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Sample records for multiple dose administration

  1. Pharmacokinetics of guaifenesin following administration of multiple doses to exercised Thoroughbred horses.

    Knych, H K; Stanley, S D; Benson, D; Arthur, R M

    2016-08-01

    Guaifenesin is an expectorant commonly used in performance horses to aid in the clearance of mucus from the airways. Guaifenesin is also a centrally acting skeletal muscle relaxant and as such is a prohibited drug with withdrawal necessary prior to competition. To the authors' knowledge, there are no reports in the literature describing single or multiple oral administrations of guaifenesin in the horse to determine a regulatory threshold and related withdrawal time. Therefore, the objective of the current study was to describe the pharmacokinetics of guaifenesin following oral administration in order to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 2 g of guaifenesin orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum guaifenesin concentrations were determined and pharmacokinetic parameters calculated. Guaifenesin was rapidly absorbed (Tmax of 15 min) following oral administration. The Cmax was 681.3 ± 323.8 ng/mL and 1080 ± 732.8 following the first and last dose, respectively. The serum elimination half-life was 2.62 ± 1.24 h. Average serum guaifenesin concentrations remained above the LOQ of the assay (0.5 ng/mL) by 48 h postadministration of the final dose in 3 of 9 horses. © 2016 John Wiley & Sons Ltd.

  2. Pharmacokinetics of sulfamethoxazole and trimethoprim in Pacific white shrimp, Litopenaeus vannamei, after oral administration of single-dose and multiple-dose.

    Ma, Rongrong; Wang, Yuan; Zou, Xiong; Hu, Kun; Sun, Beibei; Fang, Wenhong; Fu, Guihong; Yang, Xianle

    2017-06-01

    The tissue distribution and depletion of sulfamethoxazole (SMZ) and trimethoprim (TMP) were studied in Pacific white shrimp, Litopenaeus vannamei, after single-dose and multiple-dose oral administration of SMZ-TMP (5:1) via medicated feed. In single-dose oral administration, shrimps were fed once at a dose of 100 mg/kg (drug weight/body weight). In multiple-dose oral administration, shrimps were fed three times a day for three consecutive days at a dose of 100mg/kg. The results showed the kinetic characteristic of SMZ was different from TMP in Pacific white shrimp. In the single-dose administration, the SMZ was widely distributed in the tissues, while TMP was highly concentrated in the hepatopancreas. The t 1/2z values of SMZ were larger and persist longer than TMP in Pacific white shrimp. In the multiple-dose administration, SMZ accumulated well in the tissues, and reached steady state level after successive administrations, while TMP did not. TMP concentration even appeared the downward trend with the increase of drug times. Compared with the single dose, the t 1/2z values of SMZ in hepatopancreas (8.22-11.33h) and muscle (6.53-10.92h) of Pacific white shrimps rose, but the haemolymph dropped (13.76-11.03) in the multiple-dose oral administration. Meanwhile, the corresponding values of TMP also rose in hepatopancreas (4.53-9.65h) and muscle (2.12-2.71h), and declined in haemolymph (7.38-5.25h) following single-dose and multiple-dose oral administration in Pacific white shrimps. In addition, it is worth mentioning that the ratios of SMZ and TMP were unusually larger than the general aim ratio. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Pharmacokinetics of voriconazole after oral administration of single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis).

    Sanchez-Migallon Guzman, David; Flammer, Keven; Papich, Mark G; Grooters, Amy M; Shaw, Shannon; Applegate, Jeff; Tully, Thomas N

    2010-04-01

    To determine the pharmacokinetics and safety of voriconazole administered orally in single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). 15 clinically normal adult Hispaniolan Amazon parrots. Single doses of voriconazole (12 or 24 mg/kg) were administered orally to 15 and 12 birds, respectively; plasma voriconazole concentrations were determined at intervals via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) or water was administered orally to 6 and 4 birds, respectively, every 8 hours for 11 days (beginning day 0); trough plasma voriconazole concentrations were evaluated on 3 days. Birds were monitored daily, and clinicopathologic variables were evaluated before and after the trial. Voriconazole elimination half-life was short (0.70 to 1.25 hours). In the single-dose experiments, higher drug doses yielded proportional increases in the maximum plasma voriconazole concentration (C(max)) and area under the curve (AUC). In the multiple-dose trial, C(max), AUC, and plasma concentrations at 2 and 4 hours were decreased on day 10, compared with day 0 values; however, there was relatively little change in terminal half-life. With the exception of 1 voriconazole-treated parrot that developed polyuria, adverse effects were not evident. In Hispaniolan Amazon parrots, oral administration of voriconazole was associated with proportional kinetics following administration of single doses and a decrease in plasma concentration following administration of multiple doses. Oral administration of 18 mg of voriconazole/kg every 8 hours would require adjustment to maintain therapeutic concentrations during long-term treatment. Safety and efficacy of voriconazole treatment in this species require further investigation.

  4. Comparative pharmacokinetics of oxytetracycline in blunt-snout bream (Megalobrama amblycephala) with single and multiple-dose oral administration.

    Li, Ru-Qin; Ren, Yu-Wei; Li, Jing; Huang, Can; Shao, Jun-Hui; Chen, Xiao-Xuan; Wu, Zhi-Xin

    2015-06-01

    Research into the pharmacokinetics and residue elimination of oxytetracycline (OTC) is important both to determine the optimal dosage regimens and to establish a safe withdrawal time in fish. A depletion study is presented here for OTC in Megalobrama amblycephala with a single-dose (100 mg/kg) and multiple-dose (100 mg/kg for five consecutive days) oral administration. The study was conducted at 25 °C. As a result, a one-compartment model was developed. For the single dose, the absorption half-life was 5.79, 9.40, 6.96, and 8.06 h in the plasma, liver, kidney, and muscle, respectively. However, the absorption half-life was 3.62, 7.33, 4.59, and 6.02 h with multiple-dose oral administration. The elimination half-time in the plasma, liver, kidney, and muscle was 58.63, 126.43, 65.1, and 58.85 h when M. amblycephala was treated with a single dose. However, the elimination half-time changed to 91.75, 214.87, 126.22, and 135.84 h with multiple-dose oral administration.

  5. Pharmacokinetics of voriconazole after oral administration of single and multiple doses in African grey parrots (Psittacus erithacus timneh).

    Flammer, Keven; Nettifee Osborne, Julie A; Webb, Donna J; Foster, Laura E; Dillard, Stacy L; Davis, Jennifer L

    2008-01-01

    To determine the pharmacokinetics and safety of orally administered voriconazole in African grey parrots. 20 clinically normal Timneh African grey parrots (Psittacus erithacus timneh). In single-dose trials, 12 parrots were each administered 6, 12, and 18 mg of voriconazole/kg orally and plasma concentrations of voriconazole were determined via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) was administered orally to 6 birds every 12 hours for 9 days; a control group (2 birds) received tap water. Treatment effects were assessed via observation, clinicopathologic analyses (3 assessments), and measurement of trough plasma voriconazole concentrations (2 assessments). Voriconazole's elimination half-life was short (1.1 to 1.6 hours). Higher doses resulted in disproportional increases in the maximum plasma voriconazole concentration and area under the curve. Trough plasma voriconazole concentrations achieved in the multiple-dose trial were lower than those achieved after administration of single doses. Polyuria (the only adverse treatment effect) developed in treated and control birds but was more severe in the treatment group. In African grey parrots, voriconazole has dose-dependent pharmacokinetics and may induce its own metabolism. Oral administration of 12 to 18 mg of voriconazole/kg twice daily is a rational starting dose for treatment of African grey parrots infected with Aspergillus or other fungal organisms that have a minimal inhibitory concentration for voriconazole treatment. Safety and efficacy of various voriconazole treatment regimens in this species require investigation.

  6. Elimination of cetirizine following administration of multiple doses to exercised thoroughbred horses.

    Knych, H K; Stanley, S D; Arthur, R M; McKemie, D S

    2016-10-01

    Cetirizine is an antihistamine used in performance horses for the treatment of hypersensitivity reactions and as such a withdrawal time is necessary prior to competition. The objective of the current study was to describe the disposition and elimination of cetirizine following oral administration in order to provide additional serum concentration data upon which appropriate regulatory recommendations can be established. Nine exercised thoroughbred horses were administered 0.4 mg/kg of cetirizine orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum cetirizine concentrations were determined and selected pharmacokinetic parameters determined. The serum elimination half-life was 5.83 ± 0.841 h. Average serum cetirizine concentrations were still above the LOQ of the assay (0.05 ng/mL) at 48 h (final sample collected) postadministration of the final dose. © 2016 John Wiley & Sons Ltd.

  7. Clinical Parameters following Multiple Oral Dose Administration of a Standardized Andrographis paniculata Capsule in Healthy Thai Subjects.

    Suriyo, Tawit; Pholphana, Nanthanit; Ungtrakul, Teerapat; Rangkadilok, Nuchanart; Panomvana, Duangchit; Thiantanawat, Apinya; Pongpun, Wanwisa; Satayavivad, Jutamaad

    2017-06-01

    Andrographis paniculata has been widely used in Scandinavian and Asian counties for the treatment of the common cold, fever, and noninfectious diarrhea. The present study was carried out to investigate the physiological effects of short-term multiple dose administration of a standardized A. paniculata capsule used for treatment of the common cold and uncomplicated upper respiratory tract infections, including blood pressure, electrocardiogram, blood chemistry, hematological profiles, urinalysis, and blood coagulation in healthy Thai subjects. Twenty healthy subjects (10 males and 10 females) received 12 capsules per day orally of 4.2 g of a standardized A. paniculata crude powder (4 capsules of 1.4 g of A. paniculata , 3 times per day, 8 h intervals) for 3 consecutive days. The results showed that all of the measured clinical parameters were found to be within normal ranges for a healthy person. However, modulation of some parameters was observed after the third day of treatment, for example, inductions of white blood cells and absolute neutrophil count in the blood, a reduction of plasma alkaline phosphatase, and an induction of urine pH. A rapid and transient reduction in blood pressure was observed at 30 min after capsule administration, resulting in a significant reduction of mean systolic blood pressure. There were no serious adverse events observed in the subjects during the treatment period. In conclusion, this study suggests that multiple oral dosing of A. paniculata at the normal therapeutic dose for the common cold and uncomplicated upper respiratory tract infections modulates various clinical parameters within normal ranges for a healthy person. Georg Thieme Verlag KG Stuttgart · New York.

  8. Disposition of the anti-ulcer medications ranitidine, cimetidine, and omeprazole following administration of multiple doses to exercised Thoroughbred horses.

    Knych, H K; Stanley, S D; Arthur, R M; McKemie, D S

    2017-01-01

    The use of anti-ulcer medications, such as cimetidine, ranitidine, and omeprazole, is common in performance horses. The use of these drugs is regulated in performance horses, and as such a withdrawal time is necessary prior to competition to avoid a medication violation. To the authors' knowledge, there are no reports in the literature describing repeated oral administrations of these drugs in the horse to determine a regulatory threshold and related withdrawal time recommendations. Therefore, the objective of the current study was to describe the disposition and elimination pharmacokinetics of these anti-ulcer medications following oral administration to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 20 mg/kg BID of cimetidine or 8 mg/kg BID of ranitidine, both for seven doses or 2.28 g of omeprazole SID for four doses. Blood samples were collected, serum drug concentrations were determined, and elimination pharmacokinetic parameters were calculated. The serum elimination half-life was 7.05 ± 1.02, 7.43 ± 0.851 and 3.94 ± 1.04 h for cimetidine, ranitidine, and omeprazole, respectively. Serum cimetidine and ranitidine concentrations were above the LOQ and omeprazole and omeprazole sulfide below the LOQ in all horses studied upon termination of sample collection. © 2016 John Wiley & Sons Ltd.

  9. Multiple-dose pharmacokinetic study of proguanil and cycloguanil following 12-hourly administration of 100 mg proguanil hydrochloride.

    Jamaludin, A; Mohamad, M; Navaratnam, V; Yeoh, P Y; Wernsdorfer, W H

    1990-09-01

    A pharmacokinetic study with 12-hourly doses of 100 mg proguanil hydrochloride over 15 days has been conducted in six adult male Malaysian volunteers. Steady state for proguanil was established after the fourth dose on Day 2, for the active metabolite cycloguanil as from Day 3 inclusive. The steady state mean peak concentration of proguanil was 1201.6 +/- 132.4 nmol/l, the mean trough concentration 650.0 +/- 58.1 nmol/l. The corresponding values for cycloguanil were 317.0 +/- 44.4 nmol/l (mean peak) and 230.8 +/- 35.1 nmol/l (mean trough). The profiles and peak/trough ratios of proguanil and cycloguanil with 12-hourly dosing offer better prospects for protection against malaria than those obtained with 24-hourly doses of 200 mg proguanil hydrochloride, the current routine in malaria chemoprophylaxis.

  10. Andrographis paniculata: Dissolution investigation and pharmacokinetic studies of four major active diterpenoids after multiple oral dose administration in healthy Thai volunteers.

    Pholphana, Nanthanit; Panomvana, Duangchit; Rangkadilok, Nuchanart; Suriyo, Tawit; Puranajoti, Porranee; Ungtrakul, Teerapat; Pongpun, Wanwisa; Thaeopattha, Saichit; Songvut, Phanit; Satayavivad, Jutamaad

    2016-12-24

    Andrographis paniculata is included in 'The National List of Essential Herbal Drugs A.D. 1999' of Thailand as an herbal drug for the treatment of common cold symptoms and non-infectious diarrhea. The therapeutic activities of A. paniculata are attributed to four major active diterpenoids: andrographolide (1), 14-deoxy-11, 12-didehydroandrographolide (2), neoandrographolide (3), and 14-deoxyandrographolide (4). However, the pharmacokinetic studies in humans of this plant were performed after a single oral dose administration and reported the parameters related to be of only 1. This study aims to determine the pharmacokinetic parameters of four major active diterpenoids after multiple oral dose administration of A. paniculata capsules in healthy volunteers. The dissolution testing of these four diterpenoids was also performed. The dissolution testing of four major active diterpenoids was conducted in pH 1.2, pH 4.5, and pH 6.8 for 10-100min. The pharmacokinetic study of these active diterpenoids was designed as an open-label, multiple oral dose administration of A. paniculata capsules in 20 healthy Thai volunteers at 1:1 ratio of female and male. Each volunteer was given four A. paniculata capsules each time which contained 1, 2, 3, and 4 in the quantities of 32.64, 5.40, 3.60, and 3.84mg, respectively, three times a day for three consecutive days. On the fourth day, after the first dose of the day was administered, blood samples were collected at the predefined time points. The validated LC-MS/MS method was used to simultaneously determine the concentrations of these diterpenoids in the human plasma samples. The pharmacokinetic parameters of each active diterpenoid were determined. All four major active diterpenoids have been completely dissolved in the simulated pH of gastrointestinal tract within 60min of dissolution. The dissolution profiles were found to be highest in pH 6.8 and lowest in pH 1.2, especially for 3. In the pharmacokinetic study, although 1 was

  11. Fetal absorbed doses by radiopharmaceutical administration

    Rojo, Ana M; Gomez Parada, Ines M.; Di Trano, Jose L.

    2000-01-01

    The radiopharmaceutical administration with diagnostic or therapeutic purpose during pregnancy implies a prenatal radiation dose. The dose assessment and the evaluation of the radiological risks become relevant due to the great radiosensitivity of the fetal tissues in development. This paper is a revision of the available data for estimating fetal doses in the cases of the more frequently used radiopharmaceuticals in nuclear medicine, taking into account recent investigation in placental crossover. The more frequent diagnostic and therapeutic procedures were analyzed according to the radiation doses implied. (author)

  12. Treatment of chemotherapy-induced neutropenia in a rat model by using multiple daily doses of oral administration of G-CSF-containing nanoparticles.

    Su, Fang-Yi; Chuang, Er-Yuan; Lin, Po-Yen; Chou, Yi-Chun; Chen, Chiung-Tong; Mi, Fwu-Long; Wey, Shiaw-Pyng; Yen, Tzu-Chen; Lin, Kun-Ju; Sung, Hsing-Wen

    2014-04-01

    Chemotherapy-induced neutropenia often increases the likelihood of life-threatening infections. In this study, a nanoparticle (NP) system composed of chitosan and poly(γ-glutamic acid) conjugated with diethylene triamine pentaacetic acid (γPGA-DTPA) was prepared for oral delivery of granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor. The therapeutic potential of this NP system for daily administration of G-CSF to treat neutropenia associated with chemotherapy was evaluated in a rat model. In vitro results indicate that the procedures of NP loading and release preserved the structural integrity and bioactivity of the G-CSF molecules adequately. Those results further demonstrated the enzymatic inhibition activity of γPGA-DTPA towards G-CSF against intestinal proteases. Additionally, the in vivo biodistribution study clearly identified accumulations of G-CSF in the heart, liver, bone marrow, and urinary bladder, an indication of systemic absorption of G-CSF; its relative bioavailability was approximately 13.6%. Moreover, significant glucose uptake was observed in bone marrow during G-CSF treatment, suggesting increased bone marrow metabolism and neutrophil production. Consequently, neutrophil count in the blood increased in a sustained manner; this fact may help a patient's immune system recover from the side effects of chemotherapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Multiple anatomy optimization of accumulated dose

    Watkins, W. Tyler; Siebers, Jeffrey V.; Moore, Joseph A.; Gordon, James; Hugo, Geoffrey D.

    2014-01-01

    Purpose: To investigate the potential advantages of multiple anatomy optimization (MAO) for lung cancer radiation therapy compared to the internal target volume (ITV) approach. Methods: MAO aims to optimize a single fluence to be delivered under free-breathing conditions such that the accumulated dose meets the plan objectives, where accumulated dose is defined as the sum of deformably mapped doses computed on each phase of a single four dimensional computed tomography (4DCT) dataset. Phantom and patient simulation studies were carried out to investigate potential advantages of MAO compared to ITV planning. Through simulated delivery of the ITV- and MAO-plans, target dose variations were also investigated. Results: By optimizing the accumulated dose, MAO shows the potential to ensure dose to the moving target meets plan objectives while simultaneously reducing dose to organs at risk (OARs) compared with ITV planning. While consistently superior to the ITV approach, MAO resulted in equivalent OAR dosimetry at planning objective dose levels to within 2% volume in 14/30 plans and to within 3% volume in 19/30 plans for each lung V20, esophagus V25, and heart V30. Despite large variations in per-fraction respiratory phase weights in simulated deliveries at high dose rates (e.g., treating 4/10 phases during single fraction beams) the cumulative clinical target volume (CTV) dose after 30 fractions and per-fraction dose were constant independent of planning technique. In one case considered, however, per-phase CTV dose varied from 74% to 117% of prescription implying the level of ITV-dose heterogeneity may not be appropriate with conventional, free-breathing delivery. Conclusions: MAO incorporates 4DCT information in an optimized dose distribution and can achieve a superior plan in terms of accumulated dose to the moving target and OAR sparing compared to ITV-plans. An appropriate level of dose heterogeneity in MAO plans must be further investigated

  14. Multiple anatomy optimization of accumulated dose

    Watkins, W. Tyler, E-mail: watkinswt@virginia.edu; Siebers, Jeffrey V. [Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia 22908 and Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298 (United States); Moore, Joseph A. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland 21231 and Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298 (United States); Gordon, James [Henry Ford Health System, Detroit, Michigan 48202 and Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298 (United States); Hugo, Geoffrey D. [Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298 (United States)

    2014-11-01

    Purpose: To investigate the potential advantages of multiple anatomy optimization (MAO) for lung cancer radiation therapy compared to the internal target volume (ITV) approach. Methods: MAO aims to optimize a single fluence to be delivered under free-breathing conditions such that the accumulated dose meets the plan objectives, where accumulated dose is defined as the sum of deformably mapped doses computed on each phase of a single four dimensional computed tomography (4DCT) dataset. Phantom and patient simulation studies were carried out to investigate potential advantages of MAO compared to ITV planning. Through simulated delivery of the ITV- and MAO-plans, target dose variations were also investigated. Results: By optimizing the accumulated dose, MAO shows the potential to ensure dose to the moving target meets plan objectives while simultaneously reducing dose to organs at risk (OARs) compared with ITV planning. While consistently superior to the ITV approach, MAO resulted in equivalent OAR dosimetry at planning objective dose levels to within 2% volume in 14/30 plans and to within 3% volume in 19/30 plans for each lung V20, esophagus V25, and heart V30. Despite large variations in per-fraction respiratory phase weights in simulated deliveries at high dose rates (e.g., treating 4/10 phases during single fraction beams) the cumulative clinical target volume (CTV) dose after 30 fractions and per-fraction dose were constant independent of planning technique. In one case considered, however, per-phase CTV dose varied from 74% to 117% of prescription implying the level of ITV-dose heterogeneity may not be appropriate with conventional, free-breathing delivery. Conclusions: MAO incorporates 4DCT information in an optimized dose distribution and can achieve a superior plan in terms of accumulated dose to the moving target and OAR sparing compared to ITV-plans. An appropriate level of dose heterogeneity in MAO plans must be further investigated.

  15. Multiple anatomy optimization of accumulated dose.

    Watkins, W Tyler; Moore, Joseph A; Gordon, James; Hugo, Geoffrey D; Siebers, Jeffrey V

    2014-11-01

    To investigate the potential advantages of multiple anatomy optimization (MAO) for lung cancer radiation therapy compared to the internal target volume (ITV) approach. MAO aims to optimize a single fluence to be delivered under free-breathing conditions such that the accumulated dose meets the plan objectives, where accumulated dose is defined as the sum of deformably mapped doses computed on each phase of a single four dimensional computed tomography (4DCT) dataset. Phantom and patient simulation studies were carried out to investigate potential advantages of MAO compared to ITV planning. Through simulated delivery of the ITV- and MAO-plans, target dose variations were also investigated. By optimizing the accumulated dose, MAO shows the potential to ensure dose to the moving target meets plan objectives while simultaneously reducing dose to organs at risk (OARs) compared with ITV planning. While consistently superior to the ITV approach, MAO resulted in equivalent OAR dosimetry at planning objective dose levels to within 2% volume in 14/30 plans and to within 3% volume in 19/30 plans for each lung V20, esophagus V25, and heart V30. Despite large variations in per-fraction respiratory phase weights in simulated deliveries at high dose rates (e.g., treating 4/10 phases during single fraction beams) the cumulative clinical target volume (CTV) dose after 30 fractions and per-fraction dose were constant independent of planning technique. In one case considered, however, per-phase CTV dose varied from 74% to 117% of prescription implying the level of ITV-dose heterogeneity may not be appropriate with conventional, free-breathing delivery. MAO incorporates 4DCT information in an optimized dose distribution and can achieve a superior plan in terms of accumulated dose to the moving target and OAR sparing compared to ITV-plans. An appropriate level of dose heterogeneity in MAO plans must be further investigated.

  16. Corneal pharmacokinetics of the 2% diacerein eye drops between multiple administration and single administration

    Ke Yang; Shi-Wei Chen; Xin-Yan Dou; Zhi-Rui Zhang; Xin Jin; Hong-Min Zhang

    2018-01-01

    AIM: To compare the pharmacokinetic differences of the 2% diacerein eye drops between conjunctival sac multiple administration and single administration in the cornea, and to provide the experimental basis for clinicians to use the conjunctival sac multiple administration.METHODS: Male Kunming mice were randomly divided into the multiple administration group and the single administration group. The multiple administration group were given diacerein eye drop every 2min(3 times in total). The c...

  17. 1997 N-Basin Administrative Control Level Dose Extension

    Nellesen, A.L.

    1997-04-01

    This document provides justification for extending the Administrative Control Level of 500 mrem per year to 1,000 mrem per year Total Effective Dose Equivalent for workers involved with N-Reactor Basin Deactivation in accordance with established procedures

  18. Dose evaluation from multiple detector outputs using convex optimisation

    Hashimoto, M.; Iimoto, T.; Kosako, T.

    2011-01-01

    A dose evaluation using multiple radiation detectors can be improved by the convex optimisation method. It enables flexible dose evaluation corresponding to the actual radiation energy spectrum. An application to the neutron ambient dose equivalent evaluation is investigated using a mixed-gas proportional counter. The convex derives the certain neutron ambient dose with certain width corresponding to the true neutron energy spectrum. The range of the evaluated dose is comparable to the error of conventional neutron dose measurement equipments. An application to the neutron individual dose equivalent measurement is also investigated. Convexes of particular dosemeter combinations evaluate the individual dose equivalent better than the dose evaluation of a single dosemeter. The combinations of dosemeters with high orthogonality of their response characteristics tend to provide a good suitability for dose evaluation. (authors)

  19. Corneal pharmacokinetics of the 2% diacerein eye drops between multiple administration and single administration

    Ke Yang

    2018-04-01

    Full Text Available AIM: To compare the pharmacokinetic differences of the 2% diacerein eye drops between conjunctival sac multiple administration and single administration in the cornea, and to provide the experimental basis for clinicians to use the conjunctival sac multiple administration.METHODS: Male Kunming mice were randomly divided into the multiple administration group and the single administration group. The multiple administration group were given diacerein eye drop every 2min(3 times in total. The concentrations of the metabolites of diacerein in the cornea were measured by high performance liquid chromatography after given eye drop 5, 15, 30, 60, 120, and 180min. The pharmacokinetic parameters were calculated by pharmacokinetic software(DAS2.1.1. RESULTS: The metabolites of diacerein, rhein, was detected in the cornea at each time point. The concentration of the metabolite of diacerein in the cornea was 318.678±40.88, 210.02±25.66, 188.83±31.74, 112.24±11.70, 90.28±22.01 and 57.67±13.71μg/g after given eye drop 5, 15, 30, 60, 120, and 180min in the multiple administration group. The concentration in the single administration group was 145.17±19.29, 97.95±10.49, 71.18±18.70, 39.11±2.44, 18.10±2.34 and 9.08±2.04μg/g respectively. The concentration of rhein in the cornea was the highest at 5min after the administration in the two groups. The concentration of the multiple administration group was higher than that in the single administration group at 5, 15, 30, 60, 120, and 180min(PCONCLUSION: Compared with the single administration, the conjunctival sac multiple administration has the advantages of high drug concentration and long duration. Therefor the conjunctival sac multiple administration is a more effective method to treat acute infectious corneal diseases.

  20. Multiple cost criteria for occupational dose reduction

    James, J.Z.

    1983-01-01

    This paper describes a simple, feasible procedure for deciding if a proposed dose reduction measure is justified under ALARA, based on engineering economic principles of project feasibility analysis. Particular attention is given to the fixing of cost criteria: the importance of melding disparate objectives into a single parameter, and the distinction between a cost criterion and a cost consideration. (author)

  1. Biokinetic study of 131I following ablation dose administration

    Nascimento, A.C.H.; Lipsztein, J.L.; Lucena, E.A.; Dantas, B.M.; Rebelo, A.M.O.; Mello, R.C.

    2002-01-01

    Aim: The aim of this investigation is to study biokinetics from internally 131 I deposited for thyroid cancer patients during radioiodine therapy (2 to 3 days), after ablation dose administration (3.7 GBq). These data will help in the elaboration of a metabolic model, which will permit absorbed dose assessment for this specific case, since the biokinetic models for iodine available in scientific literature can not be applied to thyroidectomized patient's studies. Material and Methods: Four females patients, between 22 and 50 years old, without metastases, between 1.9 to 6% of remnant thyroid tissue uptake, agreed to contribute to this study. For the in vivo bioassay, periodical measurements were performed along internment time (2 to 3 days), just after Na 131 I dose administration (3.7 GBq). For this, we used the counting system for Nuclear Medicine model 13S002, IEN/CNEN- Brazil, which was adapted with lead filters, in order to allow the work with high rate counting. The measurements were performed in two geometries: thyroid region and thigh. Results: For each patient, we have done approximately 26 measurements for both geometries, starting at the first hour following dose administration until the release from hospital of patient. The results of counting rate (cps) were plotted against time (h). The measurements suggest a relation between remnant thyroid tissue uptake values and the time where counting rates start decreasing. In addition, it was observed a correlation between remnant thyroid tissue radioactive burdens and the circulating iodine through time. Conclusion: It is necessary to follow-up a greater number of patients aiming to confirm the observed correlations and with a greater number of measurements during the first 24 hours, in other to delimit the time range of increasing and decreasing counting rate

  2. Cumulative radiation dose of multiple trauma patients during their hospitalization

    Wang Zhikang; Sun Jianzhong; Zhao Zudan

    2012-01-01

    Objective: To study the cumulative radiation dose of multiple trauma patients during their hospitalization and to analyze the dose influence factors. Methods: The DLP for CT and DR were retrospectively collected from the patients during June, 2009 and April, 2011 at a university affiliated hospital. The cumulative radiation doses were calculated by summing typical effective doses of the anatomic regions scanned. Results: The cumulative radiation doses of 113 patients were collected. The maximum,minimum and the mean values of cumulative effective doses were 153.3, 16.48 mSv and (52.3 ± 26.6) mSv. Conclusions: Multiple trauma patients have high cumulative radiation exposure. Therefore, the management of cumulative radiation doses should be enhanced. To establish the individualized radiation exposure archives will be helpful for the clinicians and technicians to make decision whether to image again and how to select the imaging parameters. (authors)

  3. Practical considerations in medical cannabis administration and dosing.

    MacCallum, Caroline A; Russo, Ethan B

    2018-03-01

    Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities. Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  4. Intradermal Administration of Fractional Doses of Inactivated Poliovirus Vaccine: A Dose-Sparing Option for Polio Immunization.

    Okayasu, Hiromasa; Sein, Carolyn; Chang Blanc, Diana; Gonzalez, Alejandro Ramirez; Zehrung, Darin; Jarrahian, Courtney; Macklin, Grace; Sutter, Roland W

    2017-07-01

    A fractional dose of inactivated poliovirus vaccine (fIPV) administered by the intradermal route delivers one fifth of the full vaccine dose administered by the intramuscular route and offers a potential dose-sparing strategy to stretch the limited global IPV supply while further improving population immunity. Multiple studies have assessed immunogenicity of intradermal fIPV compared with the full intramuscular dose and demonstrated encouraging results. Novel intradermal devices, including intradermal adapters and disposable-syringe jet injectors, have also been developed and evaluated as alternatives to traditional Bacillus Calmette-Guérin needles and syringes for the administration of fIPV. Initial experience in India, Pakistan, and Sri Lanka suggests that it is operationally feasible to implement fIPV vaccination on a large scale. Given the available scientific data and operational feasibility shown in early-adopter countries, countries are encouraged to consider introducing a fIPV strategy into their routine immunization and supplementary immunization activities. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

  5. Topical administration of regorafenib eye drops: phase I dose-escalation study in healthy volunteers.

    Zimmermann, Torsten; Höchel, Joachim; Becka, Michael; Boettger, Michael K; Rohde, Beate; Schug, Barbara; Kunert, Kathleen S; Donath, Frank

    2018-05-01

    Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure. This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study. Subjects received regorafenib eye drops (30 mg ml -1 , 25 μl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study. Thirty-six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600-700-fold lower than after multiple oral administration of 160 mg day -1 , the dose approved in cancer indications. These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml -1 tid for use in clinical studies. © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

  6. Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits

    Daniel T. C. Cox

    2017-02-01

    Full Text Available Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a nature dose type, that is the frequency and duration (time spent in private green space and intensity (quantity of neighbourhood vegetation cover of nature exposure and (b health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare.

  7. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma

    P.G. Richardson (Paul Gerard); P. Sonneveld (Pieter); M.W. Schuster (Michael); D. Irwin (David); E.A. Stadtmauer (Edward); T. Facon (Thierry); J-L. Harousseau (Jean-Luc); D. Ben-Yehuda (Dina); S. Lonial (Sagar); H. Goldschmidt (Hartmut); D. Reece (Donna); J.F. San Miguel (Jesús Fernando); J. Bladé (Joan); M. Boccadoro (Mario); J. Cavenagh (Jamie); W. Dalton (William); A.L. Boral (Anthony); D.-L. Esseltine (Dixie-Lee); J.B. Porter (Jane); D. Schenkein (David); K.C. Anderson (Kenneth)

    2005-01-01

    textabstractBACKGROUND: This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies. METHODS: We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3

  8. Comparison of the pharmacokinetics of a new 30 mg modified-release tablet formulation of metoclopramide for once-a-day administration versus 10 mg immediate-release tablets: a single and multiple-dose, randomized, open-label, parallel study in healthy male subjects.

    Bernardo-Escudero, Roberto; Alonso-Campero, Rosalba; Francisco-Doce, María Teresa de Jesús; Cortés-Fuentes, Myriam; Villa-Vargas, Miriam; Angeles-Uribe, Juan

    2012-12-01

    The study aimed to assess the pharmacokinetics of a new, modified-release metoclopramide tablet, and compare it to an immediate-release tablet. A single and multiple-dose, randomized, open-label, parallel, pharmacokinetic study was conducted. Investigational products were administered to 26 healthy Hispanic Mexican male volunteers for two consecutive days: either one 30 mg modified-release tablet every 24 h, or one 10 mg immediate-release tablet every 8 h. Blood samples were collected after the first and last doses of metoclopramide. Plasma metoclopramide concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed through vital signs measurements, clinical evaluations, and spontaneous reports from study subjects. All 26 subjects were included in the analyses [mean (SD) age: 27 (8) years, range 18-50; BMI: 23.65 (2.22) kg/m², range 18.01-27.47)]. Peak plasmatic concentrations were not statistically different with both formulations, but occurred significantly later (p 0.05)]. One adverse event was reported in the test group (diarrhea), and one in the reference group (headache). This study suggests that the 30 mg modified-release metoclopramide tablets show features compatible with slow-release formulations when compared to immediate-release tablets, and is suitable for once-a-day administration.

  9. High-dose contrast-enhanced MRI in multiple sclerosis

    Koudriavtseva, T. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Pozzilli, C. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Di Biasi, C. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy); Iannilli, M. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy); Trasimeni, G. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy); Gasperini, C. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Argentino, C. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Gualdi, G.F. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy)

    1996-05-01

    Contrast-enhanced MRI is effective for assessing disease activity in multiple sclerosis (MS) and may provide an outcome measure for testing the efficacy of treatment in clinical trials. To compare the sensitivity of high-dose gadolinium-HP-DO3A with that of a standard dose of gadolinium-DTPA, we studied 16 patients with relapsing-remitting MS in the acute phase of the disease. Each underwent two MRI examinations within at most 48 h. The initial MRI study was with a standard dose of gadolinium-DTPA (0.1 mmol/kg), and the second one an experimental dose of gadolinium-HP-DO3A (0.3 mmol/kg). No adverse effects were attributed to the contrast media. The high-dose study revealed more enhancing lesions than the standard-dose study (56 vs 38). This difference was found to be more relevant for infratentorial and small lesions. Furthermore, with the higher dose, there was a marked qualitative improvement in the visibility and delineation of the lesions. (orig.). With 4 figs., 2 tabs.

  10. High-dose contrast-enhanced MRI in multiple sclerosis

    Koudriavtseva, T.; Pozzilli, C.; Di Biasi, C.; Iannilli, M.; Trasimeni, G.; Gasperini, C.; Argentino, C.; Gualdi, G.F.

    1996-01-01

    Contrast-enhanced MRI is effective for assessing disease activity in multiple sclerosis (MS) and may provide an outcome measure for testing the efficacy of treatment in clinical trials. To compare the sensitivity of high-dose gadolinium-HP-DO3A with that of a standard dose of gadolinium-DTPA, we studied 16 patients with relapsing-remitting MS in the acute phase of the disease. Each underwent two MRI examinations within at most 48 h. The initial MRI study was with a standard dose of gadolinium-DTPA (0.1 mmol/kg), and the second one an experimental dose of gadolinium-HP-DO3A (0.3 mmol/kg). No adverse effects were attributed to the contrast media. The high-dose study revealed more enhancing lesions than the standard-dose study (56 vs 38). This difference was found to be more relevant for infratentorial and small lesions. Furthermore, with the higher dose, there was a marked qualitative improvement in the visibility and delineation of the lesions. (orig.). With 4 figs., 2 tabs

  11. Evaluation of the Pharmacokinetics of Single- and Multiple-dose Buprenorphine Buccal Film in Healthy Volunteers.

    Bai, Stephen A; Xiang, Qinfang; Finn, Andrew

    2016-02-01

    Buprenorphine, a partial μ-receptor agonist, is approved for the management of moderate to severe pain, but it has low oral bioavailability. Two open-label studies were performed to determine the pharmacokinetic profile of buprenorphine from buccal film formulations of buprenorphine. Both studies enrolled healthy volunteers, aged 18 to 55 years, who received concurrent oral naltrexone to reduce adverse events (AEs); subjects with a history or evidence of substance abuse or current use of any product affecting cytochrome P450 3A4 activity were excluded. The first study (n = 25) was a 5-period crossover trial with 4 single doses (75 and 300 and 300 and 1200 μg) of 2 formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-μg intravenous dose of buprenorphine with a 7-day washout between periods. In the second study, each subject (n = 10) received 6 doses of 4 BBUP strengths (60, 120, 180, and 240 μg BID) in a dose-escalation design. Plasma concentrations of buprenorphine and norbuprenorphine were assayed, and pharmacokinetics were summarized with descriptive statistics and analyzed by using a linear mixed effects model (single-dose study). AEs were recorded. In the single-dose study, the 2 formulations exhibited comparable bioavailability of 46% to 51% that was independent of dose, with a single buprenorphine peak concentration from each BBUP dose occurring at 2.5 to 3 hours. The mean buprenorphine Cmax across the doses ranged from 0.17 ng/mL for the 75-µg dose to 1.43 ng/mL for the 1200-µg dose. AUC0-∞, AUC0-last, and Cmax were proportional to the dose of BBUP administered. Cmax of norbuprenorphine after BBUP administration was approximately one tenth that of buprenorphine Cmax. In the multiple-dose study, steady state was reached within 3 days of BID dosing. There was a linear increase in exposure across the dose range from 60 to 240 μg BID. Treatment-emergent AEs in both studies were consistent with those reported with opiate administration to

  12. Micro-dose hCG as luteal phase support without exogenous progesterone administration

    Andersen, C Yding; Fischer, R; Giorgione, V

    2016-01-01

    RHa trigger to induce ovulation showed that exogenous progesterone administration without hCG supplementation was insufficient to obtain satisfactory pregnancy rates. This has prompted development of alternative strategies for LPS. Augmenting the local endogenous production of progesterone by the multiple......For the last two decades, exogenous progesterone administration has been used as luteal phase support (LPS) in connection with controlled ovarian stimulation combined with use of the human chorionic gonadotropin (hCG) trigger for the final maturation of follicles. The introduction of the Gn...... corpora lutea has been one focus with emphasis on one hand to avoid development of ovarian hyper-stimulation syndrome and, on the other hand, to provide adequate levels of progesterone to sustain implantation. The present study evaluates the use of micro-dose hCG for LPS support and examines the potential...

