of maximum and 22% of maximum at Imm and 1cm depths respectively. The percentage variations are larger for smaller field sizes where the photon in phantom component of the delivered dose is the most significant contributor to dose By producing graphs or tables of % dose differences in the build up region we can provide quantitative information to the oncologist for consideration (if skin and subcutaneous tissue doses are of importance) during the beam energy selection process for treatment. Copyright (2004) Australasian College of Physical Scientists and Engineers in Medicine

  4. A Theory of Tolerance

    OpenAIRE

    Corneo, Giacomo; Jeanne, Olivier

    2006-01-01

    We develop an economic theory of tolerance where styles of behaviour are invested with symbolic value. Value systems are endogenous and taught by parents to their children. In conjunction with actual behaviour, value systems determine the esteem enjoyed by individuals. Intolerant individuals have all symbolic value invested in a single style of behaviour, whereas tolerant people have diversified values. The proposed model identifies a link between the unpredictability of children's lifestyles...

  5. 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).

  6. Two-dimensional maximum entropy image restoration

    International Nuclear Information System (INIS)

    Brolley, J.E.; Lazarus, R.B.; Suydam, B.R.; Trussell, H.J.

    1977-07-01

    An optical check problem was constructed to test P LOG P maximum entropy restoration of an extremely distorted image. Useful recovery of the original image was obtained. Comparison with maximum a posteriori restoration is made. 7 figures

  7. Considerations on the establishment of maximum permissible exposure of man

    International Nuclear Information System (INIS)

    Jacobi, W.

    1974-01-01

    An attempt is made in the information lecture to give a quantitative analysis of the somatic radiation risk and to illustrate a concept to fix dose limiting values. Of primary importance is the limiting values. Of primary importance is the limiting value of the radiation exposure to the whole population. By consequential application of the risk concept, the following points are considered: 1) Definition of the risk for radiation late damages (cancer, leukemia); 2) relationship between radiation dose and thus caused radiation risk; 3) radiation risk and the dose limiting values at the time; 4) criteria for the maximum acceptable radiation risk; 5) limiting value which can be expected at the time. (HP/LH) [de

  8. Maximum permissible concentration (MPC) values for spontaneously fissioning radionuclides

    International Nuclear Information System (INIS)

    Ford, M.R.; Snyder, W.S.; Dillman, L.T.; Watson, S.B.

    1976-01-01

    The radiation hazards involved in handling certain of the transuranic nuclides that exhibit spontaneous fission as a mode of decay were reaccessed using recent advances in dosimetry and metabolic modeling. Maximum permissible concentration (MPC) values in air and water for occupational exposure (168 hr/week) were calculated for 244 Pu, 246 Cm, 248 Cm, 250 Cf, 252 Cf, 254 Cf, /sup 254m/Es, 255 Es, 254 Fm, and 256 Fm. The half-lives, branching ratios, and principal modes of decay of the parent-daughter members down to a member that makes a negligible contribution to the dose are given, and all daughters that make a significant contribution to the dose to body organs following inhalation or ingestion are included in the calculations. Dose commitments for body organs are also given

  9. Hematopoietic tissue repair under chronic low daily dose irradiation

    International Nuclear Information System (INIS)

    Seed, T.M.

    1994-01-01

    The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). We have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d -1 ). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup (1), the failure to augment basic m-pair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments particularly marked within erythroid compartments. that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccomodated and either prone- or not prone to ML, subgroup 2 ampersand 3 appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high- tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity

  10. Phase I trial of split-dose induction docetaxel, cisplatin, and 5-fluorouracil (TPF chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1

    Directory of Open Access Journals (Sweden)

    Oertel Katrin

    2012-10-01

    Full Text Available Abstract Background Induction chemotherapy (ICT with docetaxel, cisplatin and fluorouracil (TPF followed by radiotherapy is an effective treatment option for unresectable locally advanced head and neck cancer. This phase I study was designed to investigate the safety and tolerability of a split-dose TPF ICT regimen prior to surgery for locally advanced resectable oral and oropharyngeal cancer. Methods Patients received TPF split on two dosages on day 1 and 8 per cycle for one or three 3-week cycles prior to surgery and postoperative radiotherapy or radiochemotherapy. Docetaxel was escalated in two dose levels, 40 mg/m2 (DL 0 and 30 mg/m2 (DL −1, plus 40 mg/m2 cisplatin and 2000 mg/m2 fluorouracil per week using a 3 +3 dose escalation algorithm. Results Eighteen patients were enrolled and were eligible for toxicity and response. A maximum tolerated dose of 30 mg/m2 docetaxel per week was reached. The most common grade 3+ adverse event was neutropenia during ICT in 10 patients. Surgery reached R0 resection in all cases. Nine patients (50% showed complete pathologic regression. Conclusions A split-dose regime of TPF prior to surgery is feasible, tolerated and merits additional investigation in a phase II study with a dose of 30 mg/m docetaxel per week. Trial registration number NCT01108042 (ClinicalTrials.gov Identifier

  11. Radiation dose in dental radiology

    International Nuclear Information System (INIS)

    Cohnen, M.; Kemper, J.; Moedder, U.; Moebes, O.; Pawelzik, J.