  13. Administrative support of novice science teachers: A multiple case study

    Iacuone, Leann

    Novice science teachers leave the confines of colleges and universities to embark on a new adventure in education where they aim to influence young minds, make a difference in the world, and share their love for their content. They have learned their pedagogical skills with the support and assistance of fellow classmates, a supporting professor, and a cooperating teacher. These teachers enter their new place of employment and are met with many unexpected challenges, such as a lack of resources, no one to ask questions of, and a busy staff with already established relationships, causing them to feel an overall lack of support and resulting in many new teachers rethinking their career choice and leaving the field of education within 5 years of entering. This multiple-case study investigated the administrative support 4 novice science teachers received during an academic year and the novice teachers' perceptions of the support they received to answer the following research question: How do novice science teachers who have consistent interactions with administrators develop during their first year? To answer this question, semistructured interviews, reflection journals, observations, resumes, long-range plans, and student discipline referrals were collected. The findings from this study show novice science teachers who had incidents occur in the classroom requiring administrative assistance and guidance felt more confident in enforcing their classroom management policies and procedures as the year progressed to change student behavior. The novice science teachers perceived administrators who provided resources including technology, office supplies, science supplies, and the guidance of a mentor as supportive. Novice science teachers who engaged in dialogue after administrative observations, were provided the opportunity to attend professional development outside the district, and had a mentor who taught the same discipline made more changes to their instructional

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

    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

  15. Single-dose and multiple-dose pharmacokinetics and dose proportionality of intravenous and intramuscular HPβCD-diclofenac (Dyloject) compared with other diclofenac formulations.

    Mermelstein, Fred; Hamilton, Douglas A; Wright, Curtis; Lacouture, Peter G; Ramaiya, Atulkumar; Carr, Daniel B

    2013-10-01

    To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. Clinical research center. Healthy adult volunteers. Study 1: Subjects received HPβCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPβCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. Study 1: IV HPβCD-diclofenac had a higher peak plasma concentration (Cmax ) and earlier time to reach maximum plasma concentration (Tmax ), but equivalent plasma exposure (area under the curve from time zero to t [AUC0-t ]) to IV Voltarol. The geometric mean ratio of HPβCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPβCD-diclofenac (IV) to HPβCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IV) for AUC0-t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPβCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng·hour/ml) and 37.5 mg (1843 ng·hour/ml) IV HPβCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml). Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPβCD-diclofenac compared with Voltarol and after IM administration of HPβCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPβCD-diclofenac was equivalent to IV administration of HP

  16. Dosing of Appropriate Antibiotics and Time to Administration of First Doses in the Pediatric Emergency Department.

    Bailey, Abby M; Stephan, Maria; Weant, Kyle A; Justice, Stephanie Baker

    2015-01-01

    Emergency department (ED) providers are faced with the challenge of diagnosing and treating patients in a timely fashion given many obstacles including limited patient information, complex disease states, and high patient turnover. Time delays in administration or selection of appropriate drug therapies have been associated with negative outcomes in severe infections. This study was conducted to assess the impact of an emergency medicine pharmacist (EPh) on the selection of appropriate antibiotics and the timeliness of administration in pediatric patients in the ED. Patients younger than 18 years were evaluated who were admitted through the ED and received 1 dose of intravenous antibiotic for the following conditions: community-acquired pneumonia, complicated skin and soft tissue infection (SSTI), meningitis, and sepsis. To evaluate the impact of the presence of an EPh, patients with orders placed during the EPh's hours of 1 pm and 11 pm were compared to those with an order placed between 11 pm and 1 pm. A total of 142 patients were included in the study. Patients seen during EPh hours received an appropriate first antibiotic 93.4% of the time (p = 0.157) and second antibiotic 96.8% of the time (p = 0.023). Time from order to verification was significantly shorter for the first 2 antimicrobials in the EPh group (10.5 minutes [p = 0.003] and 11.4 minutes [p = 0.047], respectively). The days from discharge to return to readmission to the ED were also significantly different (17.5 days vs. 62.4 days, p = 0.008). The available data suggest that patients are more likely to receive appropriate doses of antimicrobials, and in a more timely fashion, whenever the EPh is present. Areas for future investigation include whether the presence of EPhs at the bedside has the potential to impact areas of patient care, including readmission rates, drug costs, and medication errors.

  17. Time of administration important? Morning versus evening dosing of valsartan.

    Zappe, Dion H; Crikelair, Nora; Kandra, Albert; Palatini, Paolo

    2015-02-01

    Studies suggest that bedtime dosing of an angiotensin-converting enzyme (ACE)-inhibitor or angiotensin receptor blocker shows a more sustained and consistent 24-h antihypertensive profile, including greater night-time blood pressure (BP) reduction. We compared the antihypertensive effects of morning (a.m.) and evening (p.m.) dosing of valsartan on 24-h BP. This 26-week, multicentre, randomized, double-blind study evaluated the efficacy and safety of valsartan 320 mg, dosed a.m. or p.m., versus lisinopril 40 mg (a.m.), a long-acting ACE-inhibitor, in patients with grade 1-2 hypertension and at least one additional cardiovascular risk factor. Patients (n = 1093; BP = 156 ± 11/91 ± 8 mmHg; 62 years, 56% male, 99% white) received (1 : 1 : 1) valsartan 160 mg a.m. or p.m. or lisinopril 20 mg a.m. for 4 weeks, then force-titrated to double the initial dose for 8 weeks. At Week 12, hydrochlorothiazide (HCTZ) 12.5 mg was added for 14 weeks if office BP was more than 140/90 mmHg and/or ambulatory BP more than 130/80 mmHg. Mean 24-h ambulatory SBP change from baseline to Weeks 12 and 26 was comparable between valsartan a.m. (-10.6 and -13.3 mmHg) and p.m. (-9.8 and -12.3 mmHg) and lisinopril (-10.7 and -13.7 mmHg). There was no benefit of valsartan p.m. versus a.m. on night-time BP, early morning BP and morning BP surge. Evening dosing also did not improve BP lowering in patients requiring add-on HCTZ or in nondippers at baseline. All treatments were well tolerated. Once-daily dosing of valsartan 320 mg results in equally effective 24-h BP efficacy, regardless of dosing time. ClinicalTrials.gov Identifier: NCT00241124.

  18. Escalating dose, multiple binge methamphetamine regimen does not impair recognition memory in rats.

    Clark, Robert E; Kuczenski, Ronald; Segal, David S

    2007-07-01

    Rats exposed to methamphetamine (METH) in an acute high dose "binge" pattern have been reported to exhibit a persistent deficit in a novel object recognition (NOR) task, which may suggest a potential risk for human METH abusers. However, most high dose METH abusers initially use lower doses before progressively increasing the dose, only eventually engaging in multiple daily administrations. To simulate this pattern of METH exposure, we administered progressively increasing doses of METH to rats over a 14 day interval, then treated them with daily METH binges for 11 days. This treatment resulted in a persistent deficit in striatal dopamine (DA) levels of approximately 20%. We then tested them in a NOR task under a variety of conditions. We could not detect a deficit in their performance in the NOR task under any of the testing conditions. These results suggest that mechanisms other than or additional to the decrement in striatal DA associated with an acute METH binge are responsible for the deficit in the NOR task, and that neuroadaptations consequential to prolonged escalating dose METH pretreatment mitigate against these mechanisms.

  19. Gemfibrozil is a strong inactivator of CYP2C8 in very small multiple doses.

    Honkalammi, J; Niemi, M; Neuvonen, P J; Backman, J T

    2012-05-01

    Therapeutic doses of gemfibrozil cause mechanism-based inactivation of CYP2C8 via formation of gemfibrozil 1-O-β-glucuronide. We investigated the extent of CYP2C8 inactivation caused by three different doses of gemfibrozil twice dailyfor 5 days, using repaglinide as a probe drug, in 10 healthy volunteers. At the end of this 5-day regimen, there were dose-dependent increases in the area under the plasma concentration–time curve from 0 to infinity (AUC0–∞) of repaglinide by3.4-, 5.5-, and 7.0-fold corresponding to 30, 100, and 600 mg of gemfibrozil, respectively, as compared with the control phase (P gemfibrozil 1-O-β-glucuronide, a gemfibrozil dose of 30 mg twice daily was estimated to inhibit CYP2C8 by >70% and 100 mg twice daily was estimated to inhibit it by >90%. Hence, gemfibrozil is a strong inactivator of CYP2C8 even in very small, subtherapeutic, multiple doses. Administration of small gemfibrozil doses may be useful in optimizing the pharmacokinetics of CYP2C8 substrate drugs and in reducing the formation of their potentially toxic metabolites via CYP2C8.

  20. Fluoxetine Dose and Administration Method Differentially Affect Hippocampal Plasticity in Adult Female Rats

    Pawluski, Jodi L.; van Donkelaar, Eva; Abrams, Zipporah; Steinbusch, Harry W. M.; Charlier, Thierry D.

    2014-01-01

    Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1) cookie and (2) osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL) at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat. PMID:24757568

  1. Fluoxetine Dose and Administration Method Differentially Affect Hippocampal Plasticity in Adult Female Rats

    Jodi L. Pawluski

    2014-01-01

    Full Text Available Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1 cookie and (2 osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat.

  2. High-dose erythropoietin in patients with progressive multiple sclerosis

    Schreiber, Karen; Magyari, Melinda; Sellebjerg, Finn

    2017-01-01

    BACKGROUND: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). OBJECTIVE: To evaluate a treatment effect of EPO on progressive MS. METHODS: This was a single-center, randomized......, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6......: This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS....

  3. Transcriptional Response in Mouse Thyroid Tissue after 211At Administration: Effects of Absorbed Dose, Initial Dose-Rate and Time after Administration.

    Nils Rudqvist

    Full Text Available 211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. However, a limitation has been the preferential accumulation of released 211At in the thyroid gland, which is a critical organ for such therapy. The aim of this study was to determine the effect of absorbed dose, dose-rate, and time after 211At exposure on genome-wide transcriptional expression in mouse thyroid gland.BALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq were killed after 1, 6, or 168 h with mean thyroid absorbed doses of 0.023, 0.32, and 1.8 Gy, respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively; mean thyroid absorbed dose was 1.4 Gy. Total RNA was extracted from pooled thyroids and the Illumina RNA microarray platform was used to determine mRNA levels. Differentially expressed transcripts and enriched GO terms were determined with adjusted p-value 1.5, and p-value <0.05, respectively.In total, 1232 differentially expressed transcripts were detected after 211At administration, demonstrating a profound effect on gene regulation. The number of regulated transcripts increased with higher initial dose-rate/absorbed dose at 1 or 6 h. However, the number of regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. Furthermore, similar regulation profiles were seen for groups administered 1.7 kBq. Interestingly, few previously proposed radiation responsive genes were detected in the present study. Regulation of immunological processes were prevalent at 1, 6, and 168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy.

  4. Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

    Cui Y

    2013-12-01

    Full Text Available Yimin Cui,1 Yan Song,2 Jessie Wang,2 Zhigang Yu,2 Alan Schuster,2 Yu Chen Barrett,2 Charles Frost2 1Peking University First Hospital, Beijing, People's Republic of China; 2Bristol-Myers Squibb, Princeton, NJ, USA Background: The pharmacokinetics (PK, pharmacodynamics (PD, and safety of apixaban were assessed in healthy Chinese subjects in this randomized, placebo-controlled, double-blind, single-sequence, single- and multiple-dose study. Subjects and methods: Eighteen subjects 18–45 years of age were randomly assigned (2:1 ratio to receive apixaban or matched placebo. Subjects received a single 10 mg dose of apixaban or placebo on day 1, followed by 10 mg apixaban or placebo twice daily for 6 days (days 4–9. The PK and PD of apixaban were assessed by collecting plasma samples for 72 hours following the dose on day 1 and the morning dose on day 9, and measuring apixaban concentration and anti-Xa activity. Safety was assessed via physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory evaluations. Results: PK analysis showed similar characteristics of apixaban after single and multiple doses, including a median time to maximum concentration of ~3 hours, mean elimination half-life of ~11 hours, and renal clearance of ~1.2 L/hour. The accumulation index was 1.7, consistent with twice-daily dosing and the observed elimination half-life. Single-dose data predict multiple-dose PK, therefore apixaban PK are time-independent. The relationship between anti-Xa activity and plasma apixaban concentrations appears to be linear. Apixaban was safe and well tolerated, with no bleeding-related adverse events reported. Conclusion: Apixaban was safe and well tolerated in healthy Chinese subjects. Apixaban PK and PD were predictable and consistent with findings from previous studies in Asian and non-Asian subjects. The administration of apixaban does not require any dose modification based on race. Keywords: apixaban, oral

  5. Lyssavirus infection: 'low dose, multiple exposure' in the mouse model.

    Banyard, Ashley C; Healy, Derek M; Brookes, Sharon M; Voller, Katja; Hicks, Daniel J; Núñez, Alejandro; Fooks, Anthony R

    2014-03-06

    The European bat lyssaviruses (EBLV-1 and EBLV-2) are zoonotic pathogens present within bat populations across Europe. The maintenance and transmission of lyssaviruses within bat colonies is poorly understood. Cases of repeated isolation of lyssaviruses from bat roosts have raised questions regarding the maintenance and intraspecies transmissibility of these viruses within colonies. Furthermore, the significance of seropositive bats in colonies remains unclear. Due to the protected nature of European bat species, and hence restrictions to working with the natural host for lyssaviruses, this study analysed the outcome following repeat inoculation of low doses of lyssaviruses in a murine model. A standardized dose of virus, EBLV-1, EBLV-2 or a 'street strain' of rabies (RABV), was administered via a peripheral route to attempt to mimic what is hypothesized as natural infection. Each mouse (n=10/virus/group/dilution) received four inoculations, two doses in each footpad over a period of four months, alternating footpad with each inoculation. Mice were tail bled between inoculations to evaluate antibody responses to infection. Mice succumbed to infection after each inoculation with 26.6% of mice developing clinical disease following the initial exposure across all dilutions (RABV, 32.5% (n=13/40); EBLV-1, 35% (n=13/40); EBLV-2, 12.5% (n=5/40)). Interestingly, the lowest dose caused clinical disease in some mice upon first exposure ((RABV, 20% (n=2/10) after first inoculation; RABV, 12.5% (n=1/8) after second inoculation; EBLV-2, 10% (n=1/10) after primary inoculation). Furthermore, five mice developed clinical disease following the second exposure to live virus (RABV, n=1; EBLV-1, n=1; EBLV-2, n=3) although histopathological examination indicated that the primary inoculation was the most probably cause of death due to levels of inflammation and virus antigen distribution observed. All the remaining mice (RABV, n=26; EBLV-1, n=26; EBLV-2, n=29) survived the tertiary and

  6. Pharmacokinetics of diclofenac in pigs after intramuscular administration of a single dose

    Pejčić Zorica; Pokrajac Milena; Jezdimirović Milanka

    2006-01-01

    The pharmacokinetics of diclofenac was studied in 10 clinically normal male Yorkshire pigs, following intramuscular (i.m) administration of a single dose of diclofenac-sodium (2.5 mg/kg body weight). Diclofenac serum concentrations were determined by high pressure- liquid-chromatography (HPLC), with UV detection (226 nm). Following i.m. administration all individual diclofenac serum levels best fitted the one-compartment open model for extravascular administration. The maximal diclofenac seru...

  7. The effect of dose, dose rate, route of administration, and species on tissue and blood levels of benzene metabolites

    Henderson, R.F.; Sabourin, P.J.; Bechtold, W.E.; Griffith, W.C.; Medinsky, M.A.; Birnbaum, L.S.; Lucier, G.W.

    1989-01-01

    Studies were completed in F344/N rats and B6C3F 1 mice to determine the effect of dose, dose rate, route of administration, and rodent species on formation of total and individual benzene metabolites. Oral doses of 50 mg/kg or higher saturated the capacity for benzene metabolism in both rats and mice, resulting in an increased proportion of the administered dose being exhaled as benzene. The saturating air concentration for benzene metabolism during 6-hr exposures was between 130 and 900 ppm. At the highest exposure concentration, rats exhaled approximately half of the internal dose retained at the end of the 6-hr exposure as benzene; mice exhaled only 15% as benzene. Mice were able to convert more of the inhaled benzene to metabolites than were rats. In addition, mice metabolized more of the benzene by pathways leading to the putative toxic metabolites, benzoquinone and muconaldehyde, than did rats. In both rats and mice, the effect of increasing dose, administered orally or by inhalation, was to increase the proportion of the total metabolites that were the products of detoxification pathways relative to the products of pathways leading to putative toxic metabolites. This indicates low-affinity, high-capacity pathways for detoxification and high-affinity, low-capacity pathways leading to putative toxic metabolites. If the results of rodent studied performed at high doses were used to assess the health risk at low-dose exposures to benzene, the toxicity of benzene would be underestimated

  8. Prediction of Optimal Reversal Dose of Sugammadex after Rocuronium Administration in Adult Surgical Patients

    Shigeaki Otomo

    2014-01-01

    Full Text Available The objective of this study was to determine the point after sugammadex administration at which sufficient or insufficient dose could be determined, using first twitch height of train-of-four (T1 height or train-of-four ratio (TOFR as indicators. Groups A and B received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as a first dose when the second twitch reappeared in train-of-four stimulation, and Groups C and D received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as the first dose at posttetanic counts 1–3. Five minutes after the first dose, an additional 1 mg/kg of sugammadex was administered and changes in T1 height and TOFR were observed. Patients were divided into a recovered group and a partly recovered group, based on percentage changes in T1 height after additional dosing. T1 height and TOFR during the 5 min after first dose were then compared. In the recovered group, TOFR exceeded 90% in all patients at 3 min after sugammadex administration. In the partly recovered group, none of the patients had a TOFR above 90% at 3 min after sugammadex administration. An additional dose of sugammadex can be considered unnecessary if the train-of-four ratio is ≥90% at 3 min after sugammadex administration. This trial is registered with UMIN000007245.

  9. Pharmacokinetic evaluation of pamidronate after oral administration: a study on dose proportionality, absolute bioavailability, and effect of repeated administration

    Hyldstrup, Lars; Flesch, G; Hauffe, S A

    1993-01-01

    30 minutes at constant infusion rate. Repeated peroral doses (75 and 150 mg) were administered to 12 females (aged 51-70 years) for 10 consecutive days. Urinary excretion of pamidronate after peroral and i.v. administration was used for estimation of pamidronate absorption. Renal excretion...... of pamidronate ranged from 0.01% to 0.35% of dose, with mean values of 0.11, 0.16, and 0.18% for 75, 150, and 300 mg, respectively. After i.v. infusion, the renal excretion of pamidronate was 26-53% of the dose, lower than for other bisphosphonates. The absolute bioavailability was 0.31% (range 0.08-0.7%) after...

  10. Prediction of response to continuous irradiation at low dose rate for repeated administrations in radiotherapy with beta emitters

    Calderon, Carlos; Gonzalez, Joaquin; Quesada, Waldo

    2009-01-01

    The absorbed dose to tumors after systemic administration of radiopharmaceuticals is not sufficient to achieve acceptable levels of probability of tumor control without compromising on critical tissue toxicity (kidney and / or bone marrow (BM)). There are reports of trials with multiple administrations, about tolerance level inter-administration intervals to allow recovery of the BM, with good results. The biokinetic behavior of some radiopharmaceuticals known makes possible the application of several administrations with short intervals of time.It is the present work combines two kinetic models of tumor growth and cell kinetics in the BM for predicting the response to continuous irradiation at low dose rate. The estimation of the effects of irradiation on tumor and kidneys was done using a formulation of the linear-quadratic model functions suitable for dose rate and multi-exponential repair. The estimation of the response in WB performed using a compartmental model previously reported. The absorbed dose to organs were calculated using the MIRD formulation taking into account the effect of irradiation cross. Biokinetic data were used for therapeutic radiopharmaceuticals 90Y, 131I and 177Lu, as well as radiobiological parameters reported for experimental animals. The effect on the response by the variation of inter-administration interval in slow-growing tumors and fast, so as the radiosensitive and radioresistant tumors. You can set conditions irradiation to an acceptable level of thrombocytopenia (onset and duration of the minimum in the curve) and renal irradiation below the limit of tolerance. It is possible to design experiments evaluation of therapeutic radiopharmaceuticals with a greater degree of refinement. (author)

  11. Fast, multiple optimizations of quadratic dose objective functions in IMRT

    Breedveld, Sebastiaan; Storchi, Pascal R M; Keijzer, Marleen; Heijmen, Ben J M

    2006-01-01

    Inverse treatment planning for intensity-modulated radiotherapy may include time consuming, multiple minimizations of an objective function. In this paper, methods are presented to speed up the process of (repeated) minimization of the well-known quadratic dose objective function, extended with a smoothing term that ensures generation of clinically acceptable beam profiles. In between two subsequent optimizations, the voxel-dependent importance factors of the quadratic terms will generally be adjusted, based on an intermediate plan evaluation. The objective function has been written in matrix-vector format, facilitating the use of a recently published, fast quadratic minimization algorithm, instead of commonly applied gradient-based methods. This format also reduces the calculation time in between subsequent minimizations, related to adjustment of the voxel-dependent importance factors. Sparse matrices are used to limit the required amount of computer memory. For three patients, comparisons have been made with a gradient method. Mean speed improvements of up to a factor of 37 have been achieved

  12. The effect of high-dose dronabinol (oral THC) maintenance on cannabis self-administration.

    Schlienz, Nicolas J; Lee, Dustin C; Stitzer, Maxine L; Vandrey, Ryan

    2018-06-01

    There is a clear need for advancing the treatment of cannabis use disorders. Prior research has demonstrated that dronabinol (oral THC) can dose-dependently suppress cannabis withdrawal and reduce the acute effects of smoked cannabis. The present study was conducted to evaluate whether high-dose dronabinol could reduce cannabis self-administration among daily users. Non-treatment seeking daily cannabis users (N = 13) completed a residential within-subjects crossover study and were administered placebo, low-dose dronabinol (120 mg/day; 40 mg tid), or high-dose dronabinol (180-240 mg/day; 60-80 mg tid) for 12 consecutive days (order counterbalanced). During each 12-day dronabinol maintenance phase, participants were allowed to self-administer smoked cannabis containing <1% THC (placebo) or 5.7% THC (active) under forced-choice (drug vs. money) or progressive ratio conditions. Participants self-administered significantly more active cannabis compared with placebo in all conditions. When active cannabis was available, self-administration was significantly reduced during periods of dronabinol maintenance compared with placebo maintenance. There was no difference in self-administration between the low- and high-dose dronabinol conditions. Chronic dronabinol dosing can reduce cannabis self-administration in daily cannabis users and suppress withdrawal symptoms. Cannabinoid agonist medications should continue to be explored for therapeutic utility in the treatment of cannabis use disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

  13. Pharmacokinetics of terbinafine after oral administration of a single dose to Hispaniolan Amazon parrots (Amazona ventralis).

    Evans, Erika E; Emery, Lee C; Cox, Sherry K; Souza, Marcy J

    2013-06-01

    To determine pharmacokinetics after oral administration of a single dose of terbinafine hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). 6 healthy adult Hispaniolan Amazon parrots. A single dose of terbinafine hydrochloride (60 mg/kg) was administered orally to each bird, which was followed immediately by administration of a commercially available gavage feeding formula. Blood samples were collected at the time of drug administration (time 0) and 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration. Plasma concentrations of terbinafine were determined via high-performance liquid chromatography. Data from 1 bird were discarded because of a possible error in the dose of drug administered. After oral administration of terbinafine, the maximum concentration for the remaining 5 fed birds ranged from 109 to 671 ng/mL, half-life ranged from 6 to 13.5 hours, and time to the maximum concentration ranged from 2 to 8 hours. No adverse effects were observed. Analysis of the results indicated that oral administration of terbinafine at a dose of 60 mg/kg to Amazon parrots did not result in adverse effects and may be potentially of use in the treatment of aspergillosis. Additional studies are needed to determine treatment efficacy and safety.

  14. Estimate of the absorbed dose in the mouse organs and tissues after tritium administration

    Saito, Masahiro

    2000-01-01

    Chronic and accidental release of tritium from future fusion facilities may cause some extent of hazardous effect to the public health. Various experiments using small animals such as mice have been performed to mimic the dose accumulation due to tritium intake by the human body. An difficulty in such animal experiments using small animals is that it is rather difficult to administer tritium orally and estimate the dose to small organs or tissues. In the course of our study, a simple method to administer THO and T-labeled amino acids orally to the mouse was dictated and dose accumulation in various organs and tissues was determined. The tritium retention in the bone marrow was also determined using the micro-centrifuge method. Throughout our experiment, colony-bred DDY mice were used. The 8-10 week old male mice were orally and intraperitoneally administered THO water or T-amino acids mixture solution. For the purpose of oral administration, a 10 μl aliquot of T-containing saline solution was placed on the tongue of the mice using an automatic micropipette. At various times after tritium administration, the animals were sacrificed and the amount of tritium in various tissues and organs including bone marrow was examined. Dose accumulation pattern after THO intake and T-amino acids was compared between intraperitoneal injection and oral administration. The accumulated dose after oral administration of THO exhibited a tendency to be 10-20% higher than after intraperitoneal injection. The bone marrow dose after oral intake of THO was found to be lower than the doses to urine, blood, liver and testis. In contrast, the blood dose gave a conservative estimate for the dose to the other tissues and organs. (author)

  15. Effect of low-dose atropine administration on dobutamine dose requirement in horses anesthetized with detomidine and halothane.

    Weil, A B; Keegan, R D; Greene, S A

    1997-12-01

    To determine whether a low dose of atropine is associated with decreased requirement for cardiovascular supportive treatment in horses given detomidine prior to maintenance of general anesthesia with halothane. 3 groups of 10 healthy horses. Detomidine (20 micrograms/kg of body weight, i.m.) was administered to all 30 horses. Then, 10 horses received atropine (0.006 mg/kg, i.v.) 1 hour after detomidine administration, 10 horses received atropine (0.012 mg/kg, i.m.) at the time of detomidine administration, and 10 horses served as a control group. Heart rate was measured prior to detomidine administration and at fixed intervals throughout anesthesia. The dobutamine infusion rate necessary to maintain mean arterial blood pressure between 70 and 80 mm of Hg was recorded. Systemic blood pressures, end-tidal halothane, end-tidal CO2, and arterial blood gas tensions were measured at fixed intervals. Mean heart rate was higher among horses receiving atropine i.v. or i.m., compared with that in control horses. Horses that received atropine i.v. had higher systemic arterial blood pressure and required a lower dobutamine infusion rate than did horses of the other groups. Detomidine-treated, halothane-anesthetized horses given atropine i.v. required less dobutamine, compared with horses receiving or not receiving atropine i.m. Complications, such as colic and dysrhythmias, from use of higher doses of atropine, were not observed at this lower dose of atropine. i.v. administration of a low dose of atropine prior to induction of general anesthesia may result in improved blood pressure in horses that have received detomidine before anesthesia with halothane.

  16. Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice

    Iwai, Hiroyuki; Matsuno, Etsuko; Sasai, Keisuke; Abe, Mitsuyuki; Shibamoto, Yuta

    1994-01-01

    In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined. The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions x three fractions/48 h or 5 Gy/fractions x five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three, or four times at 2-h intervals. At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter. Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity. 12 refs., 5 figs., 1 tab

  17. Internal dose assessment in nuclear medicine: fetal doses due to radiopharmaceutical administration to the mother

    Rojo, Ana M.; Michelin, Severino C.

    2004-01-01

    The objective of this publication is to present a guideline for the dose assessment through a comprehensive introduction of knowledge on ionizing radiation, radiation protection during pregnancy and fetal dosimetry for physician and other professionals involved in nuclear medicine practices. It contains tables with recommended dose estimates at all stages of pregnancy for many radiopharmaceuticals. Compounds for which some information was available regarding placental crossover are shown in shaded rows. It includes the most common diagnostic and therapy practices in nuclear medicine considering the four radioactive isotopes selected: 99m Tc, 131 I, 201 Tl and 67 Ga. There is a special case included, it is when conception occurs after the iodine has been administered. In almost every case, the diagnostic benefit to the mother outweighs the risk of any irradiation of the fetus. However, there is one situation in which severe fetal injury can be incurred from administering a radiopharmaceutical to the mother, and that is use of iodine-131 therapy for ablation of the thyroid in cases of hyperthyroidism or carcinoma. Radioactive iodine readily crosses the placenta and concentrates in the fetal thyroid, where, because of its small organ mass, high radiation doses are received. (author)

  18. Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration

    McFadden, Lisa M; Hoonakker, Amanda J; Vieira-Brock, Paula L; Stout, Kristen A; Sawada, Nicole M; Ellis, Jonathan D; Allen, Scott C; Walters, Elliot T; Nielsen, Shannon M; Gibb, James W; Alburges, Mario E; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

    2011-01-01

    Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent (i.e., postnatal day (PND) 40) rats are less susceptible to this damage than young adult (PND90) rats. In addition, biweekly treatment with METH, beginning at PND40 and continuing throughout development, prevents the persistent dopaminergic deficits caused by a “challenge” high-dose METH regimen when administered ...

  19. The real-life experience with cardiovascular complications in the first dose of fingolimod for multiple sclerosis

    Yara Dadalti Fragoso

    2014-09-01

    Full Text Available Fingolimod is a new and efficient treatment for multiple sclerosis (MS. The drug administration requires special attention to the first dose, since cardiovascular adverse events can be observed during the initial six hours of fingolimod ingestion. The present study consisted of a review of cardiovascular data on 180 patients with MS receiving the first dose of fingolimod. The rate of bradycardia in these patients was higher than that observed in clinical trials with very strict inclusion criteria for patients. There were less than 10% of cases requiring special attention, but no fatal cases. All but one patient continued the treatment after this initial dose. This is the first report on real-life administration of fingolimod to Brazilian patients with MS, and one of the few studies with these characteristics in the world.

  20. Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers.

    Chandorkar, Gurudatt; Zhan, Qiao; Donovan, Julie; Rege, Shruta; Patino, Hernando

    2017-03-28

    Surotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile-associated diarrhea, has demonstrated minimal intestinal absorption in animal models. Safety, tolerability, and plasma pharmacokinetics of single and multiple ascending oral doses (SAD/MAD) of surotomycin in healthy volunteers were characterized in two randomized, double-blind, placebo-controlled, phase 1 studies. Participants were sequentially enrolled into one of four SAD (500, 1000, 2000, 4000 mg surotomycin) or three MAD (250, 500, 1000 mg surotomycin twice/day for 14 days) cohorts. Ten subjects were randomized 4:1 into each cohort to receive surotomycin or placebo. Surotomycin plasma concentrations rose as dose increased (maximum plasma concentration [C max ]: 10.5, 21.5, 66.6, and 86.7 ng/mL). Systemic levels were generally low, with peak median surotomycin plasma concentrations observed 6-12 h after the first dose. In the MAD study, surotomycin plasma concentrations were higher on day 14 (C max : 25.5, 37.6, and 93.5 ng/mL) than on day 1 (C max : 6.8, 11.0, and 21.1 ng/mL for increasing doses), indicating accumulation. In the SAD study, <0.01% of the administered dose was recovered in urine. Mean surotomycin stool concentration from the 1000 mg MAD cohort was 6394 μg/g on day 5. Both cohorts were well tolerated with all adverse events reported as mild to moderate. Both SAD and MAD studies of surotomycin demonstrated minimal systemic exposure, with feces the primary route of elimination following oral administration; consistent with observations with similar compounds, such as fidaxomicin. Results of these phase 1 studies support the continued clinical development of surotomycin for the treatment of Clostridium difficile-associated diarrhea. NCT02835118 and NCT02835105 . Retrospectively registered, July 13 2016.

  1. Blood volume measurement with indocyanine green pulse spectrophotometry: dose and site of dye administration

    Germans, Menno R.; de Witt Hamer, Philip C.; van Boven, Leonard J.; Zwinderman, Koos A. H.; Bouma, Gerrit J.

    2010-01-01

    (1) To determine the optimal administration site and dose of indocyanine green (ICG) for blood volume measurement using pulse spectrophotometry, (2) to assess the variation in repeated blood volume measurements for patients after subarachnoid hemorrhage and (3) to evaluate the safety and efficacy of

  2. Effect of low dose Lead (Pb) administration on tail immersion test ...

    Effect of low dose Lead (Pb) administration on tail immersion test and ... subtle decline in cognitive function, and adverse reproductive outcome at low blood Pb level. ... Twenty adult Wistar rats of both sexes (weight 150g to 200g) were used.

  3. Oral dosing by voluntary  administration of jellybeans. Refinement and reduction of variability

    Pakula, Malgorzata Maria; Dagnæs-Hansen, Frederik

    2016-01-01

    Administration of substances by oral gavage is a common procedure in biomedical research involving laboratory animals, however although highly efficient, the procedure includes fixation of the animals and is technically challenging. Oral gavage is a precise way to dose animals, however it may ind...

  4. Dose-dependent effects of oral tyrosine administration on plasma tyrosine levels and cognition in aging

    Rest, van de Ondine; Bloemendaal, Mirjam; Heus, De Rianne; Aarts, Esther

    2017-01-01

    The effects of tyrosine on plasma response and cognition in aging are unknown. We assessed the dose-dependent response to tyrosine administration in older adults in both plasma tyrosine concentrations and working memory performance. In this double blind randomized cross-over trial 17 older adults

  5. Dose-Dependent Effects of Oral Tyrosine Administration on Plasma Tyrosine Levels and Cognition in Aging

    Rest, O. van de; Bloemendaal, M.; Heus, R.A.A. de; Aarts, E.

    2017-01-01

    The effects of tyrosine on plasma response and cognition in aging are unknown. We assessed the dose-dependent response to tyrosine administration in older adults in both plasma tyrosine concentrations and working memory performance. In this double blind randomized cross-over trial 17 older adults

  6. Effect of Low Dose Lead (Pb) Administration on Tail Immersion Test ...

    olayemitoyin

    Effect of Low Dose Lead (Pb) Administration on Tail ... Acute and sub-acute effects of lead are caused by relatively large ... As such, the brain is the organ most studied in lead toxicity. ..... inflammatory Properties of Hydro-alcohol Extract of.

  7. Effect of dose increase or cimetidine co-administration on albendazole bioavailability

    Schipper, H. G.; Koopmans, R. P.; Nagy, J.; Butter, J. J.; Kager, P. A.; van Boxtel, C. J.

    2000-01-01

    The low bioavailability of albendazole affects the therapeutic response in patients with echinococcosis. Cimetidine co-administration is reported to improve bioavailability. To analyze the assumed dose-dependent bioavailability of albendazole, we administered 5 to 30 mg/kg albendazole to 6 male

  8. Evaluation of occupational radiation dose in nuclear medicine: radiopharmaceutical administration to scintiscanning exams of myocardial perfusion

    Komatsu, Cassio V.; Michelin, Charlie A.; Jakubiak, Rosangela R.; Lemes, Alyne O.; Silva, Juliana L.M.

    2013-01-01

    In nuclear medicine, workers directly involved in exams are constantly exposed to ionizing radiation. The procedure for administration of the radiopharmaceutical to the patient is one of the most critical times of exposure. In tests of myocardial perfusion scintigraphy (MPS) administration of radiopharmaceutical repeats the steps of rest and cardiac stress. In this study, we used a Geiger -Mueller detector for measuring occupational radiation doses for during the administration of technetium- 99m - sestamibi in MPS tests. In the evaluation, discriminated the stages of examination and related professional experience time to doses measures at home. It were followed 110 procedures at home (55 conducted by professionals with over 5 years experience and 55 conducted by professionals with less than 1 year of experience) and 55 effort procedures. The results showed that the rest of the procedure time and dose are related to the experience of the worker. More experienced workers were faster (mean: 43 ± 16 vs 67 ± 25 seconds / procedure), and therefore received lower doses (mean 0.57 ± 0.16 versus 0.80 ± 0.24 μSv / procedure), both with statistical significance (p <0.001). In step effort, there were procedures lasting longer (mean: 19 ± 2 minutes / procedure), which resulted in higher doses (mean 3.0 ± 0.6 μSv / procedure)

  9. Microfluidic thrombosis under multiple shear rates and antiplatelet therapy doses.

    Melissa Li

    Full Text Available The mainstay of treatment for thrombosis, the formation of occlusive platelet aggregates that often lead to heart attack and stroke, is antiplatelet therapy. Antiplatelet therapy dosing and resistance are poorly understood, leading to potential incorrect and ineffective dosing. Shear rate is also suspected to play a major role in thrombosis, but instrumentation to measure its influence has been limited by flow conditions, agonist use, and non-systematic and/or non-quantitative studies. In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s(-1 and therapy concentrations (0-2.4 µM for eptifibatide, 0-2 mM for acetyl-salicylic acid (ASA, 3.5-40 Units/L for heparin using a microfluidic device. We also measured complete blood counts (CBC and platelet activity using whole blood impedance aggregometry. Effects of shear rate and dose were analyzed using general linear models, logistic regressions, and Cox proportional hazards models. Shear rates have significant effects on thrombosis/dose-response curves for all tested therapies. ASA has little effect on high shear occlusion times, even at very high doses (up to 20 times the recommended dose. Under ASA therapy, thrombi formed at high shear rates were 4 times more prone to detachment compared to those formed under control conditions. Eptifibatide reduced occlusion when controlling for shear rate and its efficacy increased with dose concentration. In contrast, the hazard of occlusion from ASA was several orders of magnitude higher than that of eptifibatide. Our results show similar dose efficacy to our low shear measurements using whole blood aggregometry. This quantitative and statistically validated study of the effects of a wide range of shear rate and antiplatelet therapy doses on occlusive thrombosis contributes to more accurate understanding of thrombosis and to models for optimizing patient treatment.

  10. Comparison of the deviation distribution in the doses administrated with and without mask in radiotherapeutic procedures

    Santos Junior, S. dos; Ghilardi N, T.

    1998-01-01

    In order to guarantee that the error limit in the dose administration is inside of the recommended limit by the ICRU (the ICRU recommends that the doses administrated in radiotherapy must be inside of a total deviation ± 5 %), the radiotherapy services are maintaining quality control programs and dosimetry which guarantee that the equipment yield or source should be known with precision. The Quality Control Programs foresee moreover the radiation beam calibration dosimetry, the In vivo dosimetry for obtaining a greater control of the administered doses. At present it counts on greater devices for maintaining the deviations inside this margin, and one of them is the u se of masks. The present work was carried out on a Siemens equipment model Gammatron S-80 (Co-60) in the Radiotherapy Service of the Sao Paulo University Hospital where teletherapy procedures are realized. (Author)

  11. Inhibition of alloxan diabetes by low dose {gamma}-irradiation before alloxan administration

    Yamaoka, Kiyonori [Central Research Inst. of Electric Power Industry, Komae, Tokyo (Japan). Komae Research Lab.; Takehara, Yoshiki; Yoshioka, Tamotsu; Utsumi, Kozo

    1994-10-01

    We evaluated the inhibitory effects of whole body {sup 60}Co-{gamma} irradiation at a single low dose on alloxan-induced hyperglycemia in rats. (1) In rats that received alloxan, SOD activity in pancreas significantly decreased, but the decrease was inhibited by irradiation at a dose of 0.5 Gy. (2) Similarly, plasma peroxide, pancreatic peroxide, and blood glucose increased. However, the increase in pancreatic peroxide was inhibited by irradiation at a dose of 0.5 or 1.0 Gy and the increase in blood glucose by irradiation at 0.5 Gy. (3) After alloxan administration, degranulation was observed in cells, but this was inhibited by irradiation at 0.5 Gy. These results suggest that alloxan diabetes was inhibited by the increase of SOD activity in pancreas after low dose irradiation at 0.5 Gy. (author).

  12. Inhibition of alloxan diabetes by low dose γ-irradiation before alloxan administration

    Yamaoka, Kiyonori; Takehara, Yoshiki; Yoshioka, Tamotsu; Utsumi, Kozo.

    1994-01-01

    We evaluated the inhibitory effects of whole body 60 Co-γ irradiation at a single low dose on alloxan-induced hyperglycemia in rats. (1) In rats that received alloxan, SOD activity in pancreas significantly decreased, but the decrease was inhibited by irradiation at a dose of 0.5 Gy. (2) Similarly, plasma peroxide, pancreatic peroxide, and blood glucose increased. However, the increase in pancreatic peroxide was inhibited by irradiation at a dose of 0.5 or 1.0 Gy and the increase in blood glucose by irradiation at 0.5 Gy. (3) After alloxan administration, degranulation was observed in cells, but this was inhibited by irradiation at 0.5 Gy. These results suggest that alloxan diabetes was inhibited by the increase of SOD activity in pancreas after low dose irradiation at 0.5 Gy. (author)

  13. The relative importance of ingestion for multiple pathway dose assessments

    Wicker, W.; Grogan, H.; Bergstroem, U.; Hoffman, O.

    1991-01-01

    The general purpose of this report is to examine the relative importance of ingestion pathways, and particularly food chain transport in overall dose assessment. The importance of ingestion pathways is examined for various release scenarios and radionuclides because the findings are expected to differ with circumstances. The degree to which contaminated food products contribute to the total dose will affect the importance of accuracy and uncertainty of food chain model predictions, which is the main thrust of the Biospheric Model Validation Study (BIOMOVS). This analysis requires that all modes of radiation exposure be examined, including inhalation, external exposure, and the various ingestion pathways. (2 figs., 2 tabs.)

  14. T1 Shortening in the Globus Pallidus after Multiple Administrations of Gadobutrol: Assessment with a Multidynamic Multiecho Sequence.

    Kang, Koung Mi; Choi, Seung Hong; Hwang, Moonjung; Yun, Tae Jin; Kim, Ji-Hoon; Sohn, Chul-Ho

    2018-04-01

    Purpose To determine the association between the administration of the macrocyclic contrast medium gadobutrol and T1 relaxation time in the brains of patients with normal renal function by using multidynamic multiecho (MDME) magnetic resonance (MR) imaging sequences. Materials and Methods The institutional review board approved this retrospective study, and the need to obtain written informed consent was waived. This study included 46 patients (revealed by an electronic medical record search) who had received one or more gadobutrol injections and a maximum of one MR imaging contrast medium injection other than gadobutrol before MDME sequence acquisition. One radiologist performed quantitative analyses of regions of interest on quantitative T1 maps twice to cover the normal-appearing globus pallidus (GP), frontal white matter, frontal cortex, and thalamus. The number of administrations and the cumulative dose of gadobutrol, age, intervals between administrations, sex, and treatment were investigated. Univariable and multivariable linear regression analyses of the T1 values in four brain regions and the GP-to-thalamus signal intensity (SI) ratio were performed. P values of less than the Bonferroni-corrected value of .01 were considered to indicate significant differences. Results Intraobserver reproducibility was good to excellent (intraclass correlation coefficients, 0.62-0.81). Because of high multicollinearity between the number of gadobutrol administrations and accumulated dose (r = 0.96, P .01). Conclusion Multiple exposures to gadobutrol are associated with T1 shortening in the GP. © RSNA, 2017 Online supplemental material is available for this article.

  15. Evaluation of the sterility of single-dose medications used in a multiple-dose fashion.

    Martin, Elizabeth P; Mukherjee, Jean; Sharp, Claire R; Sinnott-Stutzman, Virginia B

    2017-11-01

    Bacterial proliferation was evaluated in single-dose medications used in a multi-dose fashion and when medications were intentionally inoculated with bacteria. Of 5 experimentally punctured medications, 1 of 75 vials (50% dextrose) became contaminated. When intentionally inoculated, hydroxyethyl starch and heparinized saline supported microbial growth. Based on these findings, it is recommended that hydroxyethyl starch and heparinized saline not be used in a multi-dose fashion.

  16. The normalized administration of hybrid operating room: its practical application in managing multiple injuries

    Li Xue; Zhang Weiguo; Zhang Lianyang; Chen Tingjing; Chen Jinhua

    2011-01-01

    Objective: Through carrying out the normalized administration of hybrid operating room the application of the operating room is expanded to the performing of multiple injuries, and, in this way, the operative management become standardized and programmed, the cooperation and efficiency of hybrid operations for multiple injuries are improved and the surgeries can be ensured. Methods: According to the characteristics of hybrid interventional operation for multiple injuries, the basic construction of the hybrid operating room improved, the hybrid operation team was organized, and the administrative system as well as the working program were established. The green channel for rescuing patients with multiple injuries was set up. The cooperative behavior during interventional treatment for multiple injuries was specified. Results: The coordination and working efficiency of physicians, nurses, technicians and anesthetists were well improved. The qualified rate of lamina flow administration reached 100%. The success rate of the rescue of multiple injuries was increased. Conclusion: As one-stop complex interventional operation for multiple injuries is a new technique, there is no integrated administration system. Therefore, the establishment of standardized management of one-stop complex interventional operation is of great significance in guiding clinical practice. (authors)

  17. Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice

    Amirshahrokhi, K.; Dehpour, A.R.; Hadjati, J.; Sotoudeh, M.; Ghazi-Khansari, M.

    2008-01-01

    Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of β cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a μ-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1β, tumor necrosis factor-α and interferon-γ] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of β cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of β cells and insulitis in the MLDS model of type 1 diabetes

  18. Regulation of operant oral ethanol self-administration: a dose-response curve study in rats.

    Carnicella, Sebastien; Yowell, Quinn V; Ron, Dorit

    2011-01-01

    Oral ethanol self-administration procedures in rats are useful preclinical tools for the evaluation of potential new pharmacotherapies as well as for the investigation into the etiology of alcohol abuse disorders and addiction. Determination of the effects of a potential treatment on a full ethanol dose-response curve should be essential to predict its clinical efficacy. Unfortunately, this approach has not been fully explored because of the aversive taste reaction to moderate to high doses of ethanol, which may interfere with consumption. In this study, we set out to determine whether a meaningful dose-response curve for oral ethanol self-administration can be obtained in rats. Long-Evans rats were trained to self-administer a 20% ethanol solution in an operant procedure following a history of excessive voluntary ethanol intake. After stabilization of ethanol self-administration, the concentration of the solution was varied from 2.5 to 60% (v/v), and operant and drinking behaviors, as well as blood ethanol concentration (BEC), were evaluated following the self-administration of a 20, 40, and 60% ethanol solution. Varying the concentration of ethanol from 2.5 to 60% after the development of excessive ethanol consumption led to a typical inverted U-shaped dose-response curve. Importantly, rats adapted their level and pattern of responding to changes in ethanol concentration to obtain a constant level of intake and BEC, suggesting that their operant behavior is mainly driven by the motivation to obtain a specific pharmacological effect of ethanol. This procedure can be a useful and straightforward tool for the evaluation of the effects of new potential pharmacotherapies for the treatment of alcohol abuse disorders. Copyright © 2010 by the Research Society on Alcoholism.

  19. The effects of variations in dose and method of administration on glucagon like peptide-2 activity in the rat

    Kaji, Tatsuru; Tanaka, Hiroaki; Holst, Jens Juul

    2008-01-01

    Glucagon-like peptide-2 (GLP-2) is a potent, intestinal-specific trophic hormone. However, the relationship between the dose and timing of GLP-2 administration and these trophic effects is not clear. We investigated the effects of variations in the dose and timing of GLP-2 administration on its...

  20. Pharmacokinetics of opicapone, a third-generation COMT inhibitor, after single and multiple oral administration: A comparative study in the rat

    Gonçalves, Daniela [Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra (Portugal); CNC – Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra (Portugal); Alves, Gilberto, E-mail: gilberto@fcsaude.ubi.pt [CNC – Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra (Portugal); CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã (Portugal); Fortuna, Ana [Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra (Portugal); CNC – Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra (Portugal); Soares-da-Silva, Patrício [Department of Research and Development, BIAL – Portela & Ca S.A., Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado (Portugal); MedInUP – Center for Drug Discovery and Innovative Medicines, University Porto, Porto (Portugal); Falcão, Amílcar [Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra (Portugal); CNC – Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra (Portugal)

    2017-05-15

    Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n = 8 per group) were orally treated with single (30, 60 or 90 mg/kg) or multiple (30 mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24 h post-dosing through a cannula introduced in the tail vein of rats. After quantifying opicapone and BIA 9-1079 in plasma, a non-compartmental pharmacokinetic analysis was performed. Opicapone was quickly absorbed (time to reach the maximum plasma concentration ≤ 2 h) in both dosage regimens and the extent of systemic exposure to opicapone increased approximately in a dose-proportional manner after single-dosing within the studied dose range (30–90 mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58–4.50 h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen. - Highlights: • Opicapone is relatively rapid absorbed after oral administration to rats. • Systemic exposure to opicapone increases approximately in a dose-proportional manner. • Opicapone and BIA 9-1079 show a small systemic accumulation after multiple-dosing.

  1. Effect of propranolol in head tremor: quantitative study following single-dose and sustained drug administration.

    Calzetti, S; Sasso, E; Negrotti, A; Baratti, M; Fava, R

    1992-12-01

    The effect of the beta-adrenoceptor antagonist propranolol has been investigated in nine patients suffering from isolated (six patients) or prominent (three patients) essential tremor of the head. In a double-blind, placebo-controlled study the tremorolytic efficacy of propranolol has been assessed by a quantitative accelerometric method after a single oral dose (120 mg) and following 2 weeks of sustained treatment with two different dosage regimens of the drug (120 and 240 mg daily). As compared with placebo, a significant reduction in tremor magnitude was found following a single oral dose but not on sustained administration of the beta-blocker at either dosage. The results suggest that the efficacy of sustained propranolol on isolated or prominent essential head tremor is less predictable and satisfactory than expected on the basis of the single-dose response, as compared with hand tremor.

  2. Systemic administration of mesenchymal stem cells combined with parathyroid hormone therapy synergistically regenerates multiple rib fractures.

    Cohn Yakubovich, Doron; Sheyn, Dmitriy; Bez, Maxim; Schary, Yeshai; Yalon, Eran; Sirhan, Afeef; Amira, May; Yaya, Alin; De Mel, Sandra; Da, Xiaoyu; Ben-David, Shiran; Tawackoli, Wafa; Ley, Eric J; Gazit, Dan; Gazit, Zulma; Pelled, Gadi

    2017-03-09

    A devastating condition that leads to trauma-related morbidity, multiple rib fractures, remain a serious unmet clinical need. Systemic administration of mesenchymal stem cells (MSCs) has been shown to regenerate various tissues. We hypothesized that parathyroid hormone (PTH) therapy would enhance MSC homing and differentiation, ultimately leading to bone formation that would bridge rib fractures. The combination of human MSCs (hMSCs) and a clinically relevant PTH dose was studied using immunosuppressed rats. Segmental defects were created in animals' fifth and sixth ribs. The rats were divided into four groups: a negative control group, in which animals received vehicle alone; the PTH-only group, in which animals received daily subcutaneous injections of 4 μg/kg teriparatide, a pharmaceutical derivative of PTH; the hMSC-only group, in which each animal received five injections of 2 × 10 6 hMSCs; and the hMSC + PTH group, in which animals received both treatments. Longitudinal in vivo monitoring of bone formation was performed biweekly using micro-computed tomography (μCT), followed by histological analysis. Fluorescently-dyed hMSCs were counted using confocal microscopy imaging of histological samples harvested 8 weeks after surgery. PTH significantly augmented the number of hMSCs that homed to the fracture site. Immunofluorescence of osteogenic markers, osteocalcin and bone sialoprotein, showed that PTH induced cell differentiation in both exogenously administered cells and resident cells. μCT scans revealed a significant increase in bone volume only in the hMSC + PTH group, beginning by the 4 th week after surgery. Eight weeks after surgery, 35% of ribs in the hMSC + PTH group had complete bone bridging, whereas there was complete bridging in only 6.25% of ribs (one rib) in the PTH-only group and in none of the ribs in the other groups. Based on the μCT scans, biomechanical analysis using the micro-finite element method demonstrated that

  3. Minimising activity and dose with enhanced image quality by radiopharmaceutical administrations

    Hoeschen, C.; Mattsson, S.; Cantone, M. C.; Mikuz, M.; Lacasta, C.; Ebel, G.; Clinthorne, N.; Giussani, A.

    2010-01-01

    Owing to the introduction of new diagnostic procedures, such as computed tomography (CT), positron emission tomography (PET) and single photon emission computed tomography (SPECT), the individual dose caused by medical exposures has grown rapidly in the last years. This is especially a subject to radiation protection for nuclear medical diagnosis, since in this case radiopharmaceuticals are administered to the patient, meaning not only a radiation exposure to the diseased tissue but also to the healthy tissues of large parts of the body. 'Minimizing Activity and Dose with Enhanced Image quality by Radiopharmaceutical Administrations' (MADEIRA) is a project co-funded by the European Commission within the Seventh Euratom Framework Programme that aims to improve three-dimensional (3D) nuclear medical imaging technologies significantly. MADEIRA is aiming to improve the efficacy and safety of 3D PET and SPECT functional imaging by optimising the spatial resolution and the signal-to-noise ratio, improving the knowledge of the temporal variation of the radiopharmaceuticals' uptake in and clearance from tumorous and healthy tissues, and evaluation of the corresponding patient dose. Using an optimised imaging procedure that improves the information gained per unit administered dose, MADEIRA aims especially to reduce the dose to healthy tissues of the patient. In this paper, an overall summary of the current achievements will be presented. (authors)

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

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

    1995-01-01

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

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

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

    1995-01-01

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

  6. Triple dose of gadolinium-DTPA and delayed MRI in patients with benign multiple sclerosis.

    Filippi, M; Capra, R; Campi, A; Colombo, B; Prandini, F; Marcianò, N; Gasparotti, R; Comi, G

    1996-01-01

    OBJECTIVES--To evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) or delayed MRI increase the number, size, and conspicuousness of enhancing lesions in patients with benign multiple sclerosis. METHODS--T1 weighted brain MRI was carried out on 20 patients with benign multiple sclerosis (expanded disability status scale 10 years) in two sessions. In the first session, one scan was obtained before and two scans five to seven minutes and 20-30 minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, the same procedure was repeated with 0.3 mmol/kg Gd-DTPA (triple dose). RESULTS--Nine enhancing lesions were found in seven patients (35%) using the standard dose of Gd-DTPA. The numbers of enhancing lesions increased to 13 (P = 0.03) and the number of patients with such lesions to eight (40%) on the delayed standard dose scans. On the early triple dose scans, we found 19 enhancing lesions in 10 patients (50%). The number of enhancing lesions was significantly higher (P = 0.01) than that obtained with the early standard dose. The number of enhancing lesions was 18 and the number of "active" patients 11 (55%) on the delayed triple dose scans. The enhancing areas increased progressively from the early standard dose scans to the delayed triple dose scans. The contrast ratios of the lesions detected in early standard dose scans was lower than those of lesions present in the early (P = 0.01) and delayed (P = 0.04) triple dose scans. CONCLUSIONS--More enhancing lesions were detected in patients with benign multiple sclerosis with both delay of MRI and the use of triple dose of Gd-DTPA suggesting that the amount of inflammation in the lesions of such patients is mild and heterogeneous. Images PMID:8778257

  7. Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers.

    Park, Sang-In; Oh, Jaeseong; Jang, Kyungho; Yoon, Jangsoo; Moon, Seol Ju; Park, Jong Sun; Lee, Jae Ho; Song, Junghan; Jang, In-Jin; Yu, Kyung-Sang; Chung, Jae-Yong

    2015-08-01

    Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean Cmax and AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.). Copyright © 2015, American Society for

  8. CT of multiple sclerosis: reassessment of delayed scanning with high doses of contrast material

    Spiegel, S.M.; Vinuela, F.; Fox, A.J.; Pelz, D.M.

    1985-01-01

    A prospective study involving 87 patients was carried out to evaluate the necessity for a high dose of contrast material in addition to delayed computed tomographic (CT) scanning for optimal detection of the lesions of multiple sclerosis in the brain. In patients with either clinically definite multiple sclerosis or laboratory-supported definite multiple sclerosis, CT scans were obtained with a uniform protocol. Lesions consistent with multiple sclerosis were demonstrated on the second scan in 54 patients. In 36 of these 54 patients, the high-dose delayed scan added information. These results are quite similar to those of a previous study from this institution using different patients, in whom the second scan was obtained immediately after the bolus injection of contrast material containing 40 g of organically bound iodine. The lack of real difference in the results of the two studies indicate that the increased dose, not just the delay in scanning, is necessary for a proper study

  9. The response of mouse skin to multiple small doses of radiation

    Denekamp, J.; Harris, S.R.

    1975-01-01

    The response of mouse skin has been tested by irradiating the foot of albino mice and scoring erythema and desquamation during the following month. Multiple small doses of 150, 250 and 350 rad have been given 'daily', and the test dose necessary to achieve a given reaction has been determined one day after the last small fraction. This test dose has been compared with the single dose necessary to produce the same reaction level in previously untreated mice, in order to determine the ratio of the slopes of the dose-response curve at low and high doses: Slope ratio = (single dose - test dose)/total fractionated priming dose. In three separate experiments the slope ratio decreased as the dose per fraction was reduced from 350 to 150 rad. This conflicts with the data of Dutreix et al, who found a constant slope ratio over this dose range. The present data are compared with those obtained by Denekamp using 4, 9 and 14 fractions of 300 rad and by Douglas et al, using the same experimental technique, over the dose range 45 to 200 rad/fraction. In addition, the results from multifraction experiments in which equal dose increments were administered until the requisite skin reaction was achieved are also analysed in terms of their slope ratio (Fowler et al. Douglas et al). When all these results are plotted it is impossible to be sure whether the slope ratio is decreasing over the range 300 to 45 rad per fraction, although it seems likely. Most of the values at low doses lie in the range 0.15 to 0.25, indicating that at low doses the radiation is only 15 to 25% as effective per rad in causing cell death as at higher doses. (author)

  10. Comparative chlorpyrifos pharmacokinetics via multiple routes of exposure and vehicles of administration in the adult rat

    Smith, Jordan Ned; Campbell, James A.; Busby-Hjerpe, Andrea L.; Lee, Sookwang; Poet, Torka S.; Barr, Dana B.; Timchalk, Charles

    2009-01-01

    Chlorpyrifos (CPF) is a commonly used organophosphorus pesticide. A number of toxicity and mechanistic studies have been conducted in animals, where CPF has been administered via a variety of different exposure routes and dosing vehicles. This study compared chlorpyrifos (CPF) pharmacokinetics using oral, intravenous (IV), and subcutaneous (SC) exposure routes and corn oil, saline/Tween 20, and dimethyl sulfoxide (DMSO) as dosing vehicles. Two groups of rats were co-administered target doses (5 mg/kg) of CPF and isotopically labeled CPF (L-CPF). One group was exposed by both oral (CPF) and IV (L-CPF) routes using saline/Tween 20 vehicle; whereas, the second group was exposed by the SC route using two vehicles, corn oil (CPF) and DMSO (L-CPF). A third group was only administered CPF by the oral route in corn oil. For all treatments, blood and urine time course samples were collected and analyzed for 3,5,6-trichloro-2-pyridinol (TCPy), and isotopically labeled 3,5,6-trichloro-2-pyridinol (L-TCPy). Peak TCPy/L-TCPy concentrations in blood (20.2 μmol/l), TCPy/L-TCPy blood AUC (94.9 μmol/l h), and percent of dose excreted in urine (100%) were all highest in rats dosed orally with CPF in saline/Tween 20 and second highest in rats dosed orally with CPF in corn oil. Peak TCPy concentrations in blood were more rapidly obtained after oral administration of CPF in saline/Tween 20 compared to all other dosing scenarios (>1.5 h). These results indicate that orally administered CPF is more extensively metabolized than systemic exposures of CPF (SC and IV), and vehicle of administration also has an effect on absorption rates. Thus, equivalent doses via different routes and/or vehicles of administration could potentially lead to different body burdens of CPF, different rates of bioactivation to CPF-oxon, and different toxic responses. Simulations using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF are consistent with these possibilities

  11. SU-F-BRCD-06: Multiple Anatomy Optimization of Accumulated Dose.

    Watkins, W T; Moore, J A; Sharma, M; Dial, C; Xu, H; Hugo, G D; Gordon, J J; Siebers, J V

    2012-06-01

    Multiple anatomy optimization (MAO) utilizing deformable dose accumulation on entire 4DCT data sets is implemented to overcome ambiguity between optimal dose defined on a single anatomy and optimal accumulated dose resulting from dose delivery to moving and deforming anatomy. Six lung cancer patients are planned using two methods of radiotherapy optimization: the internal target volume (ITV) envelope method and MAO, which simultaneously optimizes a single fluence for delivery to all 10 breathing phases such that the accumulated dose satisfies the plan objectives. Target dose is constrained to 70 Gy. The ITV-plan is optimized on a single breathing phase with the planning target volume defined as the ITV; the MAO target is the moving CTV. MAO is compared to single image ITV optimization based on the accumulated dose assuming equal monitor-units to each phase. Dose-volume differences between single image estimations and 10-image accumulation are examined. Single image optimal dose distributions overestimate target V70 by 4.2%±3.1% (average, one standard deviation) and in five of six cases ipsilateral lung V20 is underestimated (1.4%±0.9%). For these five cases, MAO increases V70 by 2.8%±2.5% (maximum of 6% increase in V70) and reduces ipsilateral lung V20 by up to 3% (average decrease of 1.2%±1.3%). Contralateral lung V20, esophagus V25, and heart V30 are also reduced by up to 5%, 3%, and 3%. For the sixth case, lung tumor motion is on the order of the dose voxel size (3mm), and MAO did not improve upon the ITV plan. Dose-volume optimization on a stationary image does not ensure accumulated dose coverage to the moving CTV. Multiple anatomy optimization can remove dose ambiguity and improve plan quality. P01CA11602 and Philips Medical Systems. © 2012 American Association of Physicists in Medicine.

  12. Protective Effect of Low Dose Gamma Irradiation against Oxidative Damage in Rats Administrated with Ferric- Nitrilotriacetate

    Mansonr, S.Z.

    2009-01-01

    Many studies have demonstrated the beneficial adaptive response of low dose gamma-irradiation. Low dose gamma-irradiation (LDR) might be effective for the prevention of various reactive oxygen species-related diseases. Ferric nitrilotriacetate (Fe-NTA) is a strong oxidant, which generates highly reactive hydroxyl radical and causes injuries of various organs including the kidney and liver. This study was designed to investigate the ability of low dose gamma-irradiation to restrain Fe-NT A induced oxidative stress. Sprague Dawley male albino rats were subjected to low dose gamma-irradiation (50 cGy). Animals were challenged with Fe-NT A (9 mg Fe/kg body weight, intraperitoneally). Results showed that Fe-NTA enhances lipid peroxidation (LPx) accompanied with reduction in glutathione (GSH) content, antioxidant enzymes, viz., glutathione peroxidase (GPX), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT) and phase-U metabolizing enzyme glutathione-S-transferase (GST). Fe-NTA also enhances the concentration of blood urea nitrogen (BUN) and serum creatinine as well as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) activities. Exposure to low dose gamma- irradiation (3 h after Fe-NTA administration) resulted in a significant decrease in LPx, BUN, serum creatinine contents as well as ALT, AST and GGT enzyme activities. GSH content; GST and antioxidant enzymes were also recovered to significant level. Thus, our data suggest that exposure to LDR might be a useful antioxidant mediator to suppress the Fe-NTA induced-oxidative damage in rats

  13. Protective Effect of Low Dose Gamma Irradiation against Oxidative Damage in Rats Administrated with Ferric- Nitrilotriacetate

    Mansonr, S.Z.

    2008-01-01

    Many studies have demonstrated the beneficial adaptive response of low dose gamma-irradiation. Low dose gamma-irradiation (LDR) might be effective for the prevention of various reactive oxygen species-related diseases. Ferric nitrilotriacetate (Fe-NTA) is a strong oxidant, which generates highly reactive hydroxyl radical and causes injuries of various organs including the kidney and liver. This study was designed to investigate the ability of low dose gamma-irradiation to restrain Fe-NT A induced oxidative stress. Sprague Dawley male albino rats were subjected to low dose gamma-irradiation (50 cGy). Animals were challenged with Fe-NT A (9 mg Fe/kg body weight, intraperitoneally). Results showed that Fe-NTA enhances lipid peroxidation (LPx) accompanied with reduction in glutathione (GSH) content, antioxidant enzymes, viz., glutathione peroxidase (GPX), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT) and phase-U metabolizing enzyme glutathione-S-transferase (GST). Fe-NTA also enhances the concentration of blood urea nitrogen (BUN) and serum creatinine as well as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) activities. Exposure to low dose gamma- irradiation (3 h after Fe-NTA administration) resulted in a significant decrease in LPx, BUN, serum creatinine contents as well as ALT, AST and GGT enzyme activities. GSH content; GST and antioxidant enzymes were also recovered to significant level. Thus, our data suggest that exposure to LDR might be a useful antioxidant mediator to suppress the Fe-NTA induced-oxidative damage in rats

  14. Estimation of the total effective dose from low-dose CT scans and radiopharmaceutical administrations delivered to patients undergoing SPECT/CT explorations

    Montes, C.; Hernandez, J.; Gomez-Caminero, F.; Garcia, S.; Martin, C.; Rosero, A.; Tamayo, P.

    2013-01-01

    Hybrid imaging, such as single photon emission computed tomography (SPECT)/CT, is used in routine clinical practice, allowing coregistered images of the functional and structural information provided by the two imaging modalities. However, this multimodality imaging may mean that patients are exposed to a higher radiation dose than those receiving SPECT alone. The study aimed to determine the radiation exposure of patients who had undergone SPECT/CT examinations and to relate this to the Background Equivalent Radiation Time (BERT). 145 SPECT/CT studies were used to estimate the total effective dose to patients due to both radiopharmaceutical administrations and low-dose CT scans. The CT contribution was estimated by the Dose-Length Product method. Specific conversion coefficients were calculated for SPECT explorations. The radiation dose from low-dose CTs ranged between 0.6 mSv for head and neck CT and 2.6 mSv for whole body CT scan, representing a maximum of 1 year of background radiation exposure. These values represent a decrease of 80-85% with respect to the radiation dose from diagnostic CT. The radiation exposure from radiopharmaceutical administration varied from 2.1 mSv for stress myocardial perfusion SPECT to 26 mSv for gallium SPECT in patients with lymphoma. The BERT ranged from 1 to 11 years. The contribution of low-dose CT scans to the total radiation dose to patients undergoing SPECT/CT examinations is relatively low compared with the effective dose from radiopharmaceutical administration. When a CT scan is only acquired for anatomical localization and attenuation correction, low-dose CT scan is justified on the basis of its lower dose. (author)

  15. Clinical trial: single- and multiple-dose pharmacokinetics of polyethylene glycol (PEG-3350) in healthy young and elderly subjects.

    Pelham, R W; Nix, L C; Chavira, R E; Cleveland, M Vb; Stetson, P

    2008-07-01

    The pharmacokinetics of polyethylene glycol 3350 (PEG-3350) have not been fully described because of lack of a sufficiently sensitive analytical method. To describe the pharmacokinetics of PEG-3350 in humans. A highly sensitive, high performance liquid chromatography with mass spectrometry (HPLC/MS/MS) method was developed for PEG-3350 in urine, plasma and faeces with quantification limits of 30 ng/mL, 100 ng/mL and 500 microg/g respectively. Noncompartmental pharmacokinetics methods were used and the effects of gender, age, renal status and dosing frequency were examined after the oral administration of 17 g to healthy volunteers. Peak PEG-3350 plasma concentrations occurred at 2-4 h and declined to nonquantifiable levels usually within 18 h after single and multiple doses, with a half-life of about 4-6 h. Steady state was reached within 5 days of dosing. Mean urinary excretion of the administered dose ranged from 0.19% to 0.25%. Age, gender or mild kidney impairment did not alter the pharmacokinetics of PEG-3350. Mean faecal excretion of the administered dose was 93% in young subjects. For the first time, a highly sensitive assay allowed comprehensive pharmacokinetics studies of PEG-3350 in humans. These studies confirmed that orally administered PEG-3350 is minimally absorbed, rapidly excreted and primarily eliminated via faeces.

  16. Prescription Dose Guideline Based on Physical Criterion for Multiple Metastatic Brain Tumors Treated With Stereotactic Radiosurgery

    Sahgal, Arjun; Barani, Igor J.; Novotny, Josef; Zhang Beibei; Petti, Paula; Larson, David A.; Ma Lijun

    2010-01-01

    Purpose: Existing dose guidelines for intracranial stereotactic radiosurgery (SRS) are primarily based on single-target treatment data. This study investigated dose guidelines for multiple targets treated with SRS. Methods and Materials: A physical model was developed to relate the peripheral isodose volume dependence on an increasing number of targets and prescription dose per target. The model was derived from simulated and clinical multiple brain metastatic cases treated with the Leksell Gamma Knife Perfexion at several institutions, where the total number of targets ranged from 2 to 60. The relative increase in peripheral isodose volumes, such as the 12-Gy volume, was studied in the multitarget treatment setting based on Radiation Therapy Oncology Group 90-05 study dose levels. Results: A significant increase in the 12-Gy peripheral isodose volumes was found in comparing multiple target SRS to single-target SRS. This increase strongly correlated (R 2 = 0.92) with the total number of targets but not the total target volumes (R 2 = 0.06). On the basis of the correlated curve, the 12-Gy volume for multiple target treatment was found to increase by approximately 1% per target when a low target dose such as 15 Gy was used, but approximately 4% per target when a high dose such as 20-24 Gy was used. Reduction in the prescription dose was quantified for each prescription level in maintaining the 12-Gy volume. Conclusion: Normal brain dose increases predictably with increasing number of targets for multitarget SRS. A reduction of approximately 1-2 Gy in the prescribed dose is needed compared with single target radiosurgery.

  17. Generation of Composite Dose and Biological Effective Dose (BED) Over Multiple Treatment Modalities and Multistage Planning Using Deformable Image Registration

    Zhang, Geoffrey; Huang, T-C; Feygelman, Vladimir; Stevens, Craig; Forster, Kenneth

    2010-01-01

    Currently there are no commercially available tools to generate composite plans across different treatment modalities and/or different planning image sets. Without a composite plan, it may be difficult to perform a meaningful dosimetric evaluation of the overall treatment course. In this paper, we introduce a method to generate composite biological effective dose (BED) plans over multiple radiotherapy treatment modalities and/or multistage plans, using deformable image registration. Two cases were used to demonstrate the method. Case I was prostate cancer treated with intensity-modulated radiation therapy (IMRT) and a permanent seed implant. Case II involved lung cancer treated with two treatment plans generated on two separate computed tomography image sets. Thin-plate spline or optical flow methods were used as appropriate to generate deformation matrices. The deformation matrices were then applied to the dose matrices and the resulting physical doses were converted to BED and added to yield the composite plan. Cell proliferation and sublethal repair were considered in the BED calculations. The difference in BED between normal tissues and tumor volumes was accounted for by using different BED models, α/β values, and cell potential doubling times. The method to generate composite BED plans presented in this paper provides information not available with the traditional simple dose summation or physical dose summation. With the understanding of limitations and uncertainties of the algorithms involved, it may be valuable for the overall treatment plan evaluation.

  18. Dose accumulation of multiple high dose rate prostate brachytherapy treatments in two commercially available image registration systems.

    Poder, Joel; Yuen, Johnson; Howie, Andrew; Bece, Andrej; Bucci, Joseph

    2017-11-01

    The purpose of this study was to assess whether deformable image registration (DIR) is required for dose accumulation of multiple high dose rate prostate brachytherapy (HDRPBT) plans treated with the same catheter pattern on two different CT datasets. DIR was applied to 20 HDRPBT patients' planning CT images who received two treatment fractions on sequential days, on two different CT datasets, with the same implant. Quality of DIR in Velocity and MIM image registration systems was assessed by calculating the Dice Similarity Coefficient (DSC) and mean distance to agreement (MDA) for the prostate, urethra and rectum contours. Accumulated doses from each system were then calculated using the same DIR technique and dose volume histogram (DVH) parameters compared to manual addition with no DIR. The average DSC was found to be 0.83 (Velocity) and 0.84 (MIM), 0.80 (Velocity) and 0.80 (MIM), 0.80 (Velocity) and 0.81 (MIM), for the prostate, rectum and urethra contours, respectively. The average difference in calculated DVH parameters between the two systems using dose accumulation was less than 1%, and there was no statistically significant difference found between deformably accumulated doses in the two systems versus manual DVH addition with no DIR. Contour propagation using DIR in velocity and MIM was shown to be at least equivalent to inter-observer contouring variability on CT. The results also indicate that dose accumulation through manual addition of DVH parameters may be sufficient for HDRPBT treatments treated with the same catheter pattern on two different CT datasets. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  19. Pharmacokinetics after oral and intravenous administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis).

    Souza, Marcy J; Sanchez-Migallon Guzman, David; Paul-Murphy, Joanne R; Cox, Sherry K

    2012-08-01

    To determine pharmacokinetics after IV and oral administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). 9 healthy adult Hispaniolan Amazon parrots (3 males, 5 females, and 1 of unknown sex). Tramadol (5 mg/kg, IV) was administered to the parrots. Blood samples were collected from -5 to 720 minutes after administration. After a 3-week washout period, tramadol (10 and 30 mg/kg) was orally administered to parrots. Blood samples were collected from -5 to 1,440 minutes after administration. Three formulations of oral suspension (crushed tablets in a commercially available suspension agent, crushed tablets in sterile water, and chemical-grade powder in sterile water) were evaluated. Plasma concentrations of tramadol and its major metabolites were measured via high-performance liquid chromatography. Mean plasma tramadol concentrations were > 100 ng/mL for approximately 2 to 4 hours after IV administration of tramadol. Plasma concentrations after oral administration of tramadol at a dose of 10 mg/kg were 100 ng/mL for approximately 6 hours after administration. Oral administration of the suspension consisting of the chemical-grade powder resulted in higher plasma tramadol concentrations than concentrations obtained after oral administration of the other 2 formulations; however, concentrations differed significantly only at 120 and 240 minutes after administration. Oral administration of tramadol at a dose of 30 mg/kg resulted in plasma concentrations (> 100 ng/mL) that have been associated with analgesia in Hispaniolan Amazon parrots.

  20. Dose-dependent effect of 8-day cisplatin administration upon the morphology of the albino guinea pig cochlea

    Cardinaal, RM; de Groot, JCMJ; Huizing, EH; Veldman, JE; Smoorenburg, GF

    Numerous studies investigating cisplatin ototoxicity in animals have been performed, but it is difficult to derive a clear dose-effect relation from these studies. The degree of cisplatin-induced ototoxicity depends on a multitude of,factors. Many parameters, such as dose, mode of administration,

  1. Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age.

    Hoover, Randall; Hunt, Thomas; Benedict, Michael; Paulson, Susan K; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

    2016-01-01

    The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. Delafloxacin Cmax and AUC0-∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0-∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0-∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in

  2. Acute oral administration of low doses of methylphenidate targets calretinin neurons in the rat septal area.

    Alvaro eGarcía-Aviles

    2015-03-01

    Full Text Available Methylphenidate (MPD is a commonly administered drug to treat children suffering from attention deficit hyperactivity disorder (ADHD. Alterations in septal driven hippocampal theta rhythm may underlie attention deficits observed in these patients. Amongst others, the septo-hippocampal connections have long been acknowledged to be important in preserving hippocampal function. Thus, we wanted to ascertain if methylphenidate administration, which improves attention in patients, could affect septal areas connecting with hippocampus. We used low and orally administered methylphenidate doses (1.3; 2.7 and 5mg/Kg to rats what mimics the dosage range in humans. In our model, we observed no effect when using 1.3mg/Kg methylphenidate; whereas 2.7 and 5 mg/Kg induced a significant increase in c-fos expression specifically in the medial septum, an area intimately connected to the hippocampus. We analyzed dopaminergic areas such as nucleus accumbens and striatum, and found that only 5mg/Kg induced c-fos levels increase. In these areas tyrosine hydroxylase correlated well with c-fos staining, whereas in the medial septum the sparse tyrosine hydroxylase fibres did not overlap with c-fos positive neurons. Double immunofluorescence of c-fos with neuronal markers in the septal area revealed that co-localization with choline acethyl transferase, parvalbumin, and calbindin with c-fos did not change with MPD treatment; whereas, calretinin and c-fos double labeled neurons increased after MPD administration. Altogether, these results suggest that low and acute doses of methylphenidate primary target specific populations of caltretinin medial septal neurons.