    2002-01-01

    The aim of this study was to compare radiation exposure in panoramic radiography (PR), dental CT, and digital volume tomography (DVT). An anthropomorphic Alderson-Rando phantom and two anatomical head phantoms with thermoluminescent dosimeters fixed at appropriate locations were exposed as in a dental examination. In PR and DVT, standard parameters were used while variables in CT included mA, pitch, and rotation time. Image noise was assessed in dental CT and DVT. Radiation doses to the skin and internal organs within the primary beam and resulting from scatter radiation were measured and expressed as maximum doses in mGy. For PR, DVT, and CT, these maximum doses were 0.65, 4.2, and 23 mGy. In dose-reduced CT protocols, radiation doses ranged from 10.9 to 6.1 mGy. Effective doses calculated on this basis showed values below 0.1 mSv for PR, DVT, and dose-reduced CT. Image noise was similar in DVT and low-dose CT. As radiation exposure and image noise of DVT is similar to low-dose CT, this imaging technique cannot be recommended as a general alternative to replace PR in dental radiology. (orig.)

  12. Is the dose equivalent index a quantity to be measured

    International Nuclear Information System (INIS)

    Wagner, S.R.

    1980-01-01

    ICRP introduced the concept of Effective Dose Equivalent H(sub)E and fixed the basic limits of radiation exposure in terms of H(sub)I. As H(sub)E cannot be measured, ICRP stated that with external exposure to penetrating radiation the limitation of the Dose Equivalent Index H(sub)I would afford at least as good a level of protection. However, difficulties arise in measuring H(sub)I and in calibrating instruments in terms of H(sub)I, since the height and location of the dose equivalent maximum in the sphere which is the phantom used in the definition of H(sub)I, depend on the energy and the angular distribution of the incident radiation. That is, H(sub)I is not an additive quantity relative to the partial H(sub)I(sub)i-values of the different energy and angular components. Hence, 1) the distribution of dose equivalent in the sphere must be measured in full for a determination of H(sub)I, and 2) it is not possible to calibrate an instrument which does not exhibit the scattering and absorption properties of the sphere, consistently for arbitrary radiation fields in terms of H(sub)I. Thus the calibration in an unidirectional beam would infer an uncertainty which may amount to a factor of up to 4. This would hardly be tolerable as a base for radiation protection provisions. An alternative is to introduce operational quantities which are additive, e.g. 1) the sum of maxima of the dose equivalent distributions in the sphere produced by different radiation components, and 2) the mean dose equivalent in the sphere. Their relation to H(sub)E for different types of radiation and consequences on secondary limits are discussed. (H.K.)

  13. Dose gradient curve: A new tool for evaluating dose gradient.

    Science.gov (United States)

    Sung, KiHoon; Choi, Young Eun

    2018-01-01

    Stereotactic radiotherapy, which delivers an ablative high radiation dose to a target volume for maximum local tumor control, requires a rapid dose fall-off outside the target volume to prevent extensive damage to nearby normal tissue. Currently, there is no tool to comprehensively evaluate the dose gradient near the target volume. We propose the dose gradient curve (DGC) as a new tool to evaluate the quality of a treatment plan with respect to the dose fall-off characteristics. The average distance between two isodose surfaces was represented by the dose gradient index (DGI) estimated by a simple equation using the volume and surface area of isodose levels. The surface area was calculated by mesh generation and surface triangulation. The DGC was defined as a plot of the DGI of each dose interval as a function of the dose. Two types of DGCs, differential and cumulative, were generated. The performance of the DGC was evaluated using stereotactic radiosurgery plans for virtual targets. Over the range of dose distributions, the dose gradient of each dose interval was well-characterized by the DGC in an easily understandable graph format. Significant changes in the DGC were observed reflecting the differences in planning situations and various prescription doses. The DGC is a rational method for visualizing the dose gradient as the average distance between two isodose surfaces; the shorter the distance, the steeper the dose gradient. By combining the DGC with the dose-volume histogram (DVH) in a single plot, the DGC can be utilized to evaluate not only the dose gradient but also the target coverage in routine clinical practice.

  14. Avaliação da tolerância e nefrotoxicidade do antimonial pentavalente administrado na dose de 40mg Sb v/kg/dia, de 12/12h, por 30 dias na forma cutaneo-mucosa de leishmaniose

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