  3. Radiotherapy combined with daily administration of low dose cisplatin for head and neck cancer

    Fujita, Masahiro; Murayama, Shigeyuki; Matayoshi, Yoshinobu; Ikeda, Hiroshi; Shimizutani, Kimishige; Inoue, Toshihiko; Kozuka, Takahiro; Masaki, Norie.

    1990-01-01

    Serum concentrations of cisplatin (CDDP) and acute complications were studied in patients treated for head and neck cancer by radiotherapy combined with daily administration of low doses of CDDP (5 mg/m 2 or 6 mg/body) at Osaka University Hospital between March 1988 and December 1989. Serum concentrations of total-CDDP (6 patients) and free-CDDP (2 patients) were studied in cases injected intravenously with 5 mg/m 2 daily. Total-CDDP determined just before daily administration of CDDP was increased gradually (0.35 to 0.64 μg/ml by the 7th day, 0.42 to 0.91 μg/ml by the 14th day and 0.60 to 0.82 μg/ml by the 20th or 21st day) and still observed in the serum for more than two weeks after cessation of the chemotherapy. Serum concentrations of free-CDDP were about 0.35 μg/ml at 5 minutes and 0.15 μg/ml at 30 minutes after the intravenous injection of CDDP. Incidence of the acute complications more severe than grade 2 were nausea and vomiting: 4/52 (8%), leukopenia: 11/52 (21%) and thrombocytopenia: 4/52 (8%). Incidence of myelosuppression (leukopenia and/or thrombocytopenia) was 11/26(42%) when the total dose of CDDP exceeded 120 mg, and 3/26 (12%) when it was less than 120 mg. Transient renal dysfunction (increase of serum creatinine) of grade 1 was seen in only 3 patients. (author)

  4. Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration.

    McFadden, Lisa M; Hoonakker, Amanda J; Vieira-Brock, Paula L; Stout, Kristen A; Sawada, Nicole M; Ellis, Jonathan D; Allen, Scott C; Walters, Elliot T; Nielsen, Shannon M; Gibb, James W; Alburges, Mario E; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

    2011-08-01

    Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent [i.e., postnatal day (PND) 40] rats are less susceptible to this damage than young adult (PND90) rats. In addition, biweekly treatment with METH, beginning at PND40 and continuing throughout development, prevents the persistent dopaminergic deficits caused by a "challenge" high-dose METH regimen when administered at PND90. Mechanisms underlying this "resistance" were thus investigated. Results revealed that biweekly METH treatment throughout development attenuated both the acute and persistent deficits in VMAT2 function, as well as the acute hyperthermia, caused by a challenge METH treatment. Pharmacokinetic alterations did not appear to contribute to the protection afforded by the biweekly treatment. Maintenance of METH-induced hyperthermia abolished the protection against both the acute and persistent VMAT2-associated deficits suggesting that alterations in thermoregulation were caused by exposure of rats to METH during development. These findings suggest METH during development prevents METH-induced hyperthermia and the consequent METH-related neurotoxicity. Copyright © 2011 Wiley-Liss, Inc.

  5. Irreversible neurological worsening following high-dose corticosteroids in advanced progressive multiple sclerosis

    Koch, M; De Keyser, J

    2006-01-01

    Background: A course of high-dose corticosteroids has been shown to hasten recovery from a relapse of multiple sclerosis (MS). Some patients with progressive MS ask for a course with corticosteroids outside a relapse, hoping to gain some functional improvement. Objective: To describe 4 patients with

  6. IsoGeneGUI : Multiple approaches for dose-response analysis of microarray data using R

    Otava, Martin; Sengupta, Rudradev; Shkedy, Ziv; Lin, Dan; Pramana, Setia; Verbeke, Tobias; Haldermans, Philippe; Hothorn, Ludwig A.; Gerhard, Daniel; Kuiper, Rebecca M.; Klinglmueller, Florian; Kasim, Adetayo

    2017-01-01

    The analysis of transcriptomic experiments with ordered covariates, such as dose-response data, has become a central topic in bioinformatics, in particular in omics studies. Consequently, multiple R packages on CRAN and Bioconductor are designed to analyse microarray data from various perspectives

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

    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

  8. Low-dose multiple-information retrieval algorithm for X-ray grating-based imaging

    Wang Zhentian; Huang Zhifeng; Chen Zhiqiang; Zhang Li; Jiang Xiaolei; Kang Kejun; Yin Hongxia; Wang Zhenchang; Stampanoni, Marco

    2011-01-01

    The present work proposes a low dose information retrieval algorithm for X-ray grating-based multiple-information imaging (GB-MII) method, which can retrieve the attenuation, refraction and scattering information of samples by only three images. This algorithm aims at reducing the exposure time and the doses delivered to the sample. The multiple-information retrieval problem in GB-MII is solved by transforming a nonlinear equations set to a linear equations and adopting the nature of the trigonometric functions. The proposed algorithm is validated by experiments both on conventional X-ray source and synchrotron X-ray source, and compared with the traditional multiple-image-based retrieval algorithm. The experimental results show that our algorithm is comparable with the traditional retrieval algorithm and especially suitable for high Signal-to-Noise system.

  9. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial

    Fazekas, F.; Lublin, F.D.; Li, D.

    2008-01-01

    OBJECTIVE: Several studies have reported a reduction of relapses after the long-term administration of IV immunoglobulin (IVIG) to patients with relapsing-remitting multiple sclerosis (RRMS), but they were mostly small and differed in terms of predefined outcome variables and treatment regimen. W...

  10. Administration

    Bogen handler om den praksis, vi kalder administration. Vi er i den offentlige sektor i Danmark hos kontorfolkene med deres sagsmapper, computere, telefoner,, lovsamlinger,, retningslinier og regneark. I bogen udfoldes en mangfoldighed af konkrete historier om det administrative arbejde fra...... forskellige områder i den offentlige sektor. Hensigten er at forstå den praksis og faglighed der knytter sig til det administrative arbejde...

  11. SIGMA/B, Doses in Space Vehicle for Multiple Trajectories, Various Radiation Source

    Jordan, T.M.

    2003-01-01

    1 - Description of problem or function: SIGMA/B calculates radiation dose at arbitrary points inside a space vehicle, taking into account vehicle geometry, heterogeneous placement of equipment and stores, vehicle materials, time-weighted astronaut positions and many radiation sources from mission trajectories, e.g. geomagnetically trapped protons and electrons, solar flare particles, galactic cosmic rays and their secondary radiations. The vehicle geometry, equipment and supplies, and man models are described by quadric surfaces. The irradiating flux field may be anisotropic. The code can be used to perform simultaneous dose calculations for multiple vehicle trajectories, each involving several radiation sources. Results are presented either as dose as a function of shield thickness, or the dose received through designated outer sections of the vehicle. 2 - Method of solution: Automatic sectoring of the vehicle is performed by a Simpson's rule integration over angle; the dose is computed by a numerical angular integration of the dose attenuation kernels about the dose points. The kernels are curve-fit functions constructed from input data tables. 3 - Restrictions on the complexity of the problem: The code uses variable dimensioning techniques to store data. The only restriction on problem size is the available core storage

  12. Complications Associated With High-dose Corticosteroid Administration in Children With Spinal Cord Injury.

    Cage, Jason M; Knox, Jeffrey B; Wimberly, Robert L; Shaha, Steve; Jo, ChanHee; Riccio, Anthony I

    2015-01-01

    Complications with high-dose steroid administration for spinal cord injury are documented in adult patients. Our purpose was to determine the incidence of early complications of this therapy in pediatric patients with spinal cord injuries. An IRB-approved retrospective review was performed for patients treated for spinal cord injury at a level 1 pediatric trauma center between 2003 and 2011. Demographic data, injury characteristics, and surgical interventions were documented. Complications were divided into 4 categories: infectious, gastrointestinal (GI), hyperglycemia/endocrine, and wound healing problems. Complication rates were compared using a Student's t test and Fischer's exact test. Thirty-four spinal cord injury patients were identified. Twenty-three patients (mean age 6.6 y) in the treatment group received high-dose steroid treatment and 11 patients (mean age 8.4 y) did not and comprised the control group. No statistical difference was detected between the 2 groups regarding age, mechanism of injury, rate of surgical intervention, level of injury, and injury severity. Hyperglycemia was the most common complication and was present in all patients in both the treatment and control groups. The overall infection rate was 64% in the control group compared with 26% in the treatment (Pspinal trauma in a pediatric population. Hyperglycemia was found in all spinal cord injury patients, regardless of steroid treatment. Paradoxically, infection rates were noted to be higher in the control group. GI and wound problems were not significantly different. Larger, multicenter prospective studies are needed to better understand the risks in pediatric SCI patients.

  13. Microbial contamination of single-and multiple-dose vials after opening in a pulmonary teaching hospital

    Shadi Baniasadi

    Full Text Available OBJECTIVES: Intravenous therapy is a complex procedure usually requiring the preparation of the medication in the clinical area before administration to the patient. Breaches in aseptic technique may result in microbial contaminations of vials which is a potential cause of different avoidable infections. We aimed to investigate the prevalence and pattern of microbial contamination of single- and multiple-dose vials in the largest pulmonary teaching hospital in Iran. METHODS: In a period of 2 months, opened single- and multiple-dose vials from different wards were sampled by a pharmacist. The name of the medication, ward, labeling of the vials, the date of opening, and storing temperature were recorded for each vial. Remained contents of each vial were cultured using appropriate bacterial and fungal growth media. RESULTS: Microbial contamination was identified in 11 of 205 (5.36% of vials. The highest contamination rate was 14.28% for vials used in interventional bronchoscopy unit. The most frequent contaminated medication was insulin. Gram-positive bacteria (81.82% were more significantly involved than gram-negative ones (9.09% and fungi (9.09%, with the highest frequency for Staphylococcus epidermidis . CONCLUSIONS: Our data demonstrate that repeated use of vials especially if basic sterility measures are disobeyed can cause microbial contamination of administered products to the patients. Infection preventionists are responsible to train health care workers regarding aseptic techniques and apply guidelines for aseptic handling of intravenous solutions.

  14. Microbial contamination of single-and multiple-dose vials after opening in a pulmonary teaching hospital

    Shadi Baniasadi

    2013-02-01

    Full Text Available OBJECTIVES: Intravenous therapy is a complex procedure usually requiring the preparation of the medication in the clinical area before administration to the patient. Breaches in aseptic technique may result in microbial contaminations of vials which is a potential cause of different avoidable infections. We aimed to investigate the prevalence and pattern of microbial contamination of single- and multiple-dose vials in the largest pulmonary teaching hospital in Iran. METHODS: In a period of 2 months, opened single- and multiple-dose vials from different wards were sampled by a pharmacist. The name of the medication, ward, labeling of the vials, the date of opening, and storing temperature were recorded for each vial. Remained contents of each vial were cultured using appropriate bacterial and fungal growth media. RESULTS: Microbial contamination was identified in 11 of 205 (5.36% of vials. The highest contamination rate was 14.28% for vials used in interventional bronchoscopy unit. The most frequent contaminated medication was insulin. Gram-positive bacteria (81.82% were more significantly involved than gram-negative ones (9.09% and fungi (9.09%, with the highest frequency for Staphylococcus epidermidis . CONCLUSIONS: Our data demonstrate that repeated use of vials especially if basic sterility measures are disobeyed can cause microbial contamination of administered products to the patients. Infection preventionists are responsible to train health care workers regarding aseptic techniques and apply guidelines for aseptic handling of intravenous solutions.

  15. Pharmacokinetics of meloxicam after intravenous, intramuscular, and oral administration of a single dose to Hispaniolan Amazon parrots (Amazona ventralis).

    Molter, Christine M; Court, Michael H; Cole, Gretchen A; Gagnon, David J; Hazarika, Suwagmani; Paul-Murphy, Joanne R

    2013-03-01

    To compare pharmacokinetics after IV, IM, and oral administration of a single dose of meloxicam to Hispaniolan Amazon parrots (Amazona ventralis). 11 healthy parrots. Cohorts of 8 of the 11 birds comprised 3 experimental groups for a crossover study. Pharmacokinetics were determined from plasma concentrations measured via high-performance liquid chromatography after IV, IM, and oral administration of meloxicam at a dose of 1 mg/kg. Initial mean ± SD plasma concentration of 17.3 ± 9.0 μg/mL was measured 5 minutes after IV administration, whereas peak mean concentration was 9.3 ± 1.8 μg/mL 15 minutes after IM administration. At 12 hours after administration, mean plasma concentrations for IV (3.7 ± 2.5 μg/mL) and IM (3.5 ± 2.2 μg/mL) administration were similar. Peak mean plasma concentration (3.5 ± 1.2 μg/mL) was detected 6 hours after oral administration. Absolute systemic bioavailability of meloxicam after IM administration was 100% but was lower after oral administration (range, 49% to 75%). Elimination half-lives after IV, IM, and oral administration were similar (15.9 ± 4.4 hours, 15.1 ± 7.7 hours, and 15.8 ± 8.6 hours, respectively). Pharmacokinetic data may provide useful information for use of meloxicam in Hispaniolan Amazon parrots. A mean plasma concentration of 3.5 μg/mL would be expected to provide analgesia in Hispaniolan Amazon parrots; however, individual variation may result in some birds having low plasma meloxicam concentrations after IV, IM, or oral administration. After oral administration, meloxicam concentration slowly reached the target plasma concentration, but that concentration was not sustained in most birds.

  16. Pharmacokinetics of colistin methanesulfonate (CMS) in healthy Chinese subjects after single and multiple intravenous doses.

    Zhao, Miao; Wu, Xiao-Jie; Fan, Ya-Xin; Zhang, Ying-Yuan; Guo, Bei-Ning; Yu, Ji-Cheng; Cao, Guo-Ying; Chen, Yuan-Cheng; Wu, Ju-Fang; Shi, Yao-Guo; Li, Jian; Zhang, Jing

    2018-05-01

    The high prevalence of extensively drug-resistant Gram-negative pathogens has forced clinicians to use colistin as a last-line therapy. Knowledge on the pharmacokinetics of colistin methanesulfonate (CMS), an inactive prodrug, and colistin has increased substantially; however, the pharmacokinetics in the Chinese population is still unknown due to lack of a CMS product in China. This study aimed to evaluate the pharmacokinetics of a new CMS product developed in China in order to optimise dosing regimens. A total of 24 healthy subjects (12 female, 12 male) were enrolled in single- and multiple-dose pharmacokinetic (PK) studies. Concentrations of CMS and formed colistin in plasma and urine were measured, and PK analysis was conducted using a non-compartmental approach. Following a single CMS dose [2.36 mg colistin base activity (CBA) per kg, 1 h infusion], peak concentrations (C max ) of CMS and formed colistin were 18.0 mg/L and 0.661 mg/L, respectively. The estimated half-life (t 1/2 ) of CMS and colistin were 1.38 h and 4.49 h, respectively. Approximately 62.5% of the CMS dose was excreted via urine within 24 h after dosing, whilst only 1.28% was present in the form of colistin. Following multiple CMS doses, colistin reached steady-state within 24 h; there was no accumulation of CMS, but colistin accumulated slightly (R AUC  = 1.33). This study provides the first PK data in the Chinese population and is essential for designing CMS dosing regimens for use in Chinese hospitals. The urinary PK data strongly support the use of intravenous CMS for serious urinary tract infections. Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  17. Morning administration of oral methamphetamine dose-dependently disrupts nighttime sleep in recreational stimulant users.

    Herrmann, Evan S; Johnson, Patrick S; Bruner, Natalie R; Vandrey, Ryan; Johnson, Matthew W

    2017-09-01

    Use of amphetamine-type stimulants (e.g., methamphetamine) is associated with acute sleep disruptions. No prior reports have characterized the acute effects of methamphetamine on sleep using polysomnography, the gold standard for objective sleep monitoring. Recreational stimulant users (n=19) completed a baseline assessment, which included questionnaires assessing demographic and substance use characteristics, and the Pittsburgh Sleep Quality Index (PSQI), which assesses sleep quality over the past month. Participants were administered 0mg (placebo), 20mg, or 40mg oral methamphetamine at 08:15h on study days, using a double-blind, randomized, within-subjects design. Sleep was monitored using polysomnography from 22:20 that evening until 06:15 the following morning. PSQI scores indicated more than half of participants reported poor sleep quality at baseline. Methamphetamine dose-dependently increased sleep latency, and decreased total sleep time, sleep efficiency, time in NREM 2 sleep, number of REM periods, and total time in REM sleep. Sleep under placebo conditions was consistent with what would be expected from healthy adults. Morning oral administration of methamphetamine produces robust disruptions in nighttime sleep. Future research should examine relations between stimulant use and sleep disruption in naturalistic settings, with regard to both stimulant abuse and licit prescription use. Copyright © 2017. Published by Elsevier B.V.

  18. Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study.

    Fleming, J O; Isaak, A; Lee, J E; Luzzio, C C; Carrithers, M D; Cook, T D; Field, A S; Boland, J; Fabry, Z

    2011-06-01

    Probiotic treatment strategy based on the hygiene hypothesis, such as administration of ova from the non-pathogenic helminth, Trichuris suis, (TSO) has proven safe and effective in autoimmune inflammatory bowel disease. To study the safety and effects of TSO in a second autoimmune disease, multiple sclerosis (MS), we conducted the phase 1 Helminth-induced Immunomodulatory Therapy (HINT 1) study. Five subjects with newly diagnosed, treatment-naive relapsing-remitting multiple sclerosis (RRMS) were given 2500 TSO orally every 2 weeks for 3 months in a baseline versus treatment control exploratory trial. The mean number of new gadolinium-enhancing magnetic resonance imaging (MRI) lesions (n-Gd+) fell from 6.6 at baseline to 2.0 at the end of TSO administration, and 2 months after TSO was discontinued, the mean number of n-Gd+ rose to 5.8. No significant adverse effects were observed. In preliminary immunological investigations, increases in the serum level of the cytokines IL-4 and IL-10 were noted in four of the five subjects. TSO was well tolerated in the first human study of this novel probiotic in RRMS, and favorable trends were observed in exploratory MRI and immunological assessments. Further investigations will be required to fully explore the safety, effects, and mechanism of action of this immunomodulatory treatment.

  19. Low-dose biplanar skeletal survey versus digital skeletal survey in multiple myeloma

    Boutry, Nathalie; Dutouquet, Bastien; Cotten, Anne; Leleu, Xavier; Vieillard, Marie-Helene; Duhamel, Alain

    2013-01-01

    To evaluate the low-dose biplanar (LDB) skeletal survey (SS) for the assessment of focal bone involvement in patients with multiple myeloma (MM) as compared with digital SS and to compare the two techniques in terms of image quality, patient comfort and radiation exposure. Fifty-six consecutive patients with newly diagnosed or first relapsed MM underwent LDB and digital SS on the same day. These were assessed by two radiologists for the detection of focal bone lesions. In the case of discordance, whole-body MR imaging was performed. Image quality, patient comfort and radiation dose were also assessed. Fifty-six patients (M:30, F:26, mean age, 62 years) with newly diagnosed (n = 21) or first relapse MM (n = 35) were enrolled. A total of 473 bone lesions in 46 patients (82 %) were detected. Out of that total, digital SS detected significantly more lesions than LDB SS (451 [95.35 %] versus 467 [98.73 %]), especially in osteopenic and obese patients. Overall patient satisfaction was greater with LDB SS (48.6 %) compared with digital SS (2.7 %). The radiation dose was significantly reduced (by a factor of 7.8) with the LDB X-ray device. Low-dose biplanar skeletal surveys cannot replace digital SS in all patients suffering from multiple myeloma. (orig.)

  20. Low-dose biplanar skeletal survey versus digital skeletal survey in multiple myeloma

    Boutry, Nathalie [University Hospital of Jeanne de Flandre and University of Lille 2, Departments of Pediatric and Musculoskeletal Imaging, Lille (France); University Hospital of Jeanne de Flandre and University of Lille 2, Department of Pediatric Imaging, Lille (France); Hopital Jeanne de Flandre, Service de Radiopediatrie, Lille (France); Dutouquet, Bastien; Cotten, Anne [University Hospital of Roger Salengro and University of Lille 2, Department of Musculoskeletal Imaging, Lille (France); Leleu, Xavier [University Hospital of Claude Huriez and University of Lille 2, Clinical Hematology Department, Lille (France); Vieillard, Marie-Helene [University Hospital of Roger Salengro and University of Lille 2, Rheumatology Department, Lille (France); Duhamel, Alain [University of Lille 2, Department of Medical Statistics, Lille (France)

    2013-08-15

    To evaluate the low-dose biplanar (LDB) skeletal survey (SS) for the assessment of focal bone involvement in patients with multiple myeloma (MM) as compared with digital SS and to compare the two techniques in terms of image quality, patient comfort and radiation exposure. Fifty-six consecutive patients with newly diagnosed or first relapsed MM underwent LDB and digital SS on the same day. These were assessed by two radiologists for the detection of focal bone lesions. In the case of discordance, whole-body MR imaging was performed. Image quality, patient comfort and radiation dose were also assessed. Fifty-six patients (M:30, F:26, mean age, 62 years) with newly diagnosed (n = 21) or first relapse MM (n = 35) were enrolled. A total of 473 bone lesions in 46 patients (82 %) were detected. Out of that total, digital SS detected significantly more lesions than LDB SS (451 [95.35 %] versus 467 [98.73 %]), especially in osteopenic and obese patients. Overall patient satisfaction was greater with LDB SS (48.6 %) compared with digital SS (2.7 %). The radiation dose was significantly reduced (by a factor of 7.8) with the LDB X-ray device. Low-dose biplanar skeletal surveys cannot replace digital SS in all patients suffering from multiple myeloma. (orig.)

  1. Impact of multiple-dose versus single-dose inhaler devices on COPD patients’ persistence with long-acting β2-agonists: a dispensing database analysis

    van Boven, Job FM; van Raaij, Joost J; van der Galiën, Ruben; Postma, Maarten J; van der Molen, Thys; Dekhuijzen, PN Richard; Vegter, Stefan

    2014-01-01

    Background: With a growing availability of different devices and types of medication, additional evidence is required to assist clinicians in prescribing the optimal medication in relation to chronic obstructive pulmonary disease (COPD) patients’ persistence with long-acting β2-agonists (LABAs). Aims: To assess the impact of the type of inhaler device (multiple-dose versus single-dose inhalers) on 1-year persistence and switching patterns with LABAs. Methods: A retrospective observational cohort study was performed comparing a cohort of patients initiating multiple-dose inhalers and a cohort initiating single-dose inhalers. The study population consisted of long-acting bronchodilator naive COPD patients, initiating inhalation therapy with mono-LABAs (formoterol, indacaterol or salmeterol). Analyses were performed using pharmacy dispensing data from 1994 to 2012, obtained from the IADB.nl database. Study outcomes were 1-year persistence and switching patterns. Results were adjusted for initial prescriber, initial medication, dosing regimen and relevant comorbidities. Results: In all, 575 patients initiating LABAs were included in the final study cohort. Among them, 475 (83%) initiated a multiple-dose inhaler and 100 (17%) a single-dose inhaler. Further, 269 (47%) initiated formoterol, 9 (2%) indacaterol and 297 (52%) salmeterol. There was no significant difference in persistence between users of multiple-dose or single-dose inhalers (hazard ratio: 0.98, 95% confidence interval: 0.76–1.26, P=0.99). Over 80% re-started or switched medication. Conclusions: There seems no impact of inhaler device (multiple-dose versus single-dose inhalers) on COPD patients’ persistence with LABAs. Over 80% of patients who initially seemed to discontinue LABAs, re-started their initial medication or switched inhalers or medication within 1 year. PMID:25274453

  2. Multiple local minima in IMRT optimization based on dose-volume criteria

    Wu Qiuwen; Mohan, Radhe

    2002-01-01

    Multiple local minima traps are known to exist in dose-volume and dose-response objective functions. Nevertheless, their presence and consequences are not considered impediments in finding satisfactory solutions in routine optimization of IMRT plans using gradient methods. However, there is often a concern that a significantly superior solution may exist unbeknownst to the planner and that the optimization process may not be able to reach it. We have investigated the soundness of the assumption that the presence of multiple minima traps can be ignored. To find local minima, we start the optimization process a large number of times with random initial intensities. We investigated whether the occurrence of local minima depends upon the choice of the objective function parameters and the number of variables and whether their existence is an impediment in finding a satisfactory solution. To learn about the behavior of multiple minima, we first used a symmetric cubic phantom containing a cubic target and an organ-at-risk surrounding it to optimize the beam weights of two pairs of parallel-opposed beams using a gradient technique. The phantom studies also served to test our software. Objective function parameters were chosen to ensure that multiple minima would exist. Data for 500 plans, optimized with random initial beam weights, were analyzed. The search process did succeed in finding the local minima and showed that the number of minima depends on the parameters of the objective functions. It was also found that the consequences of local minima depended on the number of beams. We further searched for the multiple minima in intensity-modulated treatment plans for a head-and-neck case and a lung case. In addition to the treatment plan scores and the dose-volume histograms, we examined the dose distributions and intensity patterns. We did not find any evidence that multiple local minima affect the outcome of optimization using gradient techniques in any clinically

  3. Development of a Monte Carlo multiple source model for inclusion in a dose calculation auditing tool.

    Faught, Austin M; Davidson, Scott E; Fontenot, Jonas; Kry, Stephen F; Etzel, Carol; Ibbott, Geoffrey S; Followill, David S

    2017-09-01

    The Imaging and Radiation Oncology Core Houston (IROC-H) (formerly the Radiological Physics Center) has reported varying levels of agreement in their anthropomorphic phantom audits. There is reason to believe one source of error in this observed disagreement is the accuracy of the dose calculation algorithms and heterogeneity corrections used. To audit this component of the radiotherapy treatment process, an independent dose calculation tool is needed. Monte Carlo multiple source models for Elekta 6 MV and 10 MV therapeutic x-ray beams were commissioned based on measurement of central axis depth dose data for a 10 × 10 cm 2 field size and dose profiles for a 40 × 40 cm 2 field size. The models were validated against open field measurements consisting of depth dose data and dose profiles for field sizes ranging from 3 × 3 cm 2 to 30 × 30 cm 2 . The models were then benchmarked against measurements in IROC-H's anthropomorphic head and neck and lung phantoms. Validation results showed 97.9% and 96.8% of depth dose data passed a ±2% Van Dyk criterion for 6 MV and 10 MV models respectively. Dose profile comparisons showed an average agreement using a ±2%/2 mm criterion of 98.0% and 99.0% for 6 MV and 10 MV models respectively. Phantom plan comparisons were evaluated using ±3%/2 mm gamma criterion, and averaged passing rates between Monte Carlo and measurements were 87.4% and 89.9% for 6 MV and 10 MV models respectively. Accurate multiple source models for Elekta 6 MV and 10 MV x-ray beams have been developed for inclusion in an independent dose calculation tool for use in clinical trial audits. © 2017 American Association of Physicists in Medicine.

  4. Pharmacokinetic interaction of enrofloxacin/trimethoprim combination following single-dose intraperitoneal and oral administration in rats.

    Choi, Myung-Jin; Yohannes, Sileshi Belew; Lee, Seung-Jin; Damte, Dereje; Kim, Jong-Choon; Suh, Joo-Won; Park, Seung-Chun

    2014-03-01

    The pharmacokinetic interaction of enrofloxacin and trimethoprim was evaluated after single-dose intraperitoneal or oral co-administration in rats. Plasma concentrations of the two drugs were determined by high-performance liquid chromatography. Following intraperitoneal combination, a significant (P trimethoprim, respectively. There was a significant (P trimethoprim. Further study is recommended in other species of animals.

  5. Immunogenicity and safety of low dose virosomal adjuvanted influenza vaccine administered intradermally compared to intramuscular full dose administration

    Künzi, Valérie; Klap, Jaco M.; Seiberling, Michael K.; Herzog, Christian; Hartmann, Katharina; Kürsteiner, Oliver; Kompier, Ronald; Grimaldi, Roberto; Goudsmit, Jaap

    2009-01-01

    BACKGROUND: Despite the established benefit of intramuscular (i.m.) influenza vaccination, new adjuvants and delivery methods for comparable or improved immunogenicity are being explored. Intradermal (i.d.) antigen administration is hypothesized to initiate an efficient immune response at reduced

  6. Lack of dose dependent kinetics of methyl salicylate-2-O-β-D-lactoside in rhesus monkeys after oral administration.

    He, Yangyang; Yan, Yu; Zhang, Tiantai; Ma, Yinzhong; Zhang, Wen; Wu, Ping; Song, Junke; Wang, Shuang; Du, Guanhua

    2015-04-22

    Methyl salicylate-2-O-β-d-lactoside (MSL) is one of the main active components isolated from Gaultheria yunnanensis, which is a traditional Chinese medicine used to treat arthritis and various aches and pains. Pharmacological researches showed that MSL had various effective activities in both in vivo and in vitro experiments. However, the pharmacokinetics features and oral bioavailability of MSL in primates were not studied up to now. To study the pharmacokinetics of different doses of MSL in rhesus monkeys and investigate the absolute bioavailability of MSL after oral administration. Male and female rhesus monkeys were either orally administrated with MSL 200, 400 and 800 mg/kg or received an intravenous dose of 20mg/kg randomly. The levels of MSL and salicylic acid (SA) in plasma were simultaneous measured by a simple, sensitive and reproducible high performance liquid chromatography method. Mean peak plasma concentration values for groups treated with 200, 400 and 800 mg/kg doses ranged from 48.79 to 171.83 μg/mL after single-dose oral administration of MSL, and mean area under the concentration-time curve values ranged from 195.16 to 1107.76 μg/mL h. Poor linearity of the kinetics of SA after oral administration of MSL was observed in the regression analysis of the Cmax-dose plot (r(2)=0.812), CL-dose plot (r(2)=0.225) and AUC(0-t)-dose plot (r(2)=0.938). Absolute bioavailability of MSL was assessed to be 118.89 ± 57.50, 213.54 ± 58.98 and 168.72 ± 76.58%, respectively. Bioavailability of MSL after oral administration in rhesus monkeys was measured for the first time. Pharmacokinetics parameters did not appear to be dose proportional among the three oral doses of treatments, and MSL showed an apparent absolute bioavailability in excess of 100% in rhesus monkeys based on the present study. In addition, a rapid, sensitive and reliable HPLC method was established and demonstrated for the research of traditional Chinese medicine in this study. Copyright

  7. Administration of a luteolytic dose of PGF2α at the time of AI

    G. Neglia

    2010-02-01

    Full Text Available The aim of this study was to verify if the administration of a luteolytic dose of PGF2α at the time of AI is able to anticipate ovulation and, hence, to increase fertility rate. Furthermore, the presence of a “farm effect” was also evaluated. The trial was performed in two commercial farms (A and B located in Caserta on 584 buffaloes (Farm A: n=389; Farm B: n=195, synchronized by the Ovsynch-TAI Program. In each farm buffaloes were divided in two groups: treated group (n=181 and n=95, respectively in farms A and B received an intramuscular injection of 0.524 mg cloprostenol (Estrumate®, Schering-Plough Animal health, S.p.A., Milan, Italy at the time of AI while control group (n=208 and n=100 received an intramuscular injection of physiologic saline (0.9% NaCl. No differences were present with regard to the number of AI/subject, in terms of pregnancy rate and ovulation rate between treated and control groups. It is worth pointing out that the control group in farm A showed a higher (P<0.01 conception rate compared to the control group in farm B (46.15 vs. 30.00. Furthermore, within farm B buffaloes treated by cloprostenol on the day of AI showed higher (P<0.01 pregnancy rate vs. animals that received saline (51.58% vs. 30.00%. These results suggest that if fertility in control group is high, treatment by cloprostenol does not affect pregnancy rate and ovulation rate.

  8. Estimation of absorbed doses in humans due to intravenous administration of fluorine-18-fluorodeoxyglucose in PET studies

    Mejia, A.A.; Nakamura, T.; Masatoshi, I.; Hatazawa, J.; Masaki, M.; Watanuki, S.

    1991-01-01

    Radiation absorbed doses due to intravenous administration of fluorine-18-fluorodeoxyglucose in positron emission tomography (PET) studies were estimated in normal volunteers. The time-activity curves were obtained for seven human organs (brain, heart, kidney, liver, lung, pancreas, and spleen) by using dynamic PET scans and for bladder content by using a single detector. These time-activity curves were used for the calculation of the cumulative activity in these organs. Absorbed doses were calculated by the MIRD method using the absorbed dose per unit of cumulated activity, 'S' value, transformed for the Japanese physique and the organ masses of the Japanese reference man. The bladder wall and the heart were the organs receiving higher doses of 1.2 x 10(-1) and 4.5 x 10(-2) mGy/MBq, respectively. The brain received a dose of 2.9 x 10(-2) mGy/MBq, and other organs received doses between 1.0 x 10(-2) and 3.0 x 10(-2) mGy/MBq. The effective dose equivalent was estimated to be 2.4 x 10(-2) mSv/MBq. These results were comparable to values of absorbed doses reported by other authors on the radiation dosimetry of this radiopharmaceutical

  9. Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

    Kirsch Lee E

    2009-12-01

    Full Text Available Abstract Background The population pharmacokinetics of artesunate (AS and its active metabolite dihydroartemisinin (DHA were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR or as a monotherapy with or without food. Methods Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability parameter estimates. Results A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka of 3.85 h-1. The population estimates of apparent clearance (CL/F and volume of distribution (V2/F for AS were 1190 L/h with 36.2% inter-individual variability (IIV and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F and central volume of distribution (V3/F were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F and peripheral volume of distribution (V4/F for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in

  10. Gamma dose estimation to the gastric wall after administration of a capsule containing a large dose of /sup 131/I

    Oyamada, H; Fukukita, H; Kawai, H; Nagaiwa, K [National Cancer Center, Tokyo (Japan); Kawachi, K

    1980-05-01

    Gamma dose to the gastric wall from a capsule containing 1.85 GBq (50 mCi) of /sup 131/I was estimated in 6 patients who had received total thyroidectomy for thyroid carcinoma some years before. The tests were done with a 37 MBq (1 mCi) capsule each in 5 patients and with a 185 MBq (5 mCi) capsule in one patient. All the patients were requested to fast in the morning. The capsule was given with a glass of water (200 ml). Then, the patient kept supine position under the scintillation camera for a period of one hour except one patient on whom the test was suspended at 30 minutes because of early clearance of the radioactivity from the stomach. In one of 5 patients who were tested for a period of one hour, serial scinticamera images showed almost no movement and minimum dissolution of the capsule. The remaining 4 patients showed slight to moderate movements of the capsules with a variety of dissolution speeds. Data processing were done by Scintipac-1200. The estimated doses at the distance of 0.5 cm from the source were 3.820, 2.074, 1.445, 1.154 and 1.462 grays (382.0, 207.4, 144.5, 115.4 and 146.2 rads) per initial one hour and 375 mGy (37.5 rad) per initial 30 minutes, respectively. From these data, it is thought to be wise to advise the patient to rotate or shake the body on bed occasionally after swallowing the capsules containing a large dose of /sup 131/I for the treatment of thyroid cancer. It is also desirable to recommend the patient to walk around even though the controlled patient's room is small. Additional water may be also meaningful to avoid unnecessary irradiation to the gastric wall.

  11. Systemic effects of low-dose dopamine during administration of cytarabine.

    Connelly, James; Benani, Dina J; Newman, Matthew; Burton, Bradley; Crow, Jessica; Levis, Mark

    2017-09-01

    Purpose Low-dose dopamine has been utilized to improve renal blood flow, urine output, and reduce drug-induced nephrotoxicity. The purpose of this study was to assess changes in renal function, cardiovascular adverse events, and neurologic toxicity in patients receiving cytarabine with or without low-dose dopamine. Methods A retrospective, single-center, cohort study of patients receiving cytarabine at 667 mg/m 2 /dose or greater, with or without dopamine at ≤5 mcg/kg/min. Cohorts were based upon initiation or absence of low-dose dopamine; cytarabine only, cytarabine + pre- and day of low-dose dopamine, and cytarabine + post-low-dose dopamine. Renal outcomes (urine output, serum creatinine, and creatinine clearance) were compared with baseline and between cohorts. Safety endpoints (arrhythmias, tachycardia, and neurotoxicity) were compared between cohorts based on low-dose dopamine exposure. Results There was no difference in urine output from baseline in all cohorts. Comparing cytarabine only and pre- and day of low-dose dopamine cohorts, there was no difference in urine output. In those receiving low-dose dopamine, there was no difference in serum creatinine and creatinine clearance from baseline. No arrhythmias were documented during the study period, and there was no difference in the incidence of tachycardia between groups (P = 0.66). Neurotoxicity was reported in three patients who were on low-dose dopamine. Conclusion Though variation existed in individual patients administered low-dose dopamine, the use of low-dose dopamine did not significantly impact renal function in this small sample at a single institution. In addition, low-dose dopamine did not negatively impact cardiovascular function.

  12. The effective dose and pattern of soybean extract administration to regulate body weight of laboratory rats

    Meilinah Hidayat

    2016-07-01

    the intake of protein and suppress appetite for short-term. Detam 1 variety is a high-quality soybean according to the Minister of Agriculture of Indonesia. Soybean protein extract Detam 1 by Deak method contains high levels of β conglycinin. The purpose of this study was to determine the effective dose of protein extract Detam 1 soybean Deak Method (PEDSDM in reducing food intake, regulate body weight, and plasma CCK level for 14 and 28 days at various dosage and pattern of treatment on male Wistar rats. Methods: There were eleven groups of treatment (n = 3, administrated with extracts at 5 mg/1x/day, 10 mg/1x/day, 20 mg/1x/day, 2.5 mg/2x/day, 5 mg/2x/day, 10 mg/2x/day and 1.7mg/3x/day, 3.4mg/3x/day, 6.7 mg/3x/day, negative control group (distilled water and positive control group (Sibutramine. Food intake (g, weight loss (g and measurement of plasma Cholecystokinin levels by ELISA (ng /ml Results: The results showed that the highest percentage decrease in food intake is: group 3.4mg /3x/ day (p <0.05, inhibition weight gain for 14 days: group 10 mg /1x/ day, for 28 days: group 1.7 mg/3x/day (p <0.05, increased plasma Cholecystokinin levels: group 20 mg /1x/day (p <0.05. Conclusions: The effective dose and pattern administrating the rats for 14 days is extract of 10 mg once a day in the morning, for 28 days is 1.7 mg three times a day. (Health Science Journal of Indonesia 2016;7:17-26 Keywords: Soybean var Detam 1 -effective dose - body weight - Cholecystokinin 

  13. Ocular Pharmacokinetics of Dorzolamide and Brinzolamide After Single and Multiple Topical Dosing: Implications for Effects on Ocular Blood FlowS⃞

    Kadam, Rajendra S.; Jadhav, Gajanan; Ogidigben, Miller

    2011-01-01

    Ophthalmic carbonic anhydrase inhibitors have been shown to improve retinal and optic nerve blood flow. However, the relative tissue distributions of commercially available carbonic anhydrase inhibitors to the optic nerve are not known. The objective of this study was to compare the ocular pharmacokinetics and tissue distribution profiles of dorzolamide and brinzolamide after single and multiple topical applications. Pigmented rabbits were treated with single or multiple topical administrations of 30 μl of Trusopt (dorzolamide hydrochloride ophthalmic solution, 2%) to one eye and 30 μl of Azopt (brinzolamide ophthalmic suspension, 1%) to the other eye. Rabbits were euthanized at 10 predetermined time intervals over a period of 24 h, and ocular tissues and plasma samples were collected. For multiple dosing, rabbits were dosed twice per day with an 8-h interval between two doses, groups of rabbits were euthanized at 7, 14, and 21 days at 1 h after the last dose, and ocular tissues and plasma samples were collected. Drug levels in tissue samples were measured using liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters (Cmax, Tmax, and AUC0–24) were estimated by noncompartmental analysis. After a single dose, dorzolamide delivery (AUC0–24) to the aqueous humor, anterior sclera, posterior sclera, anterior retina, posterior retina, anterior vitreous, and optic nerve was 2-, 7-, 2.6-, 1.4-, 1.9-, 1.2-, and 9-fold higher than those of brinzolamide. Cmax was 2- to 5-fold higher for dorzolamide than that of brinzolamide in all of the ocular tissue. After multiple dosing, dorzolamide levels in the aqueous humor, sclera, retina, vitreous humor, and optic nerve were higher than those of brinzolamide, but statistical significance was achieved only with aqueous humor, vitreous humor, and optic nerve. Dorzolamide levels in the aqueous humor, anterior vitreous, posterior vitreous, and optic nerve were 1.4- to 3.2-, 2.4- to 2.7-, 2.2- to 4.5-, and 2.4- to

  14. The route of administration (oral vs intravenous) does not influence dose or outcome in Graves' disease and unifocal autonomy

    Schneider, Peter; Biko, Johannes; Haenscheid, Heribert; Hilliger, Stephan; Koutsampelas, Christos; Kranzfelder, Michael; Ladner, Stephan; Reiners, Christoph

    2005-01-01

    In a prospective randomised study, we investigated the influence of the route of administration of radioiodide on dosimetry and therapy outcome. Fifty-four patients suffering from Graves' disease (GD) and 60 patients with unifocal autonomy (UA) participated in the study and were randomly treated with either orally or intravenously administered radioiodide. Pretherapeutic dosimetry was based on single uptake measurements with a calibrated uptake probe system. The radioiodine kinetics during hospitalisation was assessed by daily bedside uptake measurements. Therapeutic dose was determined by half-life and thyroid uptake at the time of discharge using the same uptake probe as for the radioiodine test. No improvement in accuracy of dosimetry was achieved when radioiodide was administered intravenously. Mean therapeutic doses were identical following intravenous or oral administration. Variation in the achieved dose was slightly higher in the patients receiving oral administration, this being attributable to larger deviations in discrete activities of the capsules administered as compared with the values determined by dosimetry. No differences according to treatment modality were found with regard to therapeutic outcome. Eighty-seven patients attended 6-month follow-up after therapy. In the UA group, successful treatment, defined as a normal or elevated TSH level, was observed in 94% of patients after oral administration and in 80% after intravenous administration; corresponding figures in the GD group were 68% and 65%. The causes of individual differences between targeted and therapeutically achieved doses remain undetermined. Variations in the bioavailability of radioiodide or other parameters affecting thyroid status may be involved, and further investigations are needed to clarify this. (orig.)

  15. Bayesian models and meta analysis for multiple tissue gene expression data following corticosteroid administration

    Kelemen Arpad

    2008-08-01

    Full Text Available Abstract Background This paper addresses key biological problems and statistical issues in the analysis of large gene expression data sets that describe systemic temporal response cascades to therapeutic doses in multiple tissues such as liver, skeletal muscle, and kidney from the same animals. Affymetrix time course gene expression data U34A are obtained from three different tissues including kidney, liver and muscle. Our goal is not only to find the concordance of gene in different tissues, identify the common differentially expressed genes over time and also examine the reproducibility of the findings by integrating the results through meta analysis from multiple tissues in order to gain a significant increase in the power of detecting differentially expressed genes over time and to find the differential differences of three tissues responding to the drug. Results and conclusion Bayesian categorical model for estimating the proportion of the 'call' are used for pre-screening genes. Hierarchical Bayesian Mixture Model is further developed for the identifications of differentially expressed genes across time and dynamic clusters. Deviance information criterion is applied to determine the number of components for model comparisons and selections. Bayesian mixture model produces the gene-specific posterior probability of differential/non-differential expression and the 95% credible interval, which is the basis for our further Bayesian meta-inference. Meta-analysis is performed in order to identify commonly expressed genes from multiple tissues that may serve as ideal targets for novel treatment strategies and to integrate the results across separate studies. We have found the common expressed genes in the three tissues. However, the up/down/no regulations of these common genes are different at different time points. Moreover, the most differentially expressed genes were found in the liver, then in kidney, and then in muscle.

  16. Impact of benzodiazepines on brain FDG-PET quantification after single-dose and chronic administration in rats

    Silva-Rodríguez, Jesús; García-Varela, Lara; López-Arias, Esteban; Domínguez-Prado, Inés; Cortés, Julia; Pardo-Montero, Juan; Fernández-Ferreiro, Anxo

    2016-01-01

    Introduction: Current guidelines for brain PET imaging advice against the injection of diazepam prior to brain FDG-PET examination in order to avoid possible interactions of benzodiazepines with the radiotracer uptake. Nevertheless, many patients undergoing PET studies are likely to be under chronic treatment with benzodiazepines, for example due to the use of different medications such as sleeping pills. Animal studies may provide an extensive and accurate estimation of the effect of benzodiazepines on brain metabolism in a well-defined and controlled framework. Aim: This study aims at evaluating the impact of benzodiazepines on brain FDG uptake after single-dose administration and chronic treatment in rats. Methods: Twelve Sprague–Dawley healthy rats were randomly divided into two groups, one treated with diazepam and the other used as control group. Both groups underwent PET/CT examinations after single-dose and chronic administration of diazepam (treated) or saline (controls) during twenty-eight days. Different atlas-based quantification methods were used to explore differences on the total uptake and uptake patterns of FDG between both groups. Results: Our analysis revealed a significant reduction of global FDG uptake after acute (−16.2%) and chronic (−23.2%) administration of diazepam. Moreover, a strong trend pointing to differences between acute and chronic administrations (p < 0.08) was also observed. Uptake levels returned to normal after interrupting the administration of diazepam. On the other hand, patterns of FDG uptake were not affected by the administration of diazepam. Conclusions: The administration of diazepam causes a progressive decrease of the FDG global uptake in the rat brain, but it does not change local patterns within the brain. Under these conditions, visual assessment and quantification methods based on regional differences such as asymmetry indexes or SPM statistical analysis would still be valid when administrating this

  17. Dose rate effect on micronuclei induction in human blood lymphocytes exposed to single pulse and multiple pulses of electrons.

    Acharya, Santhosh; Bhat, N N; Joseph, Praveen; Sanjeev, Ganesh; Sreedevi, B; Narayana, Y

    2011-05-01

    The effects of single pulses and multiple pulses of 7 MV electrons on micronuclei (MN) induction in cytokinesis-blocked human peripheral blood lymphocytes (PBLs) were investigated over a wide range of dose rates per pulse (instantaneous dose rate). PBLs were exposed to graded doses of 2, 3, 4, 6, and 8 Gy of single electron pulses of varying pulse widths at different dose rates per pulse, ranging from 1 × 10(6) Gy s(-1) to 3.2 × 10(8) Gy s(-1). Different dose rates per pulse were achieved by changing the dose per electron pulse by adjusting the beam current and pulse width. MN yields per unit absorbed dose after irradiation with single electron pulses were compared with those of multiple pulses of electrons. A significant decrease in the MN yield with increasing dose rates per pulse was observed, when dose was delivered by a single electron pulse. However, no reduction in the MN yield was observed when dose was delivered by multiple pulses of electrons. The decrease in the yield at high dose rates per pulse suggests possible radical recombination, which leads to decreased biological damage. Cellular response to the presence of very large numbers of chromosomal breaks may also alter the damage.

  18. Recommendations for the use of methotrexate in rheumatoid arthritis: up and down scaling of the dose and administration routes.

    Tornero Molina, Jesús; Ballina García, Francisco Javier; Calvo Alén, Jaime; Caracuel Ruiz, Miguel Ángel; Carbonell Abelló, Jordi; López Meseguer, Antonio; Moreno Muelas, José Vicente; Pérez Sandoval, Trinidad; Quijada Carrera, Jesús; Trenor Larraz, Pilar; Zea Mendoza, Antonio

    2015-01-01

    To describe the optimal therapeutic strategy for use of methotrexate in RA patients over the initial dose, route of administration, dose increase and decrease, patient monitoring, and use of folic/folinic acid. Eleven clinical experts proposed some questions to be solved. A systematic literature search was conducted. The contents were selected in a work session and subsequently validated via email to establish the level of agreement. The initial dose of methotrexate should not be 20mg/week), patient preference, very active disease or to avoid administration errors. Changing to a parenteral administration is proposed when the oral route is not effective enough, gastrointestinal toxicity appears, there is non-compliance or due to cost-effectiveness reasons before using more expensive drugs. On the contrary, due to patient preferences, intolerance to injections, dose reduction <7.5mg/week, non effectiveness of the route, poor compliance or gastrointestinal side effects. There should be a rapid dose escalation if inadequate responses occurr up to 15-20 or even 25mg/week in about 8 weeks, with increments of 2.5-5mg. The reduction will be carried out according to the dose the patient had, with decreases of 2.5-5mg every 3-6 months. Patient monitoring should be performed every 1-1.5 months until stability and then every 1-3 months. This document pretends to solve some common clinical questions and facilitate decision-making in RA patients treated with methotrexate. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  19. High-dose therapy improved the bone remodelling compartment canopy and bone formation in multiple myeloma

    Hinge, Maja; Delaissé, Jean-Marie; Plesner, Torben

    2015-01-01

    transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed......Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling....... Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell...

  20. Blind method of clustering for the evaluation of the dose received by personnel in two methods of administration of radiopharmaceuticals

    VerdeVelasco, J. M.; Gonzalez Gonzalez, M.; Montes Fuentes, C.; Verde Velasco, J.; Gonzalez Blanco, F. J.; Ramos Pacho, J. A.

    2013-01-01

    The difficulty for the injection of drugs marked with radioactive isotopes while syringe is located within the lead protector does that in many cases staff do it chooses to use the syringe outside the lead protector, increasing therefore the dose of radiation received. In our service raises the possibility of using a different methodology, channeling a pathway through a catheter, which allows administer, in all cases, with the syringe within the lead guard. We will check if significant differences can be seen both in the dose absorbed by the staff as in the time it takes to perform the administration of the drug using the method proposed compared injection without guard. (Author)

  1. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis

    Hoekstra, Monique; Haagsma, C.; Neef, C; Proost, Johannes H; Knuif, A.; van der Laar, M.

    Objective. To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA). Methods. A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (greater than or equal to25 mg weekly). Separated by 2 weeks,

  2. Pharmacokinetic study of atorvastain after single dose administration among pakistani population

    Maqsood, I.; Najmi, M. H.; Mazhar, W.; Janjua, A.; Tayyaba, B.; Sabah, S.; Bader, Z.

    2017-01-01

    Objective: To obtain pharmacokinetic data of Orvastin, a newly launched formulation of atorvastatin, in healthy males of Pakistan. Study Design: It was quasi-experimental design. Place and Duration of Study: Study was conducted at Centre for Research in Experimental and Applied Medicine (CREAM) Army Medical College, Rawalpindi and duration of study was about ten months. Material and Methods: Twenty-four healthy male subjects were taken conveniently from Pakistani population. Two tablets of Orvastin, each containing atorvastatin 40mg, were administered orally as a single dose. Multiple blood samples were taken with small gaps in between up to the period of 48hrs. High Performance Liquid Chromatography (HPLC) with UV-detector was used for quantification of atorvastatin in plasma; wavelength of UV-detector was adjusted at 247nm. Mobile phase was made up of 60 percent acetonitrile and 40 percent 0.05M sodium phosphate buffer. Flow rate of mobile phase was maintained at 1.5ml/min with 5.5 pH. Progesterone was used as an internal standard. Stock solutions of atorvastatin were made by dissolving it into methanol and acetonitrile was used for making stock solution of progesterone. Calibration curves were made for atorvastatin and internal standard from oncentration time data, values for time to achieve maximum plasma concentration. (Tmax) and maximum plasma concentration (Cmax) were directly calculated. Computer program (APO, MW PHARM, and Ver. 3.60) was used for calculation of pharmacokinetic profile of atorvastatin. Results: Atorvastatin was detected in plasma samples of all volunteers. The absorption rate constant (Ka) was 0.41 l/hr. Cmax was 26.69 ± 6.67 µg/l and Tmax was 3.33 ± 0.41 hrs. Apparent volume of distribution (Vd), of atorvastatin, was 3244.84 ± 1237.36 liters. The elimination rate constant was 0.15 l/hr. Elimination half-life of atorvastatin was 6.14 hours. Trapezoidal rule was used for calculation of AUC /sub 0-48/ and AUC /sub 0-∞/ and it was found

  3. 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

    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...

  4. Guaifenesin Pharmacokinetics Following Single‐Dose Oral Administration in Children Aged 2 to 17 Years

    Thompson, Gary A.; Solomon, Gail; Albrecht, Helmut H.; Reitberg, Donald P.

    2016-01-01

    Abstract This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age‐based doses of 100‐400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography‐tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo) and terminal volume of distribution (Vz/F) increased with age. Due to a larger increase in Vz/F than CLo, an increase in terminal exponential half‐life was also observed. Allometric scaling indicated no maturation‐related changes in CLo and Vz/F. PMID:26632082

  5. The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders.

    Patten, Denise K; Schultz, Bob G; Berlau, Daniel J

    2018-03-01

    Chronic inflammatory diseases are complex to treat and have an impact on a large number of patients. Due to the difficulty of treating these diseases and the great impact on quality of life, patients often seek off-label, complimentary, or alternative medicines to gain relief from symptoms. Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia, and other diseases. Naltrexone is a mu-opioid receptor antagonist indicated by the U.S. Food and Drug Administration for opioid and alcohol dependence. It is hypothesized that lower than standard doses of naltrexone inhibit cellular proliferation of T and B cells and block Toll-like receptor 4, resulting in an analgesic and antiinflammatory effect. It is the purpose of this review to examine the evidence of the safety, tolerability, and efficacy of low-dose naltrexone for use in chronic pain and inflammatory conditions. Currently, evidence supports the safety and tolerability of low-dose naltrexone in multiple sclerosis, fibromyalgia, and Crohn's disease. Fewer studies support the efficacy of low-dose naltrexone, with most of these focusing on subjective measures such as quality of life or self-reported pain. These studies do demonstrate that low-dose naltrexone has subjective benefits over placebo, but evidence for more objective measures is limited. However, further randomized controlled trials are needed to determine the efficacy of low-dose naltrexone due to insufficient evidence supporting its use in these disease states. This review provides practitioners with the extent of low-dose naltrexone evidence so that they can be cognizant of situations where it may not be the most appropriate therapy. © 2018 Pharmacotherapy Publications, Inc.

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

    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.

  7. Computed tomography in multiple trauma patients. Technical aspects, work flow, and dose reduction

    Fellner, F.A.; Krieger, J.; Floery, D.; Lechner, N.

    2014-01-01

    Patients with severe, life-threatening trauma require a fast and accurate clinical and imaging diagnostic workup during the first phase of trauma management. Early whole-body computed tomography has clearly been proven to be the current standard of care of these patients. A similar imaging quality can be achieved in the multiple trauma setting compared with routine imaging especially using rapid, latest generation computed tomography (CT) scanners. This article encompasses a detailed view on the use of CT in patients with life-threatening trauma. A special focus is placed on radiological procedures in trauma units and on the methods for CT workup in routine cases and in challenging situations. Another focus discusses the potential of dose reduction of CT scans in multiple trauma as well as the examination of children with severe trauma. Various studies have demonstrated that early whole-body CT positively correlates with low morbidity and mortality and is clearly superior to the use of other imaging modalities. Optimal trauma unit management means a close cooperation between trauma surgeons, anesthesiologists and radiologists, whereby the radiologist is responsible for a rapid and accurate radiological workup and the rapid communication of imaging findings. However, even in the trauma setting, aspects of patient radiation doses should be kept in mind. (orig.) [de

  8. Dose-specific transcriptional responses in thyroid tissue in mice after 131I administration

    Rudqvist, Nils; Schüler, Emil; Parris, Toshima Z.; Langen, Britta; Helou, Khalil; Forssell-Aronsson, Eva

    2015-01-01

    Introduction: In the present investigation, microarray analysis was used to monitor transcriptional activity in thyroids in mice 24 h after 131 I exposure. The aims of this study were to 1) assess the transcriptional patterns associated with 131 I exposure in normal mouse thyroid tissue and 2) propose biomarkers for 131 I exposure of the thyroid. Methods: Adult BALB/c nude mice were i.v. injected with 13, 130 or 260 kBq of 131 I and killed 24 h after injection (absorbed dose to thyroid: 0.85, 8.5, or 17 Gy). Mock-treated mice were used as controls. Total RNA was extracted from thyroids and processed using the Illumina platform. Results: In total, 497, 546, and 90 transcripts were regulated (fold change ≥ 1.5) in the thyroid after 0.85, 8.5, and 17 Gy, respectively. These were involved in several biological functions, e.g. oxygen access, inflammation and immune response, and apoptosis/anti-apoptosis. Approximately 50% of the involved transcripts at each absorbed dose level were dose-specific, and 18 transcripts were commonly detected at all absorbed dose levels. The Agpat9, Plau, Prf1, and S100a8 gene expression displayed a monotone decrease in regulation with absorbed dose, and further studies need to be performed to evaluate if they may be useful as dose-related biomarkers for 131I exposure. Conclusion: Distinct and substantial differences in gene expression and affected biological functions were detected at the different absorbed dose levels. The transcriptional profiles were specific for the different absorbed dose levels. We propose that the Agpat9, Plau, Prf1, and S100a8 genes might be novel potential absorbed dose-related biomarkers to 131 I exposure of thyroid. Advances in knowledge: During the recent years, genomic techniques have been developed; however, they have not been fully utilized in nuclear medicine and radiation biology. We have used RNA microarrays to investigate genome-wide transcriptional regulations in thyroid tissue in mice after low

  9. Sodium fusidate ameliorates the course of diabetes induced in mice by multiple low doses of streptozotocin

    Nicoletti, F; Di Marco, R; Conget, I

    2000-01-01

    We studied the effects of the immunosuppressant sodium fusidate (fusidin) on murine immunoinflammatory diabetes mellitus (DM) induced by multiple low doses of streptozotocin (SZ). Fusidin was given by gavage to three strains of mice (C57KsJ, C57BL/6, CD1) at doses 10 or 100 mg/kg body weight every...... induced in vivo by ConA, reducing the levels of IFN-gamma, IL-2 and TNF-alpha and augmenting the level of IL-6. However, only the inhibitory effect of the drug on the synthesis/release of IFN-gamma seemed to be causally related to its capacity to counteract the SZ-induced DM. In fact, the disease...... other day. The drug was administered as an early or late prophylactic regime starting either 1 day prior to the first or after the fifth and last injection of SZ. In both situations the largest dose of fusidin successfully reduced the clinical, chemical and histological signs of DM, the treated mice...

  10. Multiple toxic doses of methamphetamine alter neurotensin concentrations in various region of the rat brain

    Hanson, G.R.; Merchant, K.; Gibb, J.W.; Letter, A.A.

    1986-01-01

    The authors have previously reported that multiple high doses of methamphetamine (METH) alter neuronal monoamine metabolism and release. Recently, Hokfelt et al. showed that neurotensin, a tridecapeptide, has neurotransmitter properties which may be involved with DA neuronal activity. In the present study they investigated the possible effects of METH on the CNS neurotensin system. Five doses of METH (15 mg/kg) were administered every 6 h; control and treated rats were sacrificed 18 h after the last dose and concentrations of neurotensin-like immuno-reactivity (NTLI) were measured by radioimmunoassay. NTLI was elevated 200-300% in the nucleus accumbens, neostriatum, and substantia nigra; 30-40% increases in NTLI were measured in the hippocampus and hypothalamus. No change was observed in amygdala, A-10 or periaqueductal gray. In contrast to the above measured areas, the frontal lobe and olfactory bulb showed decreases of 25-35%. These findings demonstrate that METH treatment alters the activities of several CNS neurotensin systems, possibly due to the influence of this drug on DA pathways. The variability in the type and magnitude of these responses suggests that DA and neurotensin systems interact by more than one mechanism

  11. Multiple model predictive control for optimal drug administration of mixed immunotherapy and chemotherapy of tumours.

    Sharifi, N; Ozgoli, S; Ramezani, A

    2017-06-01

    Mixed immunotherapy and chemotherapy of tumours is one of the most efficient ways to improve cancer treatment strategies. However, it is important to 'design' an effective treatment programme which can optimize the ways of combining immunotherapy and chemotherapy to diminish their imminent side effects. Control engineering techniques could be used for this. The method of multiple model predictive controller (MMPC) is applied to the modified Stepanova model to induce the best combination of drugs scheduling under a better health criteria profile. The proposed MMPC is a feedback scheme that can perform global optimization for both tumour volume and immune competent cell density by performing multiple constraints. Although current studies usually assume that immunotherapy has no side effect, this paper presents a new method of mixed drug administration by employing MMPC, which implements several constraints for chemotherapy and immunotherapy by considering both drug toxicity and autoimmune. With designed controller we need maximum 57% and 28% of full dosage of drugs for chemotherapy and immunotherapy in some instances, respectively. Therefore, through the proposed controller less dosage of drugs are needed, which contribute to suitable results with a perceptible reduction in medicine side effects. It is observed that in the presence of MMPC, the amount of required drugs is minimized, while the tumour volume is reduced. The efficiency of the presented method has been illustrated through simulations, as the system from an initial condition in the malignant region of the state space (macroscopic tumour volume) transfers into the benign region (microscopic tumour volume) in which the immune system can control tumour growth. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Optimal precurarizing dose of rocuronium to decrease fasciculation and myalgia following succinylcholine administration.

    Kim, Kyu Nam; Kim, Kyo Sang; Choi, Hoon Il; Jeong, Ji Seon; Lee, Hee-Jong

    2014-06-01

    Succinylcholine commonly produces frequent adverse effects, including muscle fasciculation and myalgia. The current study identified the optimal dose of rocuronium to prevent succinylcholine-induced fasciculation and myalgia and evaluated the influence of rocuronium on the speed of onset produced by succinylcholine. This randomized, double-blinded study was conducted in 100 patients randomly allocated into five groups of 20 patients each. Patients were randomized to receive 0.02, 0.03, 0.04, 0.05 and 0.06 mg/kg rocuronium as a precurarizing dose. Neuromuscular monitoring after each precurarizing dose was recorded from the adductor pollicis muscle using acceleromyography with train-of-four stimulation of the ulnar nerve. All patients received succinylcholine 1.5 mg/kg at 2 minutes after the precurarization, and were assessed the incidence and severity of fasciculations, while myalgia was assessed at 24 hours after surgery. The incidence and severity of visible muscle fasciculation was significantly less with increasing the amount of precurarizing dose of rocuronium (P rocuronium, but there was no significance (P = 0.072). The onset time of succinylcholine was significantly longer with increasing the amount of precurarizing dose of rocuronium (P rocuronium was the optimal dose considering the reduction in the incidence and severity of fasciculation and myalgia with acceptable onset time, and the safe and effective precurarization.

  13. Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study.

    Lublin, Fred D; Bowen, James D; Huddlestone, John; Kremenchutzky, Marcelo; Carpenter, Adam; Corboy, John R; Freedman, Mark S; Krupp, Lauren; Paulo, Corri; Hariri, Robert J; Fischkoff, Steven A

    2014-11-01

    Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included

  14. Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

    Weisel, Katja C.; Dimopoulos, Meletios A.; Moreau, Philippe; Lacy, Martha Q.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Banos, Anne; Oriol, Albert; Alegre, Adrian; Chen, Christine; Cavo, Michele; Garderet, Laurent; Ivanova, Valentina; Martinez-Lopez, Joaquin; Knop, Stefan; Yu, Xin; Hong, Kevin; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Miguel, Jesus San

    2016-01-01

    Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 − < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 − < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30. PMID:27081177

  15. Responses of rat R-1 cells to low dose rate gamma radiation and multiple daily dose fractions

    Kal, H.B.; Bijman, J.Th.

    1981-01-01

    Multifraction irradiation may offer the same therapeutic gain as continuous irradiation. Therefore, a comparison of the efficacy of low dose rate irradiation and multifraction irradiation was the main objective of the experiments to be described. Both regimens were tested on rat rhabdomyosarcoma (R-1) cells in vitro and in vivo. Exponentially growing R-1 cells were treated in vitro by a multifraction irradiation procedure with dose fractions of 2 Gy gamma radiation and time intervals of 1 to 3 h. The dose rate was 1.3 Gy.min -1 . The results indicate that multifractionation of the total dose is more effective with respect to cell inactivation than continuous irradiation. (Auth.)

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

    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.

  17. Pediatric Patients Demonstrate Progressive T1-Weighted Hyperintensity in the Dentate Nucleus following Multiple Doses of Gadolinium-Based Contrast Agent.

    Roberts, D R; Chatterjee, A R; Yazdani, M; Marebwa, B; Brown, T; Collins, H; Bolles, G; Jenrette, J M; Nietert, P J; Zhu, X

    2016-12-01

    While there have been recent reports of brain retention of gadolinium following gadolinium-based contrast agent administration in adults, a retrospective series of pediatric patients has not previously been reported, to our knowledge. We investigated the relationship between the number of prior gadolinium-based contrast agent doses and increasing T1 signal in the dentate nucleus on unenhanced T1-weighted MR imaging. We hypothesized that despite differences in pediatric physiology and the smaller gadolinium-based contrast agent doses that pediatric patients are typically administered based on weighted-adjusted dosing, the pediatric brain would also demonstrate dose-dependent increasing T1 signal in the dentate nucleus. We included children with multiple gadolinium-based contrast agent administrations at our institution. A blinded reader placed ROIs within the dentate nucleus and adjacent cerebellar white matter. To eliminate reader bias, we also performed automated ROI delineation of the dentate nucleus, cerebellar white matter, and pons. Dentate-to-cerebellar white matter and dentate-to pons ratios were compared with the number of gadolinium-based contrast agent administrations. During 20 years at our institution, 280 patients received at least 5 gadolinium-based contrast agent doses, with 1 patient receiving 38 doses. Sixteen patients met the inclusion/exclusion criteria for ROI analysis. Blinded reader dentate-to-cerebellar white matter ratios were significantly associated with gadolinium-based contrast agent doses (r s = 0.77, P = .001). The dentate-to-pons ratio and dentate-to-cerebellar white matter ratios based on automated ROI placement were also significantly correlated with gadolinium-based contrast agent doses (t = 4.98, P contrast agent doses is significantly correlated with progressive T1-weighted dentate hyperintensity. Definitive confirmation of gadolinium deposition requires tissue analysis. Any potential clinical sequelae of gadolinium retention in

  18. Twice-monthly administration of a lower dose of epoetin beta pegol can maintain adequate hemoglobin levels in hemodialysis patients.

    Morikami, Yuki; Fujimori, Akira; Okada, Shioko; Kumei, Mai; Mizobuchi, Noriko; Sakai, Makoto

    2015-04-01

    Epoetin beta pegol is a continuous erythropoietin receptor activator (CERA) with a long half-life. Although CERA has been shown to maintain adequate hemoglobin (Hb) levels at prolonged dosing intervals, the optimal dosing schedule remains unclear. We therefore compared the efficacy of maintaining hemoglobin levels with administration of twice-monthly CERA (TWICE) versus once-monthly CERA (ONCE). Twenty hemodialysis patients receiving epoetin beta (EPO) were enrolled in this crossover study. Patients were assigned to either the TWICE or the ONCE group based on matching Hb levels and EPO doses. After 6 months of treatment, the CERA dosage was interchanged between the groups and the study was continued for an additional 6 months. The effect of the different regimens on iron metabolism was also assessed during the first 6 months of the study. Hb levels significantly increased in the TWICE group, allowing for a reduction in CERA dosage, while the dose of CERA required to maintain Hb levels in the ONCE group remained unchanged. After the interchange, a decrease in Hb levels with incremental increase in CERA dosage was observed in the TWICE→ONCE group, with the opposite effect observed in the ONCE→TWICE group. Although increases in ferritin and hepcidin-25 levels in the ONCE group were noted at one month, they disappeared at 6 months. Although Hb levels were maintained in both the ONCE and TWICE groups, a twice-monthly administration was advantageous, as it required a lower dose of CERA. © 2014 The Authors. Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis.

  19. A comparison in young and elderly subjects of the pharmacokinetics and pharmacodynamics of single and multiple doses of benazepril.

    Macdonald, N J; Elliott, H L; Hughes, D M; Reid, J L

    1993-01-01

    1. The pharmacokinetics and pharmacodynamics of single and multiple oral doses of the ACE inhibitor benazepril were investigated in young and elderly normotensive subjects. 2. Following multiple doses the trough concentrations were significantly higher in the elderly and the areas under the plasma concentration-time curves (AUC0-24) were significantly greater, by approximately 23%. 3. The fall in blood pressure tended to be greater in the elderly subjects but this is likely to be attributable to their higher initial blood pressures, although it may reflect the small differences in pharmacokinetics. 4. The age related differences in kinetics and dynamics following multiple dosing are quantitatively similar to those obtained with single doses. However, there appears to be a quantitative difference between benazepril and other ACE inhibitors in that the age related increases were of a relatively smaller magnitude. PMID:9114904

  20. The efficacy and safety of multiple doses of vortioxetine for generalized anxiety disorder: a meta-analysis

    Fu J

    2016-04-01

    Full Text Available Jie Fu,1 Lilei Peng,2 Xiaogang Li1 1Department of Neurology, 2Department of Neurosurgery, The Affiliated Hospital of Luzhou Medical College, Luzhou, People’s Republic of China Objective: Vortioxetine is a novel antidepressant approved for the treatment of major depressive disorder by the US Food and Drug Administration in September 2013. This meta-analysis assessed the efficacy and safety of different doses of vortioxetine for generalized anxiety disorder of adults.Methods: PubMed, Cochrane Library, PsycINFO, and Clinical Trials databases were searched from 2000 through 2015. The abstracts of the annual meetings of the American Psychiatric Association and previous reviews were searched to identify additional studies. The search was limited to individual randomized controlled trials (RCTs, and there was no language restriction. Four RCTs met the selection criteria. These studies included 1,843 adult patients. Results were expressed as odds ratios (ORs and 95% confidence intervals (CIs. The data were pooled with a random-effects or fixed-effects model.Results: The results showed that multiple doses (2.5, 5, and 10 mg/d of vortioxetine did not significantly improve the generalized anxiety disorder symptoms compared to placebo (OR=1.16, 95% CI=0.84–1.60, Z=0.89, P=0.38; OR=1.41, 95% CI=0.82–2.41, Z=1.25, P=0.21; OR=1.05, 95% CI=0.76–1.46, Z=0.32, P=0.75, respectively. We measured the efficacy of 2.5 mg/d vortioxetine compared to 10 mg/d, and no significant differences were observed. The common adverse effects included nausea and headache. With increased dose, nausea was found to be more frequent in the vortioxetine (5 and 10 mg/d group (OR=2.99, 95% CI=1.31–6.84, Z=2.60, P=0.009; OR=2.80, 95% CI=1.85–4.25, Z=4.85, P<0.00001, respectively, but no significant differences were observed for headache.Conclusion: The results showed no significant improvement in the treatment of generalized anxiety disorder for vortioxetine compared to placebo

  1. Pharmacokinetics of lansoprazole and its main metabolites after single and multiple intravenous doses in healthy Chinese subjects.

    Zhang, Dan; Zhang, Yanan; Liu, Man; Wang, Xiaolin; Yang, Man; Han, Jing; Liu, Huichen

    2013-09-01

    The aim of the study was to evaluate and compare the pharmacokinetics of lansoprazole (LPZ) and its main metabolites, 5'-hydroxy lansoprazole (HLPZ) and lansoprazole sulfone (LPZS), after single and multiple intravenous (i.v.) doses of LPZ in healthy Chinese subjects. Twelve subjects (six males and six females) were given a single dose of LPZ by i.v. infusion on day 1, and multiple doses from day 2 to day 6. Blood samples were collected at designated time points for analysis of plasma concentrations of LPZ, HLPZ and LPZS by an LC-MS/MS method. LPZ was generally well tolerated in healthy Chinese subjects. After single and multiple i.v. doses of 30 mg LPZ, the C max values of LPZ, HLPZ and LPZS were 1490 ± 290 and 1450 ± 280, 175 ± 71 and 154 ± 56, and 51.3 ± 82.9 and 74.1 ± 158.7 ng/mL, with the AUC0-t values 3280 ± 2550 and 4260 ± 3880, 381 ± 128 and 389 ± 111, and 389 ± 1204 and 700 ± 2255 ng h/mL, respectively. The t 1/2 and CL values of LPZ after single and multiple i.v. doses were 1.48 ± 1.03 and 2.19 ± 1.03 h, and 11.67 ± 4.49 and 9.56 ± 4.08 L/h, respectively. Compared with the pharmacokinetics of LPZ after a single dose, t 1/2 increased markedly, CL decreased significantly and AUC increased by over 20 % after multiple doses. The results indicated that there was drug accumulation of LPZ after multiple i.v. doses, and there was no gender-related difference in pharmacokinetics of LPZ and its two metabolites.

  2. Administration of single-dose GnRH agonist in the luteal phase in ICSI cycles: a meta-analysis

    Oliveira João

    2010-09-01

    Full Text Available Abstract Background The effects of gonadotrophin-releasing hormone agonist (GnRH-a administered in the luteal phase remains controversial. This meta-analysis aimed to evaluate the effect of the administration of a single-dose of GnRH-a in the luteal phase on ICSI clinical outcomes. Methods The research strategy included the online search of databases. Only randomized studies were included. The outcomes analyzed were implantation rate, clinical pregnancy rate (CPR per transfer and ongoing pregnancy rate. The fixed effects model was used for odds ratio. In all trials, a single dose of GnRH-a was administered at day 5/6 after ICSI procedures. Results All cycles presented statistically significantly higher rates of implantation (P Conclusions These findings demonstrate that the luteal-phase single-dose GnRH-a administration can increase implantation rate in all cycles and CPR per transfer and ongoing pregnancy rate in cycles with GnRH antagonist ovarian stimulation protocol. Nevertheless, by considering the heterogeneity between the trials, it seems premature to recommend the use of GnRH-a in the luteal phase. Additional randomized controlled trials are necessary before evidence-based recommendations can be provided.

  3. Pharmacokinetic/pharmacodynamic modeling of benazepril and benazeprilat after administration of intravenous and oral doses of benazepril in healthy horses.

    Serrano-Rodríguez, Juan Manuel; Gómez-Díez, Manuel; Esgueva, María; Castejón-Riber, Cristina; Mena-Bravo, Antonio; Priego-Capote, Feliciano; Ayala, Nahúm; Caballero, Juan Manuel Serrano; Muñoz, Ana

    2017-10-01

    Pharmacokinetic and pharmacodynamic (PK/PD) properties of the angiotensin-converting enzyme inhibitor (ACEI) benazeprilat have not been evaluated in horses. This study was designed to establish PK profiles for benazepril and benazeprilat after intravenous (IV) and oral (PO) administration of benazepril using a PK/PD model. This study also aims to determine the effects of benazeprilat on serum angiotensin converting enzyme (ACE), selecting the most appropriate dose that suppresses ACE activity. Six healthy horses in a crossover design received IV benazepril at 0.50mg/kg and PO at doses 0 (placebo), 0.25, 0.50 and 1.00mg/kg. Blood pressures (BP) were measured and blood samples were obtained at different times in order to measure serum drug concentrations and serum ACE activity, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and spectrophotometry, respectively. Systemic bioavailability of benazeprilat after PO benazepril was 3-4%. Maximum ACE inhibitions from baseline were 99.63% (IV benazepril), 6.77% (placebo) and 78.91%, 85.74% and 89.51% (for the three PO benazepril doses). Significant differences in BP were not found. Although oral availability was low, benazeprilat 1.00mg/kg, reached sufficient serum concentrations to induce long lasting serum ACE inhibitions (between 88 and 50%) for the first 48h. Additional research on benazepril administration in equine patients is indicated. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Absence of multiple local minima effects in intensity modulated optimization with dose-volume constraints

    Llacer, Jorge [EC Engineering Consultants, LLC 130, Forest Hill Drive, Los Gatos, CA (United States); Deasy, Joseph O [Department of Radiation Oncology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO (United States); Bortfeld, Thomas R [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 30 Fruit Street, Boston, MA (United States); Solberg, Timothy D [Department of Radiation Oncology, University of California, Los Angeles, CA (United States); Promberger, Claus [BrainLAB AG, Ammerthalstrasse 8, 85551 Heimstetten (Germany)

    2003-01-21

    This paper reports on the analysis of intensity modulated radiation treatment optimization problems in the presence of non-convex feasible parameter spaces caused by the specification of dose-volume constraints for the organs-at-risk (OARs). The main aim was to determine whether the presence of those non-convex spaces affects the optimization of clinical cases in any significant way. This was done in two phases: (1) Using a carefully designed two-dimensional mathematical phantom that exhibits two controllable minima and with randomly initialized beamlet weights, we developed a methodology for exploring the nature of the convergence characteristics of quadratic cost function optimizations (deterministic or stochastic). The methodology is based on observing the statistical behaviour of the residual cost at the end of optimizations in which the stopping criterion is progressively more demanding and carrying out those optimizations to very small error changes per iteration. (2) Seven clinical cases were then analysed with dose-volume constraints that are stronger than originally used in the clinic. The clinical cases are two prostate cases differently posed, a meningioma case, two head-and-neck cases, a spleen case and a spine case. Of the 14 different sets of optimizations (with and without the specification of maximum doses allowed for the OARs), 12 fail to show any effect due to the existence of non-convex feasible spaces. The remaining two sets of optimizations show evidence of multiple minima in the solutions, but those minima are very close to each other in cost and the resulting treatment plans are practically identical, as measured by the quality of the dose-volume histograms (DVHs). We discuss the differences between fluence maps resulting from those similar treatment plans. We provide a possible reason for the observed results and conclude that, although the study is necessarily limited, the annealing characteristics of a simulated annealing method may not be

  5. The Effect of Nicotine Administration on Physical and Psychological Signs of Withdrawal Syndrome Induced by Single or Frequent Doses of Morphine in Rats

    Mohammad Allahtavakoli; Fatemeh Amin; Elham Hakimizadeh; Ali Roohbakhsh; Sayed Ali Haeri Rohani; Ahmad Taghavi Rafsanjani; Abbas Haghparast; Ali Shamsizadeh

    2012-01-01

    Introduction. Morphine addiction and morphine withdrawal syndrome are the two main problems of today’s human society. The present study has investigated the effects of nicotine on the strength of physical and psychological dependency in single and repeated doses morphine administrated rats. Materials and methods. Male Wistar rats were subjected to morphine consumption with single or frequent dose protocols. In the single dose protocol, rats received only one dose of morphine and 24hrs later t...

  6. High doses of biotin in chronic progressive multiple sclerosis: a pilot study.

    Sedel, Frédéric; Papeix, Caroline; Bellanger, Agnès; Touitou, Valérie; Lebrun-Frenay, Christine; Galanaud, Damien; Gout, Olivier; Lyon-Caen, Olivier; Tourbah, Ayman

    2015-03-01

    No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. Uncontrolled, non-blinded proof of concept study 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  7. The Development of Multiple Intelligence Capabilities for Early Childhood Development Center, Local Administration Organization in Chaiyaphum Province

    Siphai, Sunan; Supandee, Terdsak; Raksapuk, Chunpit; Poopayang, Piangkhae; Kratoorerk, Sangsan

    2017-01-01

    The aim of this research is to promote multiple intelligence capabilities for Early Childhood Care Center of a Sub-district Administration Organization in Chaiyaphum Province. The sample applied were 61 children aging between 3 and 5 years old at Child Development Center, Tambon Ban Kok, Amphoe Chaturus, Chaiyaphum Province, who were selected…

  8. Age- and sex-specific estimation of dose to a normal thyroid from clinical administration of iodine-131

    Killough, G.G.; Eckerman, K.F.

    1986-09-01

    This report describes the derivation of an age- and sex-dependent model of radioiodine dosimetry in the thyroid and the application of the model to estimating the thyroid dose for each of 4215 patients who were exposed to 131 I in diagnostic and therapeutic procedures. In most cases, the data available consisted of the patient's age at the time of administration, the patient's sex, the quantity of activity administered, the clinically determined uptake of radioiodine by the thyroid, and the time after administration at which the uptake was determined. The model was made to conform to these data requirements by the use of age-specific estimates of the biological half-time of iodine in the thyroid and an age- and sex-dependent representation of the mass of the thyroid. Also, it was assumed that the thyroid burden was maximum at 24 hours after administration (the 131 I dose is not critically sensitive to this assumption). The metabolic model is of the form A(t) = K x (exp(-μ 1 t) - exp(-μ 2 t)) μCi where μ/sub i/ = λ/sub r/ + λ/sub i//sup b/ (i = 1, 2), λ/sub r/ is the radiological decay-rate coefficient, and the λ/sub i//sup b/ are biological removal-rate coefficients. The values of λ/sub i//sup b/ are determined by solving a nonlinear equation that depends on assumptions about the time of maximum uptake and the eventual biological loss rate (through which age dependence enters). An addendum (Appendix C) extends the method to other radioiodines and gives age- and sex-dependent dose conversion factors for most isotopes

  9. Absorbed dose estimates from a single measurement one to three days after the administration of 177Lu-DOTATATE/-TOC.

    Hänscheid, Heribert; Lapa, Constantin; Buck, Andreas K; Lassmann, Michael; Werner, Rudolf A

    2017-01-01

    To retrospectively analyze the accuracy of absorbed dose estimates from a single measurement of the activity concentrations in tumors and relevant organs one to three days after the administration of 177 Lu-DOTA-TATE/TOC assuming tissue specific effective half-lives. Activity kinetics in 54 kidneys, 30 neuroendocrine tumor lesions, 25 livers, and 27 spleens were deduced from series of planar images in 29 patients. After adaptation of mono- or bi-exponential fit functions to the measured data, it was analyzed for each fit function how precise the time integral can be estimated from fixed tissue-specific half-lives and a single measurement at 24, 48, or 72 h after the administration. For the kidneys, assuming a fixed tissue-specific half-life of 50 h, the deviations of the estimate from the actual integral were median (5 % percentile, 95 % percentile): -3 °% (-15 %>; +16 °%) for measurements after 24 h, +2 %> (-9 %>; +12 %>) for measurements after 48 h, and 0 % (-2 %; +12 %) for measurements after 72 h. The corresponding values for the other tissues, assuming fixed tissue-specific half-lives of 67 h for liver and spleen and 77 h for tumors, were +2 % (-25 %; +20 %) for measurements after 24 h, +2 °% (-16 %>; +17 %>) for measurements after 48 h, and +2 %> (-11 %>; +10 %>) for measurements after 72 h. Especially for the kidneys, which often represent the dose limiting organ, but also for liver, spleen, and neuroendocrine tumors, a meaningful absorbed dose estimate is possible from a single measurement after 2, more preferably 3 days after the administration of 177 Lu-DOTA-TATE/-TOC assuming fixed tissue specific effective half-lives. Schattauer GmbH.

  10. Pharmacokinetics of buprenorphine after single-dose subcutaneous administration in red-eared sliders (Trachemys scripta elegans).

    Kummrow, Maya S; Tseng, Florina; Hesse, Leah; Court, Michael

    2008-12-01

    Buprenorphine, a mu opioid receptor agonist, is expected to be a suitable analgesic drug for use in reptiles. However, to date, dosage recommendations have been based on anecdotal observations. The aim of this study was to provide baseline pharmacokinetic data in red-eared sliders (Trachemys scripta elegans) targeting a plasma level of 1 ng/ml reported effective for analgesia in humans. Serial blood samples were taken after subcutaneous injection of buprenorphine, and plasma buprenorphine levels were measured by radioimmunoassay. Pharmacokinetic parameters of a lower dose (0.02 mg/kg) injected into the forelimb were compared with a higher dose (0.05 mg/kg) given in the same forelimb as well as a lower dose (0.02 mg/kg) given in the hind limb of the same animals with 2 wk between studies. After administration of 0.05 mg/kg in the front limb, 85% of animals maintained the minimum effective plasma level for 24 hr, while only 43% of animals maintained this level after 0.02 mg/kg. After hind limb injection at 0.02 mg/kg, maximum plasma concentrations and areas under the buprenorphine concentration-time curve were less than 20% and 70%, respectively, of values after forelimb injection, consistent with substantial first pass extraction by the liver. Furthermore, a secondary rise in the buprenorphine level was found after having only a hind limb injection, probably from enterohepatic recirculation of glucuronidated drug. In conclusion, buprenorphine dosages of at least 0.075 mg/kg s.i.d. should be appropriate for evaluation of analgesia efficacy, and front limb administration may be preferable to hind limb administration for optimal drug exposure.

  11. Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie

    2016-01-01

    dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7 mg/kg), gabapentin (10, 30 and 100 mg/kg) or their combination (9 combinations in total) were evaluated in the rat...... plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response...... surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response...

  12. One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

    Rao, Shripada C; Srinivasjois, Ravisha; Moon, Kwi

    2016-12-06

    Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups

  13. Vertebral lesion distribution in multiple myeloma - assessed by reduced-dose whole-body MDCT

    Bier, Georg; Kloth, Christopher; Schabel, Christoph; Bongers, Malte; Nikolaou, Konstantin; Horger, Marius [Eberhard-Karls-University Tuebingen, Department of Diagnostic and Interventional Radiology, Tuebingen (Germany)

    2016-01-15

    To observe the distribution and potential distribution patterns of osteolytic and sclerotic vertebral involvement in a representative collective of multiple myeloma patients. A total of 66 consecutive patients with a diagnosis of multiple myeloma at initial diagnosis or during follow-up were examined by multidetector reduced-dose computed tomography to evaluate the distribution of bone lesions along the spine with focus on size, location, and lesion character. Confirmation of diagnosis was performed by comparison to follow-up computed tomography or magnetic resonance tomography. If >50 % of all detected malignant lesions occurred in one spinal segment, the distribution pattern was called cervical, thoracic, lumbar, or sacral, otherwise a ''mixed'' pattern was classified. Of a total number of 933 osseous spine lesions, 632 (67.7 %) were classified as malignant (98.9 % of them osteolytic) and 293 (31.5 %) as benign. The distribution pattern analysis yielded two patients (3.8 %) with a cervical, 26 (50 %) with a thoracic, 4 (7.7 %) with a lumbar, one (1.9 %) with a sacral pattern, and 19 cases (36.6 %) showed a mixed distribution pattern. Segment-wise, the mean lesion size was 6.52 ± 2.76 mm (cervical), 8.97 ± 5.43 mm (thoracic), 11.97 ± 7.11 mm (lumbar), and 17.5 ± 16.465 (sacral), whilst, related to the vertebra size, the lesion/vertebra size ratio is decreasing through the whole spine beginning from the top. Multiple myeloma bone lesions occur preferably and are larger in the thoracic and lumbar spine. Moreover, a specific distribution pattern is present in about 60 %. (orig.)

  14. Vertebral lesion distribution in multiple myeloma - assessed by reduced-dose whole-body MDCT

    Bier, Georg; Kloth, Christopher; Schabel, Christoph; Bongers, Malte; Nikolaou, Konstantin; Horger, Marius

    2016-01-01

    To observe the distribution and potential distribution patterns of osteolytic and sclerotic vertebral involvement in a representative collective of multiple myeloma patients. A total of 66 consecutive patients with a diagnosis of multiple myeloma at initial diagnosis or during follow-up were examined by multidetector reduced-dose computed tomography to evaluate the distribution of bone lesions along the spine with focus on size, location, and lesion character. Confirmation of diagnosis was performed by comparison to follow-up computed tomography or magnetic resonance tomography. If >50 % of all detected malignant lesions occurred in one spinal segment, the distribution pattern was called cervical, thoracic, lumbar, or sacral, otherwise a ''mixed'' pattern was classified. Of a total number of 933 osseous spine lesions, 632 (67.7 %) were classified as malignant (98.9 % of them osteolytic) and 293 (31.5 %) as benign. The distribution pattern analysis yielded two patients (3.8 %) with a cervical, 26 (50 %) with a thoracic, 4 (7.7 %) with a lumbar, one (1.9 %) with a sacral pattern, and 19 cases (36.6 %) showed a mixed distribution pattern. Segment-wise, the mean lesion size was 6.52 ± 2.76 mm (cervical), 8.97 ± 5.43 mm (thoracic), 11.97 ± 7.11 mm (lumbar), and 17.5 ± 16.465 (sacral), whilst, related to the vertebra size, the lesion/vertebra size ratio is decreasing through the whole spine beginning from the top. Multiple myeloma bone lesions occur preferably and are larger in the thoracic and lumbar spine. Moreover, a specific distribution pattern is present in about 60 %. (orig.)

  15. Toxicity evaluation of methoxy poly(ethylene oxide)-block-poly(ε-caprolactone) polymeric micelles following multiple oral and intraperitoneal administration to rats.

    Binkhathlan, Ziyad; Qamar, Wajhul; Ali, Raisuddin; Kfoury, Hala; Alghonaim, Mohammed

    2017-09-01

    Methoxy poly(ethylene oxide)- block -poly(ɛ-caprolactone) (PEO- b -PCL) copolymers are amphiphilic and biodegradable copolymers designed to deliver a variety of drugs and diagnostic agents. The aim of this study was to synthesize PEO- b -PCL block copolymers and assess the toxic effects of drug-free PEO- b -PCL micelles after multiple-dose administrations via oral or intraperitoneal (ip) administration in rats. Assembly of block copolymers was achieved by co-solvent evaporation method. To investigate the toxicity profile of PEO- b -PCL micelles, sixty animals were divided into two major groups: The first group received PEO- b -PCL micelles (100 mg/kg) by oral gavage daily for seven days, while the other group received the same dose of micelles by ip injections daily for seven days. Twenty-four hours following the last dose, half of the animals from each group were sacrificed and blood and organs (lung, liver, kidneys, heart and spleen) were collected. Remaining animals were observed for further 14 days and was sacrificed at the end of the third week, and blood and organs were collected. None of the polymeric micelles administered caused any significant effects on relative organ weight, animal body weight, leucocytes count, % lymphocytes, liver and kidney toxicity markers and organs histology. Although the dose of copolymers used in this study is much higher than those used for drug delivery, it did not cause any significant toxic effects in rats. Histological examination of all the organs confirmed the nontoxic nature of the micelles.

  16. Toxicity evaluation of methoxy poly(ethylene oxide-block-poly(ε-caprolactone polymeric micelles following multiple oral and intraperitoneal administration to rats

    Ziyad Binkhathlan

    2017-09-01

    Full Text Available Methoxy poly(ethylene oxide-block-poly(ɛ-caprolactone (PEO-b-PCL copolymers are amphiphilic and biodegradable copolymers designed to deliver a variety of drugs and diagnostic agents. The aim of this study was to synthesize PEO-b-PCL block copolymers and assess the toxic effects of drug-free PEO-b-PCL micelles after multiple-dose administrations via oral or intraperitoneal (ip administration in rats. Assembly of block copolymers was achieved by co-solvent evaporation method. To investigate the toxicity profile of PEO-b-PCL micelles, sixty animals were divided into two major groups: The first group received PEO-b-PCL micelles (100 mg/kg by oral gavage daily for seven days, while the other group received the same dose of micelles by ip injections daily for seven days. Twenty-four hours following the last dose, half of the animals from each group were sacrificed and blood and organs (lung, liver, kidneys, heart and spleen were collected. Remaining animals were observed for further 14 days and was sacrificed at the end of the third week, and blood and organs were collected. None of the polymeric micelles administered caused any significant effects on relative organ weight, animal body weight, leucocytes count, % lymphocytes, liver and kidney toxicity markers and organs histology. Although the dose of copolymers used in this study is much higher than those used for drug delivery, it did not cause any significant toxic effects in rats. Histological examination of all the organs confirmed the nontoxic nature of the micelles.

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

    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

  18. Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple sclerosis.

    Filippi, M; Campi, A; Martinelli, V; Colombo, B; Yousry, T; Canal, N; Scotti, G; Comi, G

    1995-01-01

    This study was performed to evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) increases the sensitivity of brain MRI for detecting enhancing lesions in patients with primary progressive multiple sclerosis (PPMS). T1 weighted brain MRI was obtained for 10 patients with PPMS in two sessions. In the first session, one scan was obtained five to seven minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, one scan before and two scans five to seven minutes and one hour after the injection of 0.3 mmol/kg Gd-DTPA (triple dose) were obtained. Four enhancing lesions were detected in two patients when the standard dose of Gd-DTPA was used. The numbers of enhancing lesions increased to 13 and the numbers of patients with such lesions to five when the triple dose of Gd-DTPA was used and to 14 and six in the one hour delayed scans. The mean contrast ratio for enhancing lesions detected with the triple dose of Gd-DTPA was higher than those for lesions present in both the standard dose (P DTPA many more enhancing lesions can be detected in patients with PPMS. This is important both for planning clinical trials and for detecting the presence of inflammation in vivo in the lesions of such patients. Images PMID:8530944

  19. Widespread increases in malondialdehyde immunoreactivity in dopamine-rich and dopamine-poor regions of rat brain following multiple, high doses of methamphetamine.

    Kristen Ashley eHorner

    2011-05-01

    Full Text Available Treatment with multiple high doses of methamphetamine (METH can induce oxidative damage, including dopamine (DA-mediated reactive oxygen species (ROS formation, which may contribute to the neurotoxic damage of monoamine neurons and long-term depletion of DA in the caudate putamen (CPu and substantia nigra pars compacta (SNpc. Malondialdehyde (MDA, a product of lipid peroxidation by ROS, is commonly used as a marker of oxidative damage and treatment with multiple high doses of METH increases MDA reactivity in the CPu of humans and experimental animals. Recent data indicate that MDA itself may contribute to the destruction of DA neurons, as MDA causes the accumulation of toxic intermediates of DA metabolism via its chemical modification of the enzymes necessary for the breakdown of DA. However, it has been shown that in human METH abusers there is also increased MDA reactivity in the frontal cortex, which receives relatively fewer DA afferents than the CPu. These data suggest that METH may induce neuronal damage regardless of the regional density of DA or origin of DA input. The goal of the current study was to examine the modification of proteins by MDA in the DA-rich nigrostriatal and mesoaccumbal systems, as well as the less DA-dense cortex and hippocampus following a neurotoxic regimen of METH treatment. Animals were treated with METH (10 mg/kg every 2h for 6h, sacrificed one week later, and examined using immunocytochemistry for changes in MDA-adducted proteins. Multiple, high doses of METH significantly increased MDA immunoreactivity (MDA-ir in the CPu, SNpc, cortex and hippocampus. Multiple METH administration also increased MDA-ir in the ventral tegmental area (VTA and nucleus accumbens (NAc. Our data indicate that multiple METH treatment can induce persistent and widespread neuronal damage that may not necessarily be limited to the nigrostriatal DA system.

  20. Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a multiple ascending dose study in opioid-naïve healthy volunteers.

    Rauck, Richard L; Oh, D Alexander; Singla, Neil; Koch, Christian; Parikh, Neha; Nalamachu, Srinivas; Wilson, Daniel; Yu, Jin; Vetticaden, Santosh

    2017-11-01

    Fentanyl sublingual spray, with its rapid onset for pain relief, may be efficacious in the management of acute or post-operative pain. Because patients in these settings may be opioid-naïve, the study was conducted to determine the safety, tolerability, and pharmacokinetics of multiple dose administration of fentanyl sublingual spray in an opioid-naïve population. Fentanyl sublingual spray (100 mcg, 200 mcg, and 400 mcg) and fentanyl citrate intravenous (IV; 50 mcg) were administered every 0.5, 1.0, 2.0, and 4.0 h for up to three doses per cohort in opioid-naïve subjects (ClinicalTrials.gov identifier: NCT02641340). Eight subjects in each cohort were randomly assigned (six subjects received fentanyl sublingual spray; two subjects received fentanyl citrate IV). Pharmacokinetic and safety-related pharmacodynamic assessments were performed through 24 h post-first dose. Safety assessments were collected through Day 7. Ninety-six opioid-naïve subjects, aged 20-55 years, with a body mass index of 18.7-31.5 kg/m 2 , participated in the study. Multiple doses of fentanyl sublingual spray (100, 200, and 400 mcg) were generally well tolerated. Hypoxia, observed in the 200-mcg and 400-mcg dose groups, increased with increasing doses and higher dosing frequency, but was readily managed by nasal cannula oxygenation. Overall, nausea increased with increasing doses, and ∼52.6% (10 out of 19) cases of nausea that occurred at the highest dose of 400 mcg were treated with concomitant medication. Overall, the reported adverse events were consistent with the known safety profile of fentanyl. Fentanyl sublingual spray (100 mcg, 200 mg, and 400 mcg) administered every 0.5, 1, 2, and 4 h was generally well tolerated in an opioid-naïve population. The results suggest that doses of 200 mcg or lower may be safe for use in an opioid-naïve population.

  1. Absorption, Distribution, and Excretion of 14C-APX001 after Single-Dose Administration to Rats and Monkeys

    Mansbach, Robert; Shaw, Karen J; Hodges, Michael R; Coleman, Samantha; Fitzsimmons, Michael E

    2017-01-01

    Abstract Background APX001 is a small-molecule therapeutic agent in clinical development for the treatment of invasive fungal infections (IFI). Methods The absorption, distribution and excretion profiles of [14C]APX001-derived radioactivity were determined in rats (albino and pigmented) and monkeys. Rats (some implanted with bile duct cannulae) were administered a single 100 mg/kg oral dose or a 30 mg/kg intravenous (IV) dose. Monkeys were administered a single 6 mg/kg IV dose. Samples of blood, urine, feces and bile, as well as carcasses, were collected through 168 hours after dosing. Samples were analyzed for total radioactivity content by liquid scintillation counting, and carcasses were analyzed by quantitative whole-body autoradiography. Results [14C]APX001-derived radioactivity was rapidly and extensively absorbed and extensively distributed to most tissues for both routes of administration in both species. In rats, tissues with the highest radioactivity Cmax values included bile, abdominal fat, reproductive fat, subcutaneous fat, and liver, but radioactivity was also detected in tissues associated with IFI, including lung, brain and eye. In monkeys, the highest Cmax values were in bile, urine, uveal tract, bone marrow, abdominal fat, liver, and kidney cortex. Liver and kidney were the tissues with highest radioactivity, but as in the rat, radioactivity was also detected in lung, brain and eye tissues. In pigmented rats, radiocarbon was densely distributed into pigmented tissue and more slowly cleared than from other tissues. Mean recovery of radioactivity in rats was approximately 95–100%. In bile duct-intact rats, >90% of radioactivity was recovered in feces. In cannulated rats, biliary excretion of radioactivity was the major route of elimination and accounted for 88.8% of the dose, whereas urinary and fecal excretion of radioactivity was minor and accounted for 2.56% and 5.42% of the dose, respectively. In monkeys, the overall recovery of radioactivity

  2. Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses.

    Wach, Achim; Dembowsky, Klaus; Dale, Glenn E

    2018-04-01

    Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified. Copyright © 2018 American Society for Microbiology.

  3. Estimation of effective dose and lifetime attributable risk from multiple head CT scans in ventriculoperitoneal shunted children

    Aw-Zoretic, J.; Seth, D.; Katzman, G.; Sammet, S.

    2014-01-01

    Purpose: The purpose of this review is to determine the averaged effective dose and lifetime attributable risk factor from multiple head computed tomography (CT) dose data on children with ventriculoperitoneal shunts (VPS). Method and materials: A total of 422 paediatric head CT exams were found between October 2008 and January 2011 and retrospectively reviewed. The CT dose data was weighted with the latest IRCP 103 conversion factor to obtain the effective dose per study and the averaged effective dose was calculated. Estimates of the lifetime attributable risk were also calculated from the averaged effective dose using a conversion factor from the latest BEIR VII report. Results: Our study found the highest effective doses in neonates and the lowest effective doses were observed in the 10–18 years age group. We estimated a 0.007% potential increase risk in neonates and 0.001% potential increased risk in teenagers over the base risk. Conclusion: Multiple head CTs in children equates to a slight potential increase risk in lifetime attributable risk over the baseline risk for cancer, slightly higher in neonates relative to teenagers. The potential risks versus clinical benefit must be assessed

  4. Clinical evaluation of the hypoxic cytotoxin tirapazamine (SR-4233): phase I experience with repeated dose administration during fractionated irradiation

    Hancock, Steven L.; Spencer, Sharon; Mariscal, Carol; Wooten, Ann; Wheeler, Richard; Brown, J. Martin; Fisher, Cheryl; Roemeling, Reinhard von

    1996-01-01

    Purpose: Regions of chronic or transient hypoxia are common in many human tumors and are thought to limit tumor cell killing and tumor control with conventional irradiation and some chemotherapeutic agents. Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide) forms a cytotoxic free radical during reductive metabolism in regions of hypoxia. In well oxygenated regions, the tirapazamine radical reacts with molecular oxygen to form the inactive parent drug. This results in markedly greater toxicity for hypoxic cells than for the well oxygenated cells that comprise most normal tissues. Tirapazamine increased the anti-tumor effects of single dose or fractionated irradiation or cis-platin chemotherapy in murine tumors,in vivo . This study evaluated the ability to repeat the administration of Tirapazamine during courses of fractionated irradiation in humans after an earlier phase I trial established a maximum tolerated dose of 390 mg per square meter of body surface area (mg/m 2 ) when given as a single dose with radiotherapy. Materials and Methods: Between December 1993 and August 1995 22 patients with locally advanced or metastatic tumors of varying histology, normal renal, hepatic, and hematologic functions, and Karnofsky performance status ≥ 60 received repeated doses of Tirapazamine during a planned, 6 weeks course of standardly fractionated radiotherapy. After anti-emetic treatment with ondansetron (32 mg) and dexamethasone (16 mg), Tirapazamine was administered during a 2 hour intravenous infusion that ended from 30 to 90 minutes before a radiation treatment. Patients were monitored for acute toxicity during the course of treatment and for a minimum of one month after radiotherapy. Results: The study was initiated with three, biweekly doses of Tirapazamine at 330 mg/m 2 . Four of 7 patients who initiated treatment at this dose refused the second (1 patient) or third dose of Tirapazamine (3 patients). Two of the three patients who received three doses

  5. Urinary steroid hormone patterns: III. Effect of continuous daily administration of low dose megestrol acetate.

    Kumari, G L; Roy, S; Allag, I S; Ghosal, J

    1975-12-01

    The effect of megestrol acetate, administered in daily doses of .5 mg, on urinary steroid levels was studied before, during, and after therapy in 4 women volunteers. In each case, pregnanediol levels were reduced, though ovulatory biphasic patterns, as reflected in basal body temperature patterns, were apparent in the majority of the cycles, which suggests that corpus luteum function, but not ovulation, was impaired. 17-ketosteroid levels were significantly (p less than .001) increased either during or after treatment, while 17-hydroxycorticoid levels were reduced in 3 of the women. 2 subjects showed a marked reduction in levels of 17-ketogenic steroids and corticoid levels. Total estrogen levels seemed to correlate with the levels of corticoid excretion.

  6. Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate

    Deise Riba Coelho

    2014-07-01

    Full Text Available Meglumine antimoniate (MA and sodium stibogluconate are pentavalent antimony (SbV drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous. Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h and a slow (t1/2 >> 24 h elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen >> bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain. The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies.

  7. Doxorubicin-Loaded PEG-PCL-PEG Micelle Using Xenograft Model of Nude Mice: Effect of Multiple Administration of Micelle on the Suppression of Human Breast Cancer

    Ming-Fa Hsieh

    2010-12-01

    Full Text Available The triblock copolymer is composed of two identical hydrophilic segments: Monomethoxy poly(ethylene glycol (mPEG and one hydrophobic segment poly(ε‑caprolactone (PCL; which is synthesized by coupling of mPEG-PCL-OH and mPEG‑COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer can self-assemble into nanoscopic micelles to accommodate doxorubixin (DOX in the hydrophobic core. The physicochemical properties and in vitro tests, including cytotoxicity of the micelles, have been characterized in our previous study. In this study, DOX was encapsulated into micelles with a drug loading content of 8.5%. Confocal microscopy indicated that DOX was internalized into the cytoplasm via endocystosis. A dose-finding scheme of the polymeric micelle (placebo showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice. Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats. A biodistribution study displayed that plasma extravasation of DOX in liver and spleen occurred in the first four hours. Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14 of DOX-loaded micelles as compared to multiple administrations of free DOX.

  8. Doxorubicin-Loaded PEG-PCL-PEG Micelle Using Xenograft Model of Nude Mice: Effect of Multiple Administration of Micelle on the Suppression of Human Breast Cancer

    Cuong, Nguyen-Van [Department of Biomedical Engineering, Chung Yuan Christian University, 200, Chung Pei Rd., Chung Li, Taiwan (China); Department of Chemical Engineering, Ho Chi Minh City University of Industry, 12 Nguyen Van Bao St, Ho Chi Minh (Viet Nam); Jiang, Jian-Lin; Li, Yu-Lun [Department of Biomedical Engineering, Chung Yuan Christian University, 200, Chung Pei Rd., Chung Li, Taiwan (China); Chen, Jim-Ray [Department of Pathology, Chang Gung Memorial Hospital at Keelung, Taiwan and Chang Gung University, College of Medicine, Taoyuan, Taiwan (China); Jwo, Shyh-Chuan [Division of General Surgery, Chang Gung Memorial Hospital at Keelung, Taiwan and Chang Gung University, College of Medicine, Taoyuan, Taiwan (China); Hsieh, Ming-Fa, E-mail: mfhsieh@cycu.edu.tw [Department of Biomedical Engineering, Chung Yuan Christian University, 200, Chung Pei Rd., Chung Li, Taiwan (China)

    2010-12-28

    The triblock copolymer is composed of two identical hydrophilic segments Monomethoxy poly(ethylene glycol) (mPEG) and one hydrophobic segment poly(ε-caprolactone) (PCL); which is synthesized by coupling of mPEG-PCL-OH and mPEG-COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer can self-assemble into nanoscopic micelles to accommodate doxorubixin (DOX) in the hydrophobic core. The physicochemical properties and in vitro tests, including cytotoxicity of the micelles, have been characterized in our previous study. In this study, DOX was encapsulated into micelles with a drug loading content of 8.5%. Confocal microscopy indicated that DOX was internalized into the cytoplasm via endocystosis. A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice. Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats. A biodistribution study displayed that plasma extravasation of DOX in liver and spleen occurred in the first four hours. Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX.

  9. Doxorubicin-Loaded PEG-PCL-PEG Micelle Using Xenograft Model of Nude Mice: Effect of Multiple Administration of Micelle on the Suppression of Human Breast Cancer

    Cuong, Nguyen-Van; Jiang, Jian-Lin; Li, Yu-Lun; Chen, Jim-Ray; Jwo, Shyh-Chuan; Hsieh, Ming-Fa

    2010-01-01

    The triblock copolymer is composed of two identical hydrophilic segments Monomethoxy poly(ethylene glycol) (mPEG) and one hydrophobic segment poly(ε-caprolactone) (PCL); which is synthesized by coupling of mPEG-PCL-OH and mPEG-COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer can self-assemble into nanoscopic micelles to accommodate doxorubixin (DOX) in the hydrophobic core. The physicochemical properties and in vitro tests, including cytotoxicity of the micelles, have been characterized in our previous study. In this study, DOX was encapsulated into micelles with a drug loading content of 8.5%. Confocal microscopy indicated that DOX was internalized into the cytoplasm via endocystosis. A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice. Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats. A biodistribution study displayed that plasma extravasation of DOX in liver and spleen occurred in the first four hours. Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX

  10. Neuroprotection of lamotrigine on hypoxic-ischemic brain damage in neonatal rats: Relations to administration time and doses

    Yong-Hong Yi

    2008-06-01

    Full Text Available Yong-Hong Yi1, Wen-Chao Guo1, Wei-Wen Sun1, Tao Su1, Han Lin1, Sheng-Qiang Chen1, Wen-Yi Deng1, Wei Zhou2, Wei-Ping Liao11Department of Neurology, Institute of Neurosciences and the Second Affiliated Hospital, 2Department of Neonatology, Affiliated Guangzhou Children’s Hospital, Guangzhou Medical College, Guangzhou, Guangdong Province, P.R. ChinaAbstract: Lamotrigine (LTG, an antiepileptic drug, has been shown to be able to improve cerebral ischemic damage by limiting the presynaptic release of glutamate. The present study investigated further the neuroprotective effect of LTG on hypoxic-ischemic brain damage (HIBD in neonatal rats and its relations to administration time and doses. The HIBD model was produced in 7-days old SD rats by left common carotid artery ligation followed by 2 h hypoxic exposure (8% oxygen. LTG was administered intraperitoneally with the doses of 5, 10, 20, and 40 mg/kg 3 h after operation and the dose of 20 mg/kg 1 h before and 3 h, 6 h after operation. Blood and brain were sampled 24 h after operation. Nissl staining, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL, and neuron-specific enolase (NSE immunohistochemical staining were used for morphological studies. Water content in left cortex and NSE concentration in serum were determined. LTG significantly reduced water content in the cerebral cortex, as well as the number of TUNEL staining neurons in the dentate gyrus and cortex in hypoxic-ischemia (HI model. Furthermore, LTG significantly decreased the NSE level in serum and increased the number of NSE staining neurons in the cortex. These effects, except that on water content, were dose-dependent and were more remarkable in the pre-treated group than in the post-treated groups. These results demonstrate that LTG may have a neuroprotective effect on acute HIBD in neonates. The effect is more prominent when administrated with higher doses and before HI.Keywords: hypoxic-ischemic brain

  11. GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects.

    Spreen, William; Ford, Susan L; Chen, Shuguang; Wilfret, David; Margolis, David; Gould, Elizabeth; Piscitelli, Stephen

    2014-12-15

    GSK1265744 (744) is an HIV-1 integrase inhibitor in clinical development as a long-acting (LA) injectable formulation. This study evaluated plasma and tissue pharmacokinetics after single-dose administration of 744 LA administered by intramuscular (IM) or subcutaneous injections. This was a phase I, open-label, 9-cohort, parallel study of 744 in healthy subjects. 744 was administered as a 200 mg/mL nanosuspension at doses of 100-800 mg IM and 100-400 mg subcutaneous. Eight (6 active and 2 placebo) male and female subjects participated in each of the first 7 cohorts. All 8 subjects, 4 males and 4 females, received active 744 LA in cohorts 8 and 9 and underwent rectal and cervicovaginal tissue sampling, respectively. Plasma pharmacokinetic sampling was performed for a minimum of 12 weeks or until 744 concentrations were ≤0.1 μg/mL. Rectal and cervicovaginal tissue biopsies were performed at weeks 2 and 8 (cohort 8) and weeks 4 and 12 (cohort 9). 744 LA was generally safe and well tolerated after single injections. A majority of subjects reported injection site reactions, all graded as mild in intensity. Plasma concentration-time profiles were prolonged with measureable concentrations up to 52 weeks after dosing. 744 LA 800 mg IM achieved mean concentrations above protein adjusted-IC90 for approximately 16 weeks. Rectal and cervicovaginal tissue concentrations ranged from injection has potential application as a monthly or less frequent HIV treatment or prevention agent.

  12. A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma

    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...

  13. Evaluation of the CT dose index for scans with an ECG using a 320-row multiple-detector CT scanner

    Kobayashi, Masanao; Asada, Yasuki; Matsubara, Kosuke; Koshida, Kichiro; Suzuki, Shouichi; Matsunaga, Yuta; Kawaguchi, Ai; Haba, Tomonobu; Katada, Kazuhiro; Toyama, Hiroshi

    2015-01-01

    The relationship between heart rate (HR) and computed tomography dose index (CTDI) was evaluated using an electrocardiogram (ECG) gate scan for scan applications such as prospective triggering, Ca scoring, target computed tomography angiography (CTA), prospective CTA and retrospective gating, continuous CTA/CFA (cardiac functional analysis) and CTA/CFA modulation. Even in the case of a volume scan, doses for the multiple scan average dose were similar to those for CTDI. Moreover, it was found that the ECG gate scan yields significantly different doses. When selecting the optimum scan, the doses were dependent on many factors such as HR, scan rotation time, active time, pre-specified cardiac phase and modulation rate. Therefore, it is necessary to take these results into consideration when selecting the scanning parameters. (authors)

  14. Cumulative effective and individual organ dose levels in paediatric patients undergoing multiple catheterizations for congenital heart disease

    Jones, T.P.; Brennan, P.C.; Ryan, E.

    2017-01-01

    This study examines the cumulative radiation dose levels received by a group of children who underwent multiple cardiac catheterisation procedures during the investigation and management of congenital heart disease (CHD). The purpose is to calculate cumulative doses, identify higher dose individuals, outline the inconsistencies with risk assessment and encourage the establishment of dose databases in order to facilitate the longitudinal research necessary to better understand health risks. A retrospective review of patient records for 117 paediatric patients who have undergone two or more cardiac catheterizations for the investigation of CHD was undertaken. This cohort consisted of patients who were catheterised over a period from September 2002 to August 2014. The age distribution was from newborn to 17 y. Archived kerma-area product (P KA ) and fluoroscopy time (T) readings were retrieved and analysed. Cumulative effective and individual organ doses were determined. The cumulative P KA levels ranged from 1.8 to 651.2 Gycm 2 , whilst cumulative effective dose levels varied from 2 to 259 mSv. The cumulative fluoroscopy time was shown to vary from 8.1 to 193.5 min. Median cumulative organ doses ranged from 3 to 94 mGy. Cumulative effective dose levels are highly variable but may exceed 250 mSv. Individual organ and effective dose measurements remain useful for comparison purposes between institutions although current methodologies used for determining lifetime risks are inadequate. (authors)

  15. Signal intensity change on unenhanced T1-weighted images in dentate nucleus following gadobenate dimeglumine in patients with and without previous multiple administrations of gadodiamide

    Ramalho, Joana [University of North Carolina Hospital, Chapel Hill, NC (United States); Centro Hospitalar de Lisboa Central, Lisbon (Portugal); Semelka, Richard C.; Castillo, Mauricio [University of North Carolina Hospital, Chapel Hill, NC (United States); AlObaidy, Mamdoh [University of North Carolina Hospital, Chapel Hill, NC (United States); King Faisal Specialist Hospital and Research Center, Riyadh (Saudi Arabia); Ramalho, Miguel [University of North Carolina Hospital, Chapel Hill, NC (United States); Hospital Garcia de Orta, Almada (Portugal); Nunes, Renato H. [University of North Carolina Hospital, Chapel Hill, NC (United States); Santa Casa de Misericordia de Sao Paulo, Sao Paulo (Brazil)

    2016-11-15

    To evaluate the impact of previous administration of gadodiamide and neural tissue gadolinium deposition in patients who received gadobenate dimeglumine. Our population included 62 patients who underwent at least three administrations of gadobenate dimeglumine, plus an additional contrast-enhanced last MRI for reference, divided into two groups: group 1, patients who in addition to gadobenate dimeglumine administrations had prior exposure to multiple doses of gadodiamide; group 2, patients without previous exposure to other gadolinium-based contrast agent (GBCAs). Quantitative analysis was performed on the first and last gadobenate dimeglumine MRIs in both groups. Dentate nucleus-to-middle cerebellar peduncle signal intensity ratios (DN/MCP) and relative change (RC) in signal over time were calculated and compared between groups using generalized additive model. Group 1 showed significant increase in baseline and follow-up DN/MCP compared to group 2 (p < 0.0001). The RC DN/MCP showed a non-statistically significant trend towards an increase in patients who underwent previous gadodiamide (p = 0.0735). There is increased T1 signal change over time in patients who underwent gadobenate dimeglumine and had received prior gadodiamide compared to those without known exposure to previous gadodiamide. A potentiating effect from prior gadodiamide on subsequent administered gadobenate dimeglumine may occur. (orig.)

  16. Taenia crassiceps Infection Attenuates Multiple Low-Dose Streptozotocin-Induced Diabetes

    Arlett Espinoza-Jiménez

    2010-01-01

    Full Text Available Taenia crassiceps, like other helminths, can exert regulatory effects on the immune system of its host. This study investigates the effect of chronic T. crassiceps infection on the outcome of Multiple Low Dose Streptozotocin-Induced Diabetes (MLDS. Healthy or previously T. crassiceps-infected mice received MLDS and type 1 diabetes (T1D symptoms were evaluated for 6 weeks following the induction of MLDS. T. crassiceps-infected mice displayed lower blood glucose levels throughout the study. A significantly lower percentage of T. crassiceps-infected mice (40% developed T1D compared to the uninfected group (100%. Insulitis was remarkably absent in T. crassiceps-infected mice, which had normal pancreatic insulin content, whereas uninfected mice showed a dramatic reduction in pancreatic insulin. Infected mice that received MLDS did not show an increase in their regulatory T cell population, however, they had a greater number of alternatively activated macrophages, higher levels of the cytokine IL-4, and lower levels of TNF-α. Therefore, infection with T. crassiceps causes an immunomodulation that modifies the incidence and development of MLDS-induced autoimmune diabetes.

  17. Lenalidomide at the dose of 25 mg every other day in patients affected by multiple myeloma and renal failure: a real-life experience.

    Cerchione, Claudio; Nappi, Davide; Pareto, Anna E; Romano, Alessandra; Martinelli, Vincenzo; Picardi, Marco; Pane, Fabrizio; Catalano, Lucio

    2018-04-01

    Renal impairment (RI) is a relevant complication of patients affected by multiple myeloma (MM); it can be present in up to 30-35% of newly diagnosed MM and is linked to a poor outcome. However, early recognition and early treatment with novel agents can overcome the negative impact of RI and even reverse kidney damage in most cases. Lenalidomide, available as an oral compound, is an immunomodulatory drug with both antiproliferative and immunomodulatory activity that is largely used in the management of MM. Dose reduction is mandatory in RI; however, there is no theoretical assumption against the possibility that protracting the time of full standard doses can be equally effective and tolerated by patients requiring reduced doses. In this report, we describe our retrospective experience, in 18 patients, with the administration of lenalidomide 25 mg every other day for patients with MM and RI. The overall response ratio was 66.5%. More than half (61.1%) of the patients had a renal response. The median progression-free survival was 8 months (range: 3-18 months). No serious adverse event occurred during treatment, and it was never necessary to disrupt or delay treatment for toxicity. These preliminary observations point to a significant therapeutic effect of lenalidomide, at the dose of 25 mg every other day for 21 days, with logistic and economic advantages. However, these results should be validated by controlled studies involving larger numbers of patients.

  18. Sex-dependent behavioral changes in rat offspring after in utero administration of a single low dose PBDE 47

    Kuriyama, S.N.; Talsness, C.E.; Chahoud, I. [Charite Univ. Medical School Berlin (Germany). Inst. of Clinical Pharmacology and Toxicology, Dept. Toxicology, Campus Benjamin Franklin

    2004-09-15

    change which could manifest itself in an irreversible fashion at later time points in life. We administered a single dose to gravid dams on gestation day 6 of either 140 {mu}g/kg BW or 700 {mu}g/kg BW of the congener, 2,2'4,4'-tetrabromo diphenyl ether (PBDE 47). These doses are pertinent to human exposure levels because a study by She et al. found a mean level of 33.3 {mu}g PBDE 47 /kg fat in human breast adipose tissue with a range from 7.01 to 196 {mu}g PBDE 47 /kg fat (10). In this study, peri-pubertal behavior effects were evaluated in rat offspring after in utero administration of low dose PBDE 47.

  19. Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice

    Tanaka, Emi; Ogawa, Yuko; Mukai, Takeo; Sato, Yoshiaki; Hamazaki, Takashi; Nagamura-Inoue, Tokiko; Harada-Shiba, Mariko; Shintaku, Haruo; Tsuji, Masahiro

    2018-01-01

    Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating

  20. Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice

    Emi Tanaka

    2018-03-01

    Full Text Available Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12, and low-dose (1 × 104 or high-dose (1 × 105 UC-MSCs were administered intravenously 48 h after the insult (P14. To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by

  1. Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs.

    Bigby, Sarah E; Beths, Thierry; Bauquier, Sébastien; Carter, Jennifer E

    2017-11-01

    To evaluate the effect of rate of administration of propofol or alfaxalone on induction dose requirements and incidence of postinduction apnea (PIA) in dogs following premedication with methadone and dexmedetomidine. Prospective, randomized clinical trial. Thirty-two healthy American Society of Anesthesiologists class I client-owned dogs (seven females, 25 males), aged between 5 and 54 months, weighing between 2.0 and 48.2 kg. Dogs were premedicated intramuscularly with 0.5 mg kg -1 methadone and 5 μg kg -1 dexmedetomidine. Thirty minutes after premedication, dogs were preoxygenated for 5 minutes before the induction agent was administered intravenously via a syringe driver until orotracheal intubation was achieved. Dogs were randomized to receive alfaxalone 0.5 mg kg -1  minute -1 (A-Slow), alfaxalone 2 mg kg -1  minute -1 (A-Fast), propofol 1 mg kg -1  minute -1 (P-Slow), or propofol 4 mg kg -1 minute -1 (P-Fast). Oxygen saturation of hemoglobin (SpO 2 ), end-tidal carbon dioxide and respiratory rate were monitored. If PIA (≥30 seconds without a breath) occurred, the time to the first spontaneous breath was measured. If SpO 2 decreased below 90%, the experiment was stopped and manual ventilation initiated. The mean±standard deviation induction doses of alfaxalone and propofol were lower in the A-Slow [A-Slow 0.9±0.3 mg kg -1 , A-Fast 2.2±0.5 mg kg -1 (p≤0.001)] and P-Slow [P-Slow 1.8±0.6 mg kg -1 , P-Fast 4.1±0.7 mg kg -1 (p≤0.001)] groups, respectively. The incidence of PIA was 25% for the A-Slow and P-Slow groups and 100% for the A-Fast and P-Fast groups (p = 0.007). Both propofol and alfaxalone following methadone and dexmedetomidine premedication caused PIA. Induction dose requirement and incidence of PIA were affected by the rate of administration of both drugs. When possible, propofol and alfaxalone doses should be reduced and administered slowly to reduce PIA. Copyright © 2017 Association of Veterinary

  2. Whole Brain Irradiation With Hippocampal Sparing and Dose Escalation on Multiple Brain Metastases: A Planning Study on Treatment Concepts

    Prokic, Vesna; Wiedenmann, Nicole; Fels, Franziska; Schmucker, Marianne; Nieder, Carsten; Grosu, Anca-Ligia

    2013-01-01

    Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 ± 0.62 Gy and 6.29 ± 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 ± 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 ± 0.7 Gy and 32.7 ± 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 ± 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.

  3. Modulation of radiation injuries in rats receiving multiple doses of Aloe Vera

    Azab, Kh.SH.

    2007-01-01

    This study has been performed to examine the efficacy of Aloe vera juice (Aloe barbadensis Miller) against radiation injuries of 7 Gy whole body gamma irradiation (single dose). Inductions of lipid peroxidation (thiobarbituric acid reactive substances, (TBARS)) of biomembranes lipids as well as the subsequent changes in the activities of subcellular organelle marker enzymes were discussed. Activities of glutamate dehydrogenase (GDH), acid phosphatase and glucose-6-phosphatase (marker enzymes of mitochondria, lysosome and microsomes, respectively) were estimated. The activities of these enzymes were also measured in cytosol. Subcellular fractionation's were performed in liver, heart and spleen tissues. Aloe vera was supplemented daily to rats (0.25 ml/kg body wt/day) by gavage, 5 days before irradiation and treatment was extended for 10 days post irradiation. Experimental investigations were performed on the 3 rd and 10 th day after exposure to radiation. The results obtained indicated that, Aloe vera administration has significantly minimized the radiation-induced increase in the amount of TBARS in different cell fractions as compared with control rats. Significant amelioration in the activities of organelles marker enzymes GDH, acid phosphatase and glucose-6-phosphatase was observed from 3 rd up to 10 th days for the 3 tissues. The results also detected improvement in cytosolic enzyme activities due to Aloe vera intake. It could be suggested that the diverse active constituents of Aloe vera play a significant role in decreasing the peroxidation of subcellular membrane lipids induced by radiation exposure, prevent diffusion of organelle enzymes to cytosol and consequently salvage the integrity of living cell

  4. Multiple myeloma among atomic bomb survivors in Hiroshima and Nagasaki, 1950-76: relationship to radiation dose absorbed by marrow

    Ichimaru, M.; Ishimaru, T.; Mikami, M.; Matsunaga, M.

    1982-01-01

    The relationship between atomic bomb exposure and the incidence of multiple myeloma has been examined in a fixed cohort of atomic bomb survivors and controls in the life-span study sample for Hiroshima and Nagasaki. From October 1950 to December 1976, 29 cases of multiple myeloma were confirmed in this sample. Our analysis shows that the standardized relative risk (RR) adjusted for city, sex, and age at the time of bombings (ATB) increased with marrow-absorbed radiation dose. The increased RR does not appear to differ between cities or sexes and is demonstrable only for those survivors whose age ATB was between 20 and 59 years. The estimated risk in these individuals is approximately 0.48 cases/million person-years/rad for bone marrow total dose. This excess risk did not become apparent in individuals receiving 50 rad or more in marrow total dose until 20 years or more after exposure

  5. Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol

    Stojanov, Dragan A. [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Center for Radiology, Nis (Serbia); Aracki-Trenkic, Aleksandra [Clinical Center Nis, Center for Radiology, Nis (Serbia); Vojinovic, Slobodan; Ljubisavljevic, Srdjan [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Clinic for Neurology, Nis (Serbia); Benedeto-Stojanov, Daniela [University of Nis, Faculty of Medicine, Nis (Serbia)

    2016-03-15

    To evaluate correlation between cumulative dose of gadobutrol and signal intensity (SI) within dentate nucleus and globus pallidus on unenhanced T1-weighted images in patients with relapsing-remitting multiple sclerosis (RRMS). Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios, and renal and liver functions, were evaluated after multiple intravenous administrations of 0.1 mmol/kg gadobutrol at 27, 96-98, and 168 weeks. We compared SI ratios based on the number of administrations, total amount of gadobutrol administered, and time between injections. Globus pallidus-to-thalamus (p = 0.025) and dentate nucleus-to-pons (p < 0.001) SI ratios increased after multiple gadobutrol administrations, correlated with the number of administrations (ρ = 0.263, p = 0.046, respectively) and depended on the length of administration (p = 0.017, p = 0.037, respectively). Patients receiving gadobutrol at 27 weeks showed the greatest increase in both SI ratios (p = 0.006; p = 0.014, respectively, versus 96-98 weeks). GGT increased at the end of the study (p = 0.004). In patients with RRMS, SI within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images after multiple gadobutrol injections. Administration of the same total amount of gadobutrol over a shorter period caused greater SI increase. (orig.)

  6. A comparative bioavailability study of two ibuprofen formulations after single-dose administration in healthy volunteers

    Metta S.S. Wiria

    2007-09-01

    Full Text Available This study was aimed to investigate the bioequivalence of ibuprofen 125 mg suppository formulation (Ibukal®, test formulation from PT. Kalbe Farma, Tbk., Jakarta and the ibuprofen suppository comparative formulation (Proris®, from PT. Pharos Indonesia, Jakarta in 12 healthy volunteers. The pharmacokinetic parameters used in this study were the area under the concentration-time curve from time zero to hour 10 (AUC0-t, the area under the concentration-time curve from time zero to infinite (AUC0-inf, the maximum concentration (Cmax, and the time needed to reach the maximum concentration (tmax. The study was designed as a random cross-over fashion, single-blinded which included 12 healthy adult volunteers. The volunteers were fasted overnight and in the morning they received a suppository of the test drug (Ibukal® or a suppository of the comparative drug (Proris®. Blood samples were withdrawn on hour 0 (control, 20 min; 40 min; 1; 1.5; 2; 2.5; 3; 4; 6; 8; and 10 time points after the administration of the drug. Following a wash-out period of 1 week, this procedure was repeated using the other drug. The serum concentration of the drug was determined by means of high-performance liquid chromatography with ultraviolet detection. The results of the study showed that, the mean (SD of AUC0-t, AUC0-inf, Cmax and tmax of the test drug were, respectively, 28.59(3.37 μg.h.mL-1, 30.47(3.56 μg.h.mL-1, 8.24(1.44 μg/mL, and 1.33(0.44 h. The mean (SD of AUC0-t, AUC0-inf, Cmax and tmax of the comparative drug were, respectively, 28.13(8.14 μg.h.mL-1, 30.56(8.05 μg.h.mL-1, 8.27(2.88 μg/mL, and 1.79(0.33 h. The geometric means ratio of the test to the comparative drug were 104.38% (CI 90%: 90.38-120.54% for AUC0-t, 101.97% (CI 90%: 89.51-116.16% for AUC0-inf, and 104.02% (CI 90%: 85.73-126.16% for Cmax. There was no side effect of the drug detected in this study. From the results we can conclude that the 125 mg of ibuprofen suppository of PT Kalbe Farma

  7. Multiple sclerosis in Germany: data analysis of administrative prevalence and healthcare delivery in the statutory health system.

    Höer, Ariane; Schiffhorst, Guido; Zimmermann, Anne; Fischaleck, Johann; Gehrmann, Luise; Ahrens, Henrik; Carl, Gunther; Sigel, Karl-Otto; Osowski, Ulrike; Klein, Maria; Bleß, Hans-Holger

    2014-09-10

    Healthcare-utilization data for multiple sclerosis (MS) are scarce in Germany. The Purpose of the study was to analyse administrative prevalence of MS, medication use and type of specialists involved in MS treatment in the outpatient setting in Bavaria. Pseudonymized claims data from Bavarian Statutory Health Insurance (SHI)-accredited physicians were used. Administrative prevalence of MS was defined as having ≥1 MS diagnosis (International Classification of Diseases, 10th edition, code G35) documented by a neurologist or psychiatrist, or ≥1 prescription for disease-modifying drugs (DMDs)). The administrative prevalence calculated for Bavaria was projected to Germany. DMD prescription and involvement of different specialities in health care service for MS patients was analysed. Administrative prevalence of MS in Bavaria increased from 0.123% to 0.175% of insured persons between 2005 and 2009; when projected, this yielded ~102,000-143,000 patients with MS in the German population. The percentage of patients receiving ≥1 DMD prescription increased from 45.5% to 50.5%. Patients with MS were mainly treated by neurologists in the ambulatory care setting. These results provide important information on the administrative prevalence of MS in Bavaria and on healthcare provision for patients, which is relevant for resource planning in the healthcare sector.

  8. Comparison of doses received by the hippocampus in patients treated with single isocenter– vs multiple isocenter–based stereotactic radiation therapy to the brain for multiple brain metastases

    Algan, Ozer; Giem, Jared; Young, Julie; Ali, Imad; Ahmad, Salahuddin; Hossain, Sabbir

    2015-01-01

    To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiation therapy using a single isocenter (SI)–based or multiple isocenter (MI)–based treatment planning in patients with less than 4 brain metastases. In total, 10 patients with magnetic resonance imaging (MRI) demonstrating 2-3 brain metastases were included in this retrospective study, and 2 sets of stereotactic intensity-modulated radiation therapy (IMRT) treatment plans (SI vs MI) were generated. The hippocampus was contoured on SPGR sequences, and doses received by the hippocampus and the brain were calculated and compared between the 2 treatment techniques. A total of 23 lesions in 10 patients were evaluated. The median tumor volume, the right hippocampus volume, and the left hippocampus volume were 3.15, 3.24, and 2.63 mL, respectively. In comparing the 2 treatment plans, there was no difference in the planning target volume (PTV) coverage except in the tail for the dose-volume histogram (DVH) curve. The only statistically significant dosimetric parameter was the V_1_0_0. All of the other measured dosimetric parameters including the V_9_5, V_9_9, and D_1_0_0 were not significantly different between the 2 treatment planning techniques. None of the dosimetric parameters evaluated for the hippocampus revealed any statistically significant difference between the MI and SI plans. The total brain doses were slightly higher in the SI plans, especially in the lower dose region, although this difference was not statistically different. The use of SI-based treatment plan resulted in a 35% reduction in beam-on time. The use of SI treatments for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain when compared with MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.

  9. Comparison of doses received by the hippocampus in patients treated with single isocenter- vs multiple isocenter-based stereotactic radiation therapy to the brain for multiple brain metastases.

    Algan, Ozer; Giem, Jared; Young, Julie; Ali, Imad; Ahmad, Salahuddin; Hossain, Sabbir

    2015-01-01

    To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiation therapy using a single isocenter (SI)-based or multiple isocenter (MI)-based treatment planning in patients with less than 4 brain metastases. In total, 10 patients with magnetic resonance imaging (MRI) demonstrating 2-3 brain metastases were included in this retrospective study, and 2 sets of stereotactic intensity-modulated radiation therapy (IMRT) treatment plans (SI vs MI) were generated. The hippocampus was contoured on SPGR sequences, and doses received by the hippocampus and the brain were calculated and compared between the 2 treatment techniques. A total of 23 lesions in 10 patients were evaluated. The median tumor volume, the right hippocampus volume, and the left hippocampus volume were 3.15, 3.24, and 2.63mL, respectively. In comparing the 2 treatment plans, there was no difference in the planning target volume (PTV) coverage except in the tail for the dose-volume histogram (DVH) curve. The only statistically significant dosimetric parameter was the V100. All of the other measured dosimetric parameters including the V95, V99, and D100 were not significantly different between the 2 treatment planning techniques. None of the dosimetric parameters evaluated for the hippocampus revealed any statistically significant difference between the MI and SI plans. The total brain doses were slightly higher in the SI plans, especially in the lower dose region, although this difference was not statistically different. The use of SI-based treatment plan resulted in a 35% reduction in beam-on time. The use of SI treatments for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain when compared with MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment. Copyright © 2015 American Association of

  10. Comparison of doses received by the hippocampus in patients treated with single isocenter– vs multiple isocenter–based stereotactic radiation therapy to the brain for multiple brain metastases

    Algan, Ozer, E-mail: oalgan@ouhsc.edu; Giem, Jared; Young, Julie; Ali, Imad; Ahmad, Salahuddin; Hossain, Sabbir

    2015-01-01

    To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiation therapy using a single isocenter (SI)–based or multiple isocenter (MI)–based treatment planning in patients with less than 4 brain metastases. In total, 10 patients with magnetic resonance imaging (MRI) demonstrating 2-3 brain metastases were included in this retrospective study, and 2 sets of stereotactic intensity-modulated radiation therapy (IMRT) treatment plans (SI vs MI) were generated. The hippocampus was contoured on SPGR sequences, and doses received by the hippocampus and the brain were calculated and compared between the 2 treatment techniques. A total of 23 lesions in 10 patients were evaluated. The median tumor volume, the right hippocampus volume, and the left hippocampus volume were 3.15, 3.24, and 2.63 mL, respectively. In comparing the 2 treatment plans, there was no difference in the planning target volume (PTV) coverage except in the tail for the dose-volume histogram (DVH) curve. The only statistically significant dosimetric parameter was the V{sub 100}. All of the other measured dosimetric parameters including the V{sub 95}, V{sub 99}, and D{sub 100} were not significantly different between the 2 treatment planning techniques. None of the dosimetric parameters evaluated for the hippocampus revealed any statistically significant difference between the MI and SI plans. The total brain doses were slightly higher in the SI plans, especially in the lower dose region, although this difference was not statistically different. The use of SI-based treatment plan resulted in a 35% reduction in beam-on time. The use of SI treatments for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain when compared with MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.

  11. Complex, non-monotonic dose-response curves with multiple maxima: Do we (ever) sample densely enough?

    Cvrčková, Fatima; Luštinec, Jiří; Žárský, Viktor

    2015-01-01

    We usually expect the dose-response curves of biological responses to quantifiable stimuli to be simple, either monotonic or exhibiting a single maximum or minimum. Deviations are often viewed as experimental noise. However, detailed measurements in plant primary tissue cultures (stem pith explants of kale and tobacco) exposed to varying doses of sucrose, cytokinins (BA or kinetin) or auxins (IAA or NAA) revealed that growth and several biochemical parameters exhibit multiple reproducible, statistically significant maxima over a wide range of exogenous substance concentrations. This results in complex, non-monotonic dose-response curves, reminiscent of previous reports of analogous observations in both metazoan and plant systems responding to diverse pharmacological treatments. These findings suggest the existence of a hitherto neglected class of biological phenomena resulting in dose-response curves exhibiting periodic patterns of maxima and minima, whose causes remain so far uncharacterized, partly due to insufficient sampling frequency used in many studies.

  12. Assessment of radioactive residues arising from radiolabel instability in a multiple dose tissue distribution study in rats

    Slatter, J.G. [Pharmacia Corp., Peapack, NJ (United States); Sams, J.P.; Easter, J.A. [Pharmacia Corp., Kalamazoo, MI (United States)] [and others

    2003-05-01

    Our study objectives were to quantitatively determine the effect of radiolabel instability on terminal phase radioactive tissue residues in a multiple dose tissue distribution study, to quantitatively compare tissue residue artifacts (non drug-related radioactivity) from two chemically-distinct radiolabel locations, and to conduct a definitive multiple dose tissue distribution study using the better of the two radiolabeled compounds. We compared the excretion and tissue distribution in rats of [{sup 14}C]linezolid, radiolabeled in two different locations, after 7 consecutive once daily [{sup 14}C] oral doses. The radiolabels were in the acetamide (two carbon) and oxazolidinone (isolated carbon) functional groups. Terminal phase tissue residue and excretion data were compared to data from rats dosed orally with [{sup 14}C]sodium acetate. Drug-related radioactivity was excreted rapidly over 24 h. After a single dose, the acetamide and oxazolidinone radiolabel sites both gave 3% of dose as exhaled {sup 14}CO{sub 2}. After 7 daily [{sup 14}C] oral doses, terminal phase radioactive tissue residues were higher from the acetamide radiolabel, relative to the oxazolidinone radiolabel, and were primarily not drug-related. In the definitive tissue distribution study, low concentrations of drug-related radioactivity in skin and thyroid were observed. We conclude that although small amounts of radiolabel instability do not significantly affect single dose tissue radioactivity C{sub max} and area under the curve (AUC), artifacts arising from radiolabel instability can prolong the apparent terminal phase half life and complicate study data interpretation. When possible, it is always preferable to use a completely stable radiolabel site. (author)

  13. Assessment of radioactive residues arising from radiolabel instability in a multiple dose tissue distribution study in rats

    Slatter, J.G.; Sams, J.P.; Easter, J.A.

    2003-01-01

    Our study objectives were to quantitatively determine the effect of radiolabel instability on terminal phase radioactive tissue residues in a multiple dose tissue distribution study, to quantitatively compare tissue residue artifacts (non drug-related radioactivity) from two chemically-distinct radiolabel locations, and to conduct a definitive multiple dose tissue distribution study using the better of the two radiolabeled compounds. We compared the excretion and tissue distribution in rats of [ 14 C]linezolid, radiolabeled in two different locations, after 7 consecutive once daily [ 14 C] oral doses. The radiolabels were in the acetamide (two carbon) and oxazolidinone (isolated carbon) functional groups. Terminal phase tissue residue and excretion data were compared to data from rats dosed orally with [ 14 C]sodium acetate. Drug-related radioactivity was excreted rapidly over 24 h. After a single dose, the acetamide and oxazolidinone radiolabel sites both gave 3% of dose as exhaled 14 CO 2 . After 7 daily [ 14 C] oral doses, terminal phase radioactive tissue residues were higher from the acetamide radiolabel, relative to the oxazolidinone radiolabel, and were primarily not drug-related. In the definitive tissue distribution study, low concentrations of drug-related radioactivity in skin and thyroid were observed. We conclude that although small amounts of radiolabel instability do not significantly affect single dose tissue radioactivity C max and area under the curve (AUC), artifacts arising from radiolabel instability can prolong the apparent terminal phase half life and complicate study data interpretation. When possible, it is always preferable to use a completely stable radiolabel site. (author)

  14. Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents

    Lohrke, Jessica; Frisk, Anna-Lena; Frenzel, Thomas; Schöckel, Laura; Rosenbruch, Martin; Jost, Gregor; Lenhard, Diana Constanze; Sieber, Martin A.; Nischwitz, Volker; Küppers, Astrid; Pietsch, Hubertus

    2017-01-01

    Objectives Retrospective studies in patients with primary brain tumors or other central nervous system pathologies as well as postmortem studies have suggested that gadolinium (Gd) deposition occurs in the dentate nucleus (DN) and globus pallidus (GP) after multiple administrations of primarily linear Gd-based contrast agents (GBCAs). However, this deposition has not been associated with any adverse effects or histopathological alterations. The aim of this preclinical study was to systematically examine differences between linear and macrocyclic GBCAs in their potential to induce changes in brain and skin histology including Gd distribution in high spatial resolution. Materials and Methods Fifty male Wistar-Han rats were randomly allocated into control (saline, n = 10 rats) and 4 GBCA groups (linear GBCAs: gadodiamide and gadopentetate dimeglumine, macrocyclic GBCAs: gadobutrol and gadoteridol; n = 10 rats per group). The animals received 20 daily intravenous injections at a dose of 2.5 mmol Gd/kg body weight. Eight weeks after the last GBCA administration, the animals were killed, and the brain and skin samples were histopathologically assessed (hematoxylin and eosin; cresyl violet [Nissl]) and by immunohistochemistry. The Gd concentration in the skin, bone, brain, and skeletal muscle samples were analyzed using inductively coupled plasma mass spectroscopy (ICP-MS, n = 4). The spatial Gd distribution in the brain and skin samples was analyzed in cryosections using laser ablation coupled with ICP-MS (LA-ICP-MS, n = 3). For the ultra-high resolution of Gd distribution, brain sections of rats injected with gadodiamide or saline (n = 1) were assessed by scanning electron microscopy coupled to energy dispersive x-ray spectroscopy and transmission electron microscopy, respectively. Results No histological changes were observed in the brain. In contrast, 4 of 10 animals in the gadodiamide group but none of the animals in other groups showed macroscopic and histological

  15. Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents.

    Lohrke, Jessica; Frisk, Anna-Lena; Frenzel, Thomas; Schöckel, Laura; Rosenbruch, Martin; Jost, Gregor; Lenhard, Diana Constanze; Sieber, Martin A; Nischwitz, Volker; Küppers, Astrid; Pietsch, Hubertus

    2017-06-01

    Retrospective studies in patients with primary brain tumors or other central nervous system pathologies as well as postmortem studies have suggested that gadolinium (Gd) deposition occurs in the dentate nucleus (DN) and globus pallidus (GP) after multiple administrations of primarily linear Gd-based contrast agents (GBCAs). However, this deposition has not been associated with any adverse effects or histopathological alterations. The aim of this preclinical study was to systematically examine differences between linear and macrocyclic GBCAs in their potential to induce changes in brain and skin histology including Gd distribution in high spatial resolution. Fifty male Wistar-Han rats were randomly allocated into control (saline, n = 10 rats) and 4 GBCA groups (linear GBCAs: gadodiamide and gadopentetate dimeglumine, macrocyclic GBCAs: gadobutrol and gadoteridol; n = 10 rats per group). The animals received 20 daily intravenous injections at a dose of 2.5 mmol Gd/kg body weight. Eight weeks after the last GBCA administration, the animals were killed, and the brain and skin samples were histopathologically assessed (hematoxylin and eosin; cresyl violet [Nissl]) and by immunohistochemistry. The Gd concentration in the skin, bone, brain, and skeletal muscle samples were analyzed using inductively coupled plasma mass spectroscopy (ICP-MS, n = 4). The spatial Gd distribution in the brain and skin samples was analyzed in cryosections using laser ablation coupled with ICP-MS (LA-ICP-MS, n = 3). For the ultra-high resolution of Gd distribution, brain sections of rats injected with gadodiamide or saline (n = 1) were assessed by scanning electron microscopy coupled to energy dispersive x-ray spectroscopy and transmission electron microscopy, respectively. No histological changes were observed in the brain. In contrast, 4 of 10 animals in the gadodiamide group but none of the animals in other groups showed macroscopic and histological nephrogenic systemic fibrosis-like skin

  16. TH-AB-207A-03: Skin Dose to Patients Receiving Multiple CTA and CT Exams of the Head

    Nawfel, RD; Young, G

    2016-01-01

    Purpose: To measure patient skin dose from CT angiography (CTA) and CT exams of the head, and determine if patients having multiple exams could receive cumulative doses that approach or exceed deterministic thresholds. Methods: This study was HIPAA compliant and conducted with IRB approval. Patient skin doses were measured over a 4 month period using nanoDot OSL dosimeters placed on the head of 52 patients for two CT scanners. On each scanner, 26 patients received CT exams (scanner 1: 10 females, 16 males, mean age 64.2 years; scanner 2: 18 females, 8 males, mean age 61.2 years). CT exam dose metrics, CTDIvol and dose-length product (DLP) were recorded for each exam. Additionally, skin dose was measured on an acrylic skull phantom in each scanner and on a neuro-interventional imaging system using clinical protocols. Measured dose data was used to estimate peak skin dose (PSD) for 4 patients receiving multiple exams including CTA, head CT, and cerebral angiography. Results: For scanner 1, the mean PSD for CTA exams (98.9 ± 5.3 mGy) and for routine head CT exams (39.2 ± 3.7 mGy) agreed reasonably well with the PSD measured on the phantom, 105.4 mGy and 40.0 mGy, respectively. Similarly for scanner 2, the mean PSD for CTA exams (98.8 ± 7.4 mGy) and for routine head CT exams (42.9 ± 9.4 mGy) compared well with phantom measurements, 95.2 mGy and 37.6 mGy, respectively. In addition, the mean PSD was comparable between scanners for corresponding patient exams, CTA and routine head CT respectively. PSD estimates ranged from 1.9 – 4.5 Gy among 4 patients receiving multiple exams. Conclusion: Patients having several exams including both CTA and routine head CT may receive cumulative doses approaching or exceeding the threshold for single dose deterministic effects.

  17. TH-AB-207A-03: Skin Dose to Patients Receiving Multiple CTA and CT Exams of the Head

    Nawfel, RD; Young, G [Brigham & Women’s Hospital, Boston, MA (United States)

    2016-06-15

    Purpose: To measure patient skin dose from CT angiography (CTA) and CT exams of the head, and determine if patients having multiple exams could receive cumulative doses that approach or exceed deterministic thresholds. Methods: This study was HIPAA compliant and conducted with IRB approval. Patient skin doses were measured over a 4 month period using nanoDot OSL dosimeters placed on the head of 52 patients for two CT scanners. On each scanner, 26 patients received CT exams (scanner 1: 10 females, 16 males, mean age 64.2 years; scanner 2: 18 females, 8 males, mean age 61.2 years). CT exam dose metrics, CTDIvol and dose-length product (DLP) were recorded for each exam. Additionally, skin dose was measured on an acrylic skull phantom in each scanner and on a neuro-interventional imaging system using clinical protocols. Measured dose data was used to estimate peak skin dose (PSD) for 4 patients receiving multiple exams including CTA, head CT, and cerebral angiography. Results: For scanner 1, the mean PSD for CTA exams (98.9 ± 5.3 mGy) and for routine head CT exams (39.2 ± 3.7 mGy) agreed reasonably well with the PSD measured on the phantom, 105.4 mGy and 40.0 mGy, respectively. Similarly for scanner 2, the mean PSD for CTA exams (98.8 ± 7.4 mGy) and for routine head CT exams (42.9 ± 9.4 mGy) compared well with phantom measurements, 95.2 mGy and 37.6 mGy, respectively. In addition, the mean PSD was comparable between scanners for corresponding patient exams, CTA and routine head CT respectively. PSD estimates ranged from 1.9 – 4.5 Gy among 4 patients receiving multiple exams. Conclusion: Patients having several exams including both CTA and routine head CT may receive cumulative doses approaching or exceeding the threshold for single dose deterministic effects.

  18. Comparison of microdose flare-up and antagonist multiple-dose protocols for poor-responder patients: a randomized study.

    Demirol, Aygul; Gurgan, Timur

    2009-08-01

    To compare the efficacy of the microdose flare-up and multiple-dose antagonist protocols for poor-responder patients in intracytoplasmic sperm injection-ET cycles. A randomized, prospective study. Center for assisted reproductive technology in Turkey. Ninety patients with poor ovarian response in a minimum of two previous IVF cycles. All women were prospectively randomized into two groups by computer-assisted randomization. The patients in group 1 were stimulated according to the microdose flare-up protocol (n = 45), while the patients in group 2 were stimulated according to antagonist multiple-dose protocol (n = 45). The mean number of mature oocytes retrieved was the primary outcome measure, and fertilization rate, implantation rate per embryo, and clinical pregnancy rates were secondary outcome measures. The mean age of the women, the mean duration of infertility, basal FSH level, and the number of previous IVF cycles were similar in both groups. The total gonadotropin dose used was significantly higher in group 2, while the number of oocytes retrieved was significantly greater in group 1. Although the fertilization and clinical pregnancy rates were nonsignificantly higher in group 1 compared with group 2, the implantation rate was significantly higher in the microdose flare-up group than in the multiple-dose antagonist group (22% vs. 11%). The microdose flare-up protocol seems to have a better outcome in poor-responder patients, with a significantly higher mean number of mature oocytes retrieved and higher implantation rate.

  19. Comparison of single-dose and multiple-dose antibiotics for lower urinary tract infection in pregnancy.

    Usta, Taner A; Dogan, Ozgur; Ates, Ugur; Yucel, Burak; Onar, Zehra; Kaya, Erdal

    2011-09-01

    To compare the efficacy of fosfomycin trometamol, cefuroxime axetil, and amoxicillin clavulanate antibiotics, and to assess the difference in patient compliance, in the treatment of urinary tract infections during pregnancy. Between September 2007 and May 2008, 90 out of 324 pregnant women with complaints of lower urinary tract infection, who were followed at the outpatient clinic or referred to the emergency department of Vakif Gureba Education and Research Hospital, were enrolled in a prospective study. Patients were randomized into 3 equal groups for treatment with single-dose fosfomycin trometamol, or 5-day courses of amoxicillin clavulanate or cefuroxime axetil. After follow-up, study data were obtained for 28, 27, and 29 patients, respectively. The treatment groups did not differ significantly in terms of demographics, clinical success rate, microbiological cure rate, or adverse effects. Significantly higher drug compliance was observed in the fosfomycin trometamol group than in the other 2 groups (PUTI as the standard course of treatment with amoxicillin clavulanate or cefuroxime axetil. Fosfomycin trometamol may be a preferable treatment for UTI because of its simpler use and better rates of compliance. Copyright © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  20. Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody

    Schwartz, J; O' Donoghue, J A; Humm, J L [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); Jaggi, J S [Bristol-Myers Squibb, Plainsboro, NJ (United States); Ruan, S; Larson, S M [Nuclear Medicine Service Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); McDevitt, M; Scheinberg, D A, E-mail: schwarj1@mskcc.org [Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10065 (United States)

    2011-02-07

    Clinical therapeutic studies using {sup 225}Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of {sup 225}Ac. The purpose of this study was to determine the amount of {sup 225}Ac and non-equilibrium progeny in the mouse kidney after the injection of {sup 225}Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with {sup 225}Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess {sup 213}Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess {sup 213}Bi reaching the kidney ({gamma}-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq{sup -1}, of which 0.46 (SD 0.16) Gy kBq{sup -1} (i.e. 60%) was due to non-equilibrium excess {sup 213}Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess {sup 213}Bi (0.31 (SD 0.11) Gy kBq{sup -1}) represented {approx}46% of the total. For the medulla the dose contribution from excess {sup 213}Bi (0.81 (SD 0.28) Gy kBq{sup -1}) was {approx}80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq{sup -1} following administration of {sup 225}Ac-huM195 with non-equilibrium excess {sup 213}Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the

  1. Reduced dose uncertainty in MRI-based polymer gel dosimetry using parallel RF transmission with multiple RF sources

    Sang-Young Kim; Jung-Hoon Lee; Jin-Young Jung; Do-Wan Lee; Seu-Ran Lee; Bo-Young Choe; Hyeon-Man Baek; Korea University of Science and Technology, Daejeon; Dae-Hyun Kim; Jung-Whan Min; Ji-Yeon Park

    2014-01-01

    In this work, we present the feasibility of using a parallel RF transmit with multiple RF sources imaging method (MultiTransmit imaging) in polymer gel dosimetry. Image quality and B 1 field homogeneity was statistically better in the MultiTransmit imaging method than in conventional single source RF transmission imaging method. In particular, the standard uncertainty of R 2 was lower on the MultiTransmit images than on the conventional images. Furthermore, the MultiTransmit measurement showed improved dose resolution. Improved image quality and B 1 homogeneity results in reduced dose uncertainty, thereby suggesting the feasibility of MultiTransmit MR imaging in gel dosimetry. (author)

  2. Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma

    Xu, Xu Steven; Yan, Xiaoyu; Puchalski, Thomas

    2017-01-01

    New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first-in-class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen...... for daratumumab is challenging due to its target-mediated drug disposition, leading to time- and concentration-dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM. This article is protected by copyright. All...

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

    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.

  4. Analgesic Efficacy of a New Immediate-Release/Extended-Release Formulation of Ibuprofen: Results From Single- and Multiple-Dose Postsurgical Dental Pain Studies.

    Christensen, Steven; Paluch, Ed; Jayawardena, Shyamalie; Daniels, Stephen; Meeves, Suzanne

    2017-05-01

    Analgesic effects of ibuprofen immediate-release/extended-release (IR/ER) 600-mg tablets were evaluated in 2 randomized, double-blind, placebo-controlled dental pain studies. Patients 16-40 years old with moderate-severe pain following third-molar extraction received single-dose ibuprofen 600 mg IR/ER (formulation A or B), naproxen sodium 220 mg, or placebo (2:2:2:1; study 1) or 4 doses of ibuprofen 600 mg IR/ER (formulation A) or placebo (1:1; study 2). In study 1 (n = 196), mean (standard deviation [SD]) time-weighted sum of pain intensity difference scores for placebo, ibuprofen IR/ER A, ibuprofen IR/ER B, and naproxen, respectively, were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) over 0-12 hours and -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) over 8-12 hours (all P ibuprofen IR/ER, respectively (P ibuprofen. Gastrointestinal adverse events predominated with placebo both after study medication administration and after rescue medication use, if applicable. Ibuprofen 600 mg IR/ER provided safe and effective analgesia after single and multiple doses. © 2016, The American College of Clinical Pharmacology.

  5. Nonrandomized study comparing the effects of preoperative radiotherapy and daily administration of low-dose cisplatin with those radiotherapy alone for oral cancer

    Kurita, Hiroshi; Azegami, Takuya; Kobayashi, Hirokazu; Kurashina, Kenji; Tanaka, Kouichi; Kotani, Akira; Oguchi, Masahiko; Tamura, Minoru.

    1997-01-01

    The purpose of this study was to compare the effect of preoperative radiotherapy and daily administration of low-dose cisplatin with those of radiotherapy alone for oral cancer. Ten patients underwent preoperative radiotherapy of 30 to 40 Gy with concomitant daily administration of low-dose cisplatin (5 mg/body or 5 mg/m 2 ). Ten patients received external radiotherapy alone. The locoregional response rates (complete response and partial response) did not differ significantly between the two groups (80% for combined therapy and 60% for radiotherapy alone). On histopathologic evaluation of surgical specimens, however, the combined-therapy group (80%) had a higher response rate than did the radiotherapy-alone group (10%; p<0.01). We conclude that daily administration of low-dose cisplatin enhances the efficacy of radiotherapy against primary tumors. We also suggested that combined therapy may be beneficial as an initial treatment for oral cancer before a planned operation. (author)

  6. The expression and evolution of virulence in multiple infections: the role of specificity, relative virulence and relative dose.

    Ben-Ami, Frida; Routtu, Jarkko

    2013-05-03

    Multiple infections of the same host by different strains of the same microparasite species are believed to play a crucial role during the evolution of parasite virulence. We investigated the role of specificity, relative virulence and relative dose in determining the competitive outcome of multiple infections in the Daphnia magna-Pasteuria ramosa host-parasite system. We found that infections by P. ramosa clones (single genotype) were less virulent and produced more spores than infections by P. ramosa isolates (possibly containing multiple genotypes). We also found that two similarly virulent isolates of P. ramosa differed considerably in their within-host competitiveness and their effects on host offspring production when faced with coinfecting P. ramosa isolates and clones. Although the relative virulence of a P. ramosa isolate/clone appears to be a good indicator of its competitiveness during multiple infections, the relative dose may alter the competitive outcome. Moreover, spore counts on day 20 post-infection indicate that the competitive outcome is largely decided early in the parasite's growth phase, possibly mediated by direct interference or apparent competition. Our results emphasize the importance of epidemiology as well as of various parasite traits in determining the outcome of within-host competition. Incorporating realistic epidemiological and ecological conditions when testing theoretical models of multiple infections, as well as using a wider range of host and parasite genotypes, will enable us to better understand the course of virulence evolution.

  7. Evaluation of an every-other-day palonosetron schedule to control emesis in multiple-day high-dose chemotherapy.

    Mirabile, Aurora; Celio, Luigi; Magni, Michele; Bonizzoni, Erminio; Gianni, Alessandro Massimo; Di Nicola, Massimo

    2014-12-01

    Efficacy of intermittent palonosetron dosing in patients undergoing multiple-day, high-dose chemotherapy (HDC) was investigated. Fifty-eight patients received palonosetron (0.25 mg intravenous [iv.]) every other day plus daily dexamethasone (8 mg iv. twice daily) dosing. The primary end point was complete control (CC; no emesis, no rescue anti-emetics, and no more than mild nausea) in the overall acute-period (until 24 h after chemotherapy completion). Acute-period CC occurred in 81% and 50% of patients receiving palonosetron and ondansetron (historical control cohort), respectively. Palonosetron (odds ratio [OR]: 4.37; p = 0.001) and a longer duration of HDC regimen (OR: 3.47; p = 0.011) independently predicted a better anti-emetic outcome. Palonosetron every other day plus daily dexamethasone is an effective anti-emetic coverage in patients undergoing HDC.

  8. Successful pregnancy following low-dose hCG administration in addition to hMG in a patient with hypothalamic amenorrhea due to weight loss.

    Tsutsumi, Ryo; Fujimoto, Akihisa; Osuga, Yutaka; Harada, Miyuki; Takemura, Yuri; Koizumi, Minako; Yano, Tetsu; Taketani, Yuji

    2012-06-01

    We describe successful ovulation induction with low-dose hCG administration in addition to hMG in a patient with refractory hypothalamic amenorrhea. A 24-year-old woman with weight loss-related amenorrhea underwent ovulation induction and intracytoplasmic sperm injection (ICSI). Administration of exogenous gonadotropins was ineffective in ovulation induction. Supplementation with low-dose hCG in order to increase luteinizing hormone (LH) activity in the late follicular phase produced late folliculogenesis and steroidogenesis, and ovulation was then successfully induced. This report reacknowledges the critical role that LH plays cooperatively with follicle-stimulating hormone in both folliculogenesis and steroidogenesis.

  9. Lessons learned from administration of high-dose methylprednisolone sodium succinate for acute pediatric spinal cord injuries.

    Caruso, Michelle C; Daugherty, Margot C; Moody, Suzanne M; Falcone, Richard A; Bierbrauer, Karin S; Geis, Gary L

    2017-12-01

    OBJECTIVE Methylprednisolone sodium succinate (MPSS) has been studied as a pharmacological adjunct that may be given to patients with acute spinal cord injury (ASCI) to improve neurological recovery. MPSS treatment became the standard of care in adults despite a lack of evidence supporting clinical benefit. More recently, new guidelines from neurological surgeon groups recommended no longer using MPSS for ASCI, due to questionable clinical benefit and known complications. However, little information exists in the pediatric population regarding MPSS use in the setting of ASCI. The aim of this paper was to describe steroid use and side effects in patients with ASCI at the authors' Level 1 pediatric trauma center in order to inform other hospitals that may still use this therapy. METHODS A retrospective chart review was conducted to determine adherence in ordering and delivery according to the guideline of the authors' institution and to determine types and frequency of complications. Inclusion criteria included age < 17 years, blunt trauma, physician concern for ASCI, and admission for ≥ 24 hours or treatment with high-dose intravenous MPSS. Exclusion criteria included penetrating trauma, no documentation of ASCI, and incomplete medical records. Charts were reviewed for a predetermined list of complications. RESULTS A total of 602 patient charts were reviewed; 354 patients were included in the study. MPSS was administered in 59 cases. In 34 (57.5%) the order was placed correctly. In 13 (38.2%) of these 34 cases, MPSS was administered according to the recommended timeline protocol. Overall, only 13 (22%) of 59 patients received the therapy according to protocol with regard to accurate ordering and administration. Among the patients with ASCI, 20 (55.6%) of the 36 who received steroids had complications, which was a significantly higher rate than in those who did not receive steroids (8 [24.2%] of 33, p = 0.008). Among the patients without ASCI, 10 (43.5%) of the 23

  10. An explanation for the multiplicative and the additive dose-effect relationship with the single-hit model

    Kottbauer, M.M.; Fleck, C.M.; Schoellnberger, H.

    1997-01-01

    For solid tumors and for leukemia the excess cancer rate after a single radiation dose D is different. The multiplicative model describes the excess solid tumor probability rate which is proportional to the background rate of cancer and dependent on dose D. The additive model describes the excess probability rate for leukaemia which is proportional to the dose D but unrelated to the spontaneous rate of cancer. A second great difference between the two models is the duration of the increased cancer probability rate. The multiplicative mode predicts that the additional cancer risk persist the whole lifetime after exposure and the additive model predicts excess risk over a period of time. With the Single-hit model (SHM) which is a multistage cancer model both dose-response relationships can be described. It will be shown that only small differences in the derivation will lead to the different relationships. We then analyze the incidence data of leukemia (1950-1987) and of all solid tumors (1958-1987) of the atomic bomb survivors. (author)

  11. Dose-rate effects in synchronous mammalian cells in culture. II. A comparison of the life cycle of HeLa cells during continuous irradiation or multiple-dose fractionation

    Mitchell, J.B.; Bedford, J.S.

    1977-01-01

    The life cycle of synchronized S3 HeLa cells was examined during continuous irradiation at a dose rate of approximately 37 rad/hr and during multiple dose fractionation schedules of the same average dose rate (total dose / overall time = average dose rate). For all regimes given at this dose rate the effects on the life cyclee were similar. Cells progressed through G1 and S without appreciable delay and experienced a minimum G2 delay of about 10 hr. Cells eventually entered mitosis but virtually none were able to complete a successful division

  12. Undetected Severe Fetal Myelosuppression following Administration of High-Dose Cytarabine for Acute Myeloid Leukemia: Is More Frequent Surveillance Necessary?

    Jessica Parrott

    2017-01-01

    Full Text Available Background. Cytarabine use during pregnancy carries a 5–7% risk of neonatal cytopenia. We report two cases of fetal myelosuppression following high-dose cytarabine administration for acute myeloid leukemia (AML. Case 1. A 36-year-old G9P6 diagnosed with AML at 21 weeks was monitored for fetal anemia weekly and growth monthly. At 33 weeks (after 2 cycles, BPP was 2/10 and MCA PSV was elevated at 1.51 MoM. Urgent cesarean section was performed. The infant had an initial pH of 6.78 and pancytopenia (hematocrit 13.3%, platelets 3 K/UL, and white blood cell count 2.0 K/UL. Initially transfusion dependent, the neonate had count recovery by 3 weeks. Case 2. A 30-year-old G4P3 with AML at 26 weeks was monitored for fetal anemia twice weekly and growth monthly. At 34 weeks (after cycle 1, she was admitted with neutropenic fever. The fetal MCA PSV was borderline at 1.48 MoM. It improved to 1.38 MoM at 35 weeks but the fetal tracing worsened. At delivery the fetus was found to have a hematocrit of 30%, but with normal platelet and WBC. The fetus did not require any transfusions. Conclusion. Cytarabine use during pregnancy may cause neonatal myelosuppression. We recommend monitoring for fetal anemia with MCA Dopplers twice weekly.

  13. Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody.

    Donahue, Renee N; Lepone, Lauren M; Grenga, Italia; Jochems, Caroline; Fantini, Massimo; Madan, Ravi A; Heery, Christopher R; Gulley, James L; Schlom, Jeffrey

    2017-01-01

    Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb which has been shown in prior in vitro studies to mediate ADCC versus a range of human tumor cells, and clinical studies have demonstrated anti-tumor activity versus a range of human cancers. This study was designed to investigate the effect on immune cell subsets in the peripheral blood of cancer patients prior to and following multiple administrations of avelumab. One hundred twenty-three distinct immune cell subsets in the peripheral blood of cancer patients ( n  = 28) in a phase I trial were analyzed by flow cytometry prior to and following one, three, and nine cycles of avelumab. Changes in soluble (s) CD27 and sCD40L in plasma were also evaluated. In vitro studies were also performed to determine if avelumab would mediate ADCC of PBMC. No statistically significant changes in any of the 123 immune cell subsets analyzed were observed at any dose level, or number of doses, of avelumab. Increases in the ratio of sCD27:sCD40L were observed, suggesting potential immune activation. Controlled in vitro studies also showed lysis of tumor cells by avelumab versus no lysis of PBMC from five donors. These studies demonstrate the lack of any significant effect on multiple immune cell subsets, even those expressing PD-L1, following multiple cycles of avelumab. These results complement prior studies showing anti-tumor effects of avelumab and comparable levels of adverse events with avelumab versus other anti-PD-1/PD-L1 MAbs. These studies provide the rationale to further exploit the potential ADCC mechanism of action of avelumab as well as other human IgG1 checkpoint

  14. Multiple methods for assessing the dose to skin exposed to radioactive contamination

    Dubeau, J.; Heinmiller, B.E.; Corrigan, M.

    2017-01-01

    There is the possibility for a worker at a nuclear installation, such as a nuclear power reactor, a fuel production facility or a medical facility, to come in contact with radioactive contaminants. When such an event occurs, the first order of business is to care for the worker by promptly initiating a decontamination process. Usually, the radiation protection personnel performs a G-M pancake probe measurement of the contamination in situ and collects part or all of the radioactive contamination for further laboratory analysis. The health physicist on duty must then perform, using the available information, a skin dose assessment that will go into the worker's permanent dose record. The contamination situations are often complex and the dose assessment can be laborious. This article compares five dose assessment methods that involve analysis, new technologies and new software. The five methods are applied to 13 actual contamination incidents consisting of direct skin contact, contamination on clothing and contamination on clothing in the presence of an air gap between the clothing and the skin. This work shows that, for the cases studied, the methods provided dose estimates that were usually within 12% (1σ) of each other, for those cases where absolute activity information for every radionuclide was available. One method, which relies simply on a G-M pancake probe measurement, appeared to be particularly useful in situations where a contamination sample could not be recovered for laboratory analysis. (authors)

  15. Pharmacokinetic Study of Intravenous Acetaminophen Administered to Critically Ill Multiple-Trauma Patients at the Usual Dosage and a New Proposal for Administration.

    Fuster-Lluch, Oscar; Zapater-Hernández, Pedro; Gerónimo-Pardo, Manuel

    2017-10-01

    The pharmacokinetic profile of intravenous acetaminophen administered to critically ill multiple-trauma patients was studied after 4 consecutive doses of 1 g every 6 hours. Eleven blood samples were taken (predose and 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 minutes postdose), and urine was collected (during 6-hour intervals between doses) to determine serum and urine acetaminophen concentrations. These were used to calculate the following pharmacokinetic parameters: maximum and minimum concentrations, terminal half-life, area under serum concentration-time curve from 0 to 6 hours, mean residence time, volume of distribution, and serum and renal clearance of acetaminophen. Daily doses of acetaminophen required to obtain steady-state minimum (bolus dosing) and average plasma concentrations (continuous infusion) of 10 μg/mL were calculated (10 μg/mL is the presumed lower limit of the analgesic range). Data are expressed as median [interquartile range]. Twenty-two patients were studied, mostly young (age 44 [34-64] years) males (68%), not obese (weight 78 [70-84] kg). Acetaminophen concentrations and pharmacokinetic parameters were these: maximum concentration 33.6 [25.7-38.7] μg/mL and minimum concentration 0.5 [0.2-2.3] μg/mL, all values below 10 μg/mL and 8 below the detection limit; half-life 1.2 [1.0-1.9] hours; area under the curve for 6 hours 34.7 [29.7-52.7] μg·h/mL; mean residence time 1.8 [1.3-2.6] hours; steady-state volume of distribution 50.8 [42.5-66.5] L; and serum and renal clearance 28.8 [18.9-33.7] L/h and 15 [11-19] mL/min, respectively. Theoretically, daily doses for a steady-state minimum concentration of 10 μg/mL would be 12.2 [7.8-16.4] g/day (166 [112-202] mg/[kg·day]); for an average steady-state concentration of 10 μg/mL, they would be 6.9 [4.5-8.1] g/day (91 [59-111] mg/[kg·day]). In conclusion, administration of acetaminophen at the recommended dosage of 1 g per 6 hours to critically ill multiple-trauma patients yields

  16. The comparison of microdose flare-up and multiple dose antagonist protocols based on hCG day estradiol (E2), progesterone (P) and P/E2 ratio among poor responder patients in ICSI-ET cycles.

    Cicek, M N; Kahyaoglu, I; Kahyaoglu, S

    2015-02-01

    Elevated progesterone levels surpassing exact treshold values impede endometrial receptivity and decrease clinical pregnancy rates in different responder patients during assisted reproductive techniques. A progesterone (P): estradiol (E2) ratio of > 1 on the day of hCG administration has also been suggested to be a manifestation of low ovarian reserve. The clinical significance of P/E2 ratio on the day of hCG administration was investigated among poor responder patients. Based on the ESHRE Bologna consensus criteria related to poor ovarian response diagnosis, 48 poor responder patients were treated with the microdose flare-up regimen and 34 patients were treated with the multiple-dose GnRH antagonist protocol. All patients were destined to perform a ICSI-ET procedure at the end of the stimulation protocols. Progesterone levels and P/E2 ratios have been detected during controlled ovarian hyperstimulation. In the microdose flare-up group; the duration of stimulation, total gonadotropin dose used and hCG day E2 levels were significantly higher than the multiple dose antagonist group. However, the mean hCG day P/E2 rate in the microdose flare-up group was less than that in the multiple-dose antagonist group. The clinical pregnancy rates were non significantly higher in the multiple dose antagonist protocol group than in microdose flare-up group. Impaired endometrial receptivity caused by elevated P levels results with lower pregnancy rates. Regardless of the selected stimulation protocol, poor responder patients are not prone to exhibit high P and E2 secretion. Increased P/E2 ratio of > 1 on hCG day has limited value to predict cycle outcomes in poor responder patients because of ovarian follicle depletion.

  17. Efficacy of Single-dose and 2-dose Intravenous Administration of Ramosetron in Preventing Postoperative Nausea and Vomiting After Laparoscopic Gynecologic Operation: A Randomized, Double-blind, Placebo-controlled, Phase 2 Trial.

    Lee, Banghyun; Kim, Kidong; Suh, Dong Hoon; Shin, Hyun-Jung; No, Jae Hong; Lee, Jung Ryeol; Jee, Byung Chul; Hwang, Jung Won; Do, Sang Hwan; Kim, Yong Beom

    2017-06-01

    This randomized trial investigated whether a 2-dose administration of intravenous ramosetron (5-hydroxytryptamine type 3 receptor antagonist) is more effective than a single-dose administration in preventing postoperative nausea and vomiting (PONV) in 89 patients who were scheduled to undergo laparoscopic operation for benign gynecologic diseases and to receive intravenous patient-controlled analgesia for relief of postoperative pain. After assignment at a ratio of 1:1, intravenous ramosetron (0.3 mg) was initially administered at the end of skin closure in all patients. Thereafter, ramosetron (0.3 mg) and placebo were administered to the study and control groups, respectively, at 4 hours after the operation. The baseline and operative characteristics were similar between the groups. The incidence of PONV during the 24-hour period after operation which was assessed as the primary endpoint did not differ between the groups. No serious adverse events occurred in either group. A 2-dose administration of intravenous ramosetron may not be superior to a single-dose administration in preventing PONV in patients undergoing laparoscopic operation for benign gynecologic diseases.

  18. Quantitative MR changes in Gd-DTPA enhancement after high dose intravenous methylprednisolone in multiple sclerosis

    Barkhof, F.; Valk, J.; Hommes, O.R.; Scheltens, P.

    1991-01-01

    The purpose of this study was to investigate the effect of high dose intravenous methylprednisolone (MP) on gadolinium-DTPA enhancement in MS-lesions. By means of this the influence of MP on the permeability of the blood-brain barrier can be studied. (author). 19 refs.; 1 fig

  19. Lung tuberculosis in children, and radiation doses imported during multiple exposures

    Milkovic, Dj.; Ranogajec Komor, M.; Knezevic, Z.; Milkovic, I.

    1996-01-01

    Most of the artificial ionizing radiation sources are located in medical institutions. The largest contribution to popular irradiation, apart from natural sources, also originates from their use. The application of ionizing radiation in medicine is continuously developing and spreading. Not only the individual absorbed dose is steadily growing, the whole population is more and more exposed. By lung radiogram analysis, important diagnostic data are obtained for tuberculosis treatment. So chest radiography remains the most important method at diagnosing and attending TB patients, children or adults equally. Unfortunately, radiological treatment is accompanied by the risk of radiation doses being received on organs which are unprotectable during examination. It should be remembered that TB patients are frequently x-rayed, whereby the accumulated dose, and the damage risk increase. To make the risk as small, and the benefit of ionizing radiation use as big as possible, certain principles have to be followed: a) Treat a patient with x-rays only if there is a positive and justified medical indication. b) If it is unavoidable, it has to be performed in an institution where technique and protection methods are well known to the staff. c) Monitor the received radiation doses by using suitable and precise dosimetry equipment. (author)

  20. Absence of hydrocortisone from cytoplasmic hormone-protein complexes formed in vivo after administration of biologically active doses of [3H] hydrocortisone

    Voigt, J.; Grote, H.; Sekeris, C.E.

    1981-01-01

    After administration of [ 3 H] hydrocortisone to adrenalectomized rats, hormone-protein complexes were isolated from liver cytosol by DEAE-cellulose chromatography. After application of biologically active and inactive doses of hydrocortisone five binding components were detected eluting at the same salt concentrations as the hormone-protein complexes observed after incubation of cytosol with [ 3 H] hydrocortisone in vitro. The isolated hormone-protein fractions were acidified and extracted with ethylacetate and the steroids were analyzed by thin-layer chromatography. No significant amount of hydrocortisone could be detected in any of the complexes formed in vivo 5-60 min after administration of biologically active doses of hydrocortisone. 3xi,11β,17α,20xi, 21-Pentahydroxypregnane, steroidal carboxy acids, glucuronides and a very polar conjugate of hydrocortisone were found in the different fractions. After an in vivo dose of hydrocortisone of about 1/5000th of the minimal dose required for enzyme induction, hydrocortisone could be found in all the cytoplasmic hormone-protein complexes formed. In contrast to the cytoplasmic hormone-protein complexes, hydrocortisone could be readily demonstrated in nuclei isolated after the administration of biologically active doses of hormone, although acid metabolites were found to represent the main part of the radioactive compounds present in the nuclei. These acid metabolites were located in the nuclear envelope. (orig.)

  1. Theoretical estimation of absorbed dose to organs in radioimmunotherapy using radionuclides with multiple unstable daughters

    Hamacher, K.A.; Sgouros, G.

    2001-01-01

    The toxicity and clinical utility of long-lived alpha emitters such as Ac-225 and Ra-223 will depend upon the fate of alpha-particle emitting unstable intermediates generated after decay of the conjugated parent. For example, decay of Ac-225 to a stable element yields four alpha particles and seven radionuclides. Each of these progeny has its own free-state biodistribution and characteristic half-life. Therefore, their inclusion for a more accurate prediction of absorbed dose and potential toxicity requires a formalism that takes these factors into consideration as well. To facilitate the incorporation of such intermediates into the dose calculation, a previously developed methodology (model 1) has been extended. Two new models (models 2 and 3) for allocation of daughter products are introduced and are compared with the previously developed model. Model 1 restricts the transport to a function that yields either the place of origin or the place(s) of biodistribution depending on the half-life of the parent radionuclide. Model 2 includes the transient time within the bloodstream and model 3 incorporates additional binding at or within the tumor. This means that model 2 also allows for radionuclide decay and further daughter production while moving from one location to the next and that model 3 relaxes the constraint that the residence time within the tumor is solely based on the half-life of the parent. The models are used to estimate normal organ absorbed doses for the following parent radionuclides: Ac-225, Pb-212, At-211, Ra-223, and Bi-213. Model simulations are for a 0.1 g rapidly accessible tumor and a 10 g solid tumor. Additionally, the effects of varying radiolabled carrier molecule purity and amount of carrier molecules, as well as tumor cell antigen saturation are examined. The results indicate that there is a distinct advantage in using parent radionuclides such as Ac-225 or Ra-223, each having a half-life of more than 10 days and yielding four alpha

  2. Pharmacokinetic comparison of sustained- and immediate-release oral formulations of cilostazol in healthy Korean subjects: a randomized, open-label, 3-part, sequential, 2-period, crossover, single-dose, food-effect, and multiple-dose study.

    Lee, Donghwan; Lim, Lay Ahyoung; Jang, Seong Bok; Lee, Yoon Jung; Chung, Jae Yong; Choi, Jong Rak; Kim, Kiyoon; Park, Jin Woo; Yoon, Hosang; Lee, Jaeyong; Park, Min Soo; Park, Kyungsoo

    2011-12-01

    A sustained-release (SR) formulation of cilostazol was recently developed in Korea and was expected to yield a lower C(max) and a similar AUC to the immediate-release (IR) formulation. The goal of the present study was to compare the pharmacokinetic profiles of a newly developed SR formulation and an IR formulation of cilostazol after single- and multiple-dose administration and to evaluate the influence of food in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. This was a randomized, 3-part, sequential, open-label, 2-period crossover study. Each part consisted of different subjects between the ages of 19 and 55 years. In part 1, each subject received a single dose of SR (200 mg × 1 tablet, once daily) and IR (100 mg × 2 tablets, BID) formulations of cilostazol orally 7 days apart in a fasted state. In part 2, each subject received a single dose of the SR (200 mg × 1 tablet, once daily) formulation of cilostazol 7 days apart in a fasted and a fed state. In part 3, each subject received multiple doses of the 2 formulations for 8 consecutive days 21 days apart. Blood samples were taken for 72 hours after the dose. Cilostazol pharmacokinetics were determined for both the parent drug and its metabolites (OPC-13015 and OPC-13213). Adverse events were evaluated through interviews and physical examinations. Among the 92 enrolled subjects (66 men, 26 women; part 1, n = 26; part 2, n = 26; part 3, n = 40), 87 completed the study. In part 1, all the primary pharmacokinetic parameters satisfied the criterion for assumed bioequivalence both in cilostazol and its metabolites, yielding 90% CI ratios of 0.9624 to 1.2323, 0.8873 to 1.1208, and 0.8919 to 1.1283 for C(max) and 0.8370 to 1.0134, 0.8204 to 0.9807, and 0.8134 to 0.9699 for AUC(0-last) of cilostazol, OPC-13015, and OPC-13213, respectively. In part 2, food intake increased C(max) and AUC significantly (P food and 23 with a high

  3. Evaluation of occupational radiation dose in nuclear medicine: radiopharmaceutical administration to scintiscanning exams of myocardial perfusion; Avaliacao da dose de radiacao ocupacional em medicina nuclear: administracao de radiofarmacos em exames de cintilografria de perfusao miocardica

    Komatsu, Cassio V., E-mail: cassiok@yahoo.com [Medicina Nuclear do Triangulo (MNT), Uberlandia, MG (Brazil); Michelin, Charlie A.; Jakubiak, Rosangela R., E-mail: charlie@utfpr.edu.br, E-mail: requi@utfpr.edu.br [Universidade Tecnologica Federal do Parana (UTFPR), Curitiba, PR (Brazil); Lemes, Alyne O.; Silva, Juliana L.M., E-mail: alyne275@gmail.com, E-mail: jujumontesdocinho@gmail.com [Faculdade do Trabalho (FATRA), Uberlandia, MG (Brazil)

    2013-11-01

    In nuclear medicine, workers directly involved in exams are constantly exposed to ionizing radiation. The procedure for administration of the radiopharmaceutical to the patient is one of the most critical times of exposure. In tests of myocardial perfusion scintigraphy (MPS) administration of radiopharmaceutical repeats the steps of rest and cardiac stress. In this study, we used a Geiger -Mueller detector for measuring occupational radiation doses for during the administration of technetium- {sup 99m}- sestamibi in MPS tests. In the evaluation, discriminated the stages of examination and related professional experience time to doses measures at home. It were followed 110 procedures at home (55 conducted by professionals with over 5 years experience and 55 conducted by professionals with less than 1 year of experience) and 55 effort procedures. The results showed that the rest of the procedure time and dose are related to the experience of the worker. More experienced workers were faster (mean: 43 {+-} 16 vs 67 {+-} 25 seconds / procedure), and therefore received lower doses (mean 0.57 {+-} 0.16 versus 0.80 {+-} 0.24 {mu}Sv / procedure), both with statistical significance (p <0.001). In step effort, there were procedures lasting longer (mean: 19 {+-} 2 minutes / procedure), which resulted in higher doses (mean 3.0 {+-} 0.6 {mu}Sv / procedure)

  4. Neuroprotection and mechanisms of atractylenolide III in preventing learning and memory impairment induced by chronic high-dose homocysteine administration in rats.

    Zhao, H; Ji, Z-H; Liu, C; Yu, X-Y

    2015-04-02

    Studies demonstrated that chronic high-dose homocysteine administration induced learning and memory impairment in animals. Atractylenolide III (Aen-III), a neuroprotective constituent of Atractylodis macrocephalae Koidz, was isolated in our previous study. In this study, we investigated potential benefits of Aen-III in preventing learning and memory impairment following chronic high-dose homocysteine administration in rats. Results showed that administration of Aen-III significantly ameliorated learning and memory impairment induced by chronic high-dose homocysteine administration in rats, decreased homocysteine-induced reactive oxygen species (ROS) formation and restored homocysteine-induced decrease of phosphorylated protein kinase C expression level. Moreover, Aen-III protected primary cultured neurons from apoptotic death induced by homocysteine treatment. This study provides the first evidence for the neuroprotective effect of Aen-III in preventing learning and impairment induced by chronic administration of homocysteine. Aen-III may have therapeutic potential in treating homocysteine-mediated cognitive impairment and neuronal injury. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Effects of multiple low dose radiation on spleen T lymphocyte subgroups in eight-week diabetic rats

    Guan Feng; Li Yanbo; Zhao Hongguang; Guo Wei; Wang Zhicheng; Gong Shouliang; Guo Caixia

    2008-01-01

    Objective: To explore the changes of spleen lymphocyte subgroups in diabetic rats after multiple low dose radiation (LDR). Methods: The experiment was divided into normal control group, pure diabetes mellitus (DM) group, and DM plus different doses of irradiation groups (the irradiation doses were 0.025, 0.050 and 0.075 Gy, respectively). The diabetic rat model was induced by intraperitoneal injection of streptozotocin. After the diabetic rats were irradiated 15 times, the percentages of spleen CD4 + and CD8 + T cells and ratio of CD4 + /CD8 + T cells were detected with flow cytometry on the fourth weekend. Results: The diabetic rats manifested obvious polydipsia, polyphagia, polyuria and weight loss. On the fourth weekend after irradiation, as compared with normal control group, the percentage of spleen CD4 + T cells increased significantly (P + T cells decreased significantly (P + /CD8 + T cells was increased significantly (P + T cells were declined markedly in both 0.050 and 0.075 Gy plus DM groups (P + T cells increased significantly in LDR plus DM groups (P + /CD8 + T cells was declined obviously (P<0.01). Conclusion: The multiple LDR could regulate the immune function in diabetic rats, and rectificate the immunological imbalance in order to protect body. (authors)

  6. Impact of high- versus low-dose neuromuscular blocking agent administration on unplanned 30-day readmission rates in retroperitoneal laparoscopic surgery.

    Martijn Boon

    Full Text Available Recent data shows that a neuromuscular block (NMB induced by administration of high doses of rocuronium improves surgical conditions in certain procedures. However, there are limited data on the effect such practices on postoperative outcomes. We performed a retrospective analysis to compare unplanned 30-day readmissions in patients that received high-dose versus low-dose rocuronium administration during general anesthesia for laparoscopic retroperitoneal surgery. This retrospective cohort study was performed in the Netherlands in an academic hospital where routine high-dose rocuronium NMB has been practiced since July 2015. Charts of patients receiving anesthesia between January 2014 and December 2016 were searched for surgical cases receiving high-dose rocuronium and matched with respect to procedure, age, sex and ASA classification to patients receiving low-dose rocuronium. The primary post-operative outcome was unplanned 30-day readmission rate. There were 130 patients in each cohort. Patients in the high- and low-dose rocuronium cohorts received 217 ± 49 versus 37 ± 5 mg rocuronium, respectively. In the high-dose rocuronium group neuromuscular activity was consistently monitored; matched patients were unreliably monitored. All patients receiving high-dose rocuronium were reversed with sugammadex, while just 33% of matched patients were reversed with sugammadex and 20% with neostigmine; the remaining patients were not reversed. Unplanned 30-day readmission rate was significantly lower in the high-dose compared to the low-dose rocuronium cohort (3.8% vs. 12.7%; p = 0.03; odds ratio = 0.33, 95% C.I. 0.12-0.95. This small retrospective study demonstrates a lower incidence of unplanned readmissions within 30-days following laparoscopic retroperitoneal surgery with high-dose relaxant anesthesia and sugammadex reversal in comparison to low-dose relaxant anesthesia. Further prospective studies are needed in larger samples to corroborate our

  7. Impact of high- versus low-dose neuromuscular blocking agent administration on unplanned 30-day readmission rates in retroperitoneal laparoscopic surgery.

    Boon, Martijn; Martini, Chris; Yang, H Keri; Sen, Shuvayu S; Bevers, Rob; Warlé, Michiel; Aarts, Leon; Niesters, Marieke; Dahan, Albert

    2018-01-01

    Recent data shows that a neuromuscular block (NMB) induced by administration of high doses of rocuronium improves surgical conditions in certain procedures. However, there are limited data on the effect such practices on postoperative outcomes. We performed a retrospective analysis to compare unplanned 30-day readmissions in patients that received high-dose versus low-dose rocuronium administration during general anesthesia for laparoscopic retroperitoneal surgery. This retrospective cohort study was performed in the Netherlands in an academic hospital where routine high-dose rocuronium NMB has been practiced since July 2015. Charts of patients receiving anesthesia between January 2014 and December 2016 were searched for surgical cases receiving high-dose rocuronium and matched with respect to procedure, age, sex and ASA classification to patients receiving low-dose rocuronium. The primary post-operative outcome was unplanned 30-day readmission rate. There were 130 patients in each cohort. Patients in the high- and low-dose rocuronium cohorts received 217 ± 49 versus 37 ± 5 mg rocuronium, respectively. In the high-dose rocuronium group neuromuscular activity was consistently monitored; matched patients were unreliably monitored. All patients receiving high-dose rocuronium were reversed with sugammadex, while just 33% of matched patients were reversed with sugammadex and 20% with neostigmine; the remaining patients were not reversed. Unplanned 30-day readmission rate was significantly lower in the high-dose compared to the low-dose rocuronium cohort (3.8% vs. 12.7%; p = 0.03; odds ratio = 0.33, 95% C.I. 0.12-0.95). This small retrospective study demonstrates a lower incidence of unplanned readmissions within 30-days following laparoscopic retroperitoneal surgery with high-dose relaxant anesthesia and sugammadex reversal in comparison to low-dose relaxant anesthesia. Further prospective studies are needed in larger samples to corroborate our findings and

  8. Increased serum bile acid concentration following low-dose chronic administration of thioacetamide in rats, as evidenced by metabolomic analysis

    Jeong, Eun Sook; Kim, Gabin; Shin, Ho Jung [Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 (Korea, Republic of); Park, Se-Myo; Oh, Jung-Hwa; Kim, Yong-Bum; Moon, Kyoung-Sik [Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343 (Korea, Republic of); Choi, Hyung-Kyoon [College of Pharmacy, Chung-Ang University, Seoul (Korea, Republic of); Jeong, Jayoung [Ministry of Food and Drug Safety, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 361-951 (Korea, Republic of); Shin, Jae-Gook [Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 (Korea, Republic of); Kim, Dong Hyun, E-mail: dhkim@inje.ac.kr [Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 (Korea, Republic of)

    2015-10-15

    A liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS)-based metabolomics approach was employed to identify endogenous metabolites as potential biomarkers for thioacetamide (TAA)-induced liver injury. TAA (10 and 30 mg/kg), a well-known hepatotoxic agent, was administered daily to male Sprague–Dawley (SD) rats for 28 days. We then conducted untargeted analyses of endogenous serum and liver metabolites. Partial least squares discriminant analysis (PLS-DA) was performed on serum and liver samples to evaluate metabolites associated with TAA-induced perturbation. TAA administration resulted in altered levels of bile acids, acyl carnitines, and phospholipids in serum and in the liver. We subsequently demonstrated and confirmed the occurrence of compromised bile acid homeostasis. TAA treatment significantly increased serum levels of conjugated bile acids in a dose-dependent manner, which correlated well with toxicity. However, hepatic levels of these metabolites were not substantially changed. Gene expression profiling showed that the hepatic mRNA levels of Ntcp, Bsep, and Oatp1b2 were significantly suppressed, whereas those of basolateral Mrp3 and Mrp4 were increased. Decreased levels of Ntcp, Oatp1b2, and Ostα proteins in the liver were confirmed by western blot analysis. These results suggest that serum bile acids might be increased due to the inhibition of bile acid enterohepatic circulation rather than increased endogenous bile acid synthesis. Moreover, serum bile acids are a good indicator of TAA-induced hepatotoxicity. - Highlights: • Endogenous metabolic profiles were assessed in rat after treatment of thioacetamide. • It significantly increased the levels of bile acids in serum but not in the liver. • Expression of the genes related to bile acid secretion and reuptake was decreased. • Increased serum bile acids result from block of enterohepatic circulation of bile acids.

  9. Increased serum bile acid concentration following low-dose chronic administration of thioacetamide in rats, as evidenced by metabolomic analysis

    Jeong, Eun Sook; Kim, Gabin; Shin, Ho Jung; Park, Se-Myo; Oh, Jung-Hwa; Kim, Yong-Bum; Moon, Kyoung-Sik; Choi, Hyung-Kyoon; Jeong, Jayoung; Shin, Jae-Gook; Kim, Dong Hyun

    2015-01-01

    A liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS)-based metabolomics approach was employed to identify endogenous metabolites as potential biomarkers for thioacetamide (TAA)-induced liver injury. TAA (10 and 30 mg/kg), a well-known hepatotoxic agent, was administered daily to male Sprague–Dawley (SD) rats for 28 days. We then conducted untargeted analyses of endogenous serum and liver metabolites. Partial least squares discriminant analysis (PLS-DA) was performed on serum and liver samples to evaluate metabolites associated with TAA-induced perturbation. TAA administration resulted in altered levels of bile acids, acyl carnitines, and phospholipids in serum and in the liver. We subsequently demonstrated and confirmed the occurrence of compromised bile acid homeostasis. TAA treatment significantly increased serum levels of conjugated bile acids in a dose-dependent manner, which correlated well with toxicity. However, hepatic levels of these metabolites were not substantially changed. Gene expression profiling showed that the hepatic mRNA levels of Ntcp, Bsep, and Oatp1b2 were significantly suppressed, whereas those of basolateral Mrp3 and Mrp4 were increased. Decreased levels of Ntcp, Oatp1b2, and Ostα proteins in the liver were confirmed by western blot analysis. These results suggest that serum bile acids might be increased due to the inhibition of bile acid enterohepatic circulation rather than increased endogenous bile acid synthesis. Moreover, serum bile acids are a good indicator of TAA-induced hepatotoxicity. - Highlights: • Endogenous metabolic profiles were assessed in rat after treatment of thioacetamide. • It significantly increased the levels of bile acids in serum but not in the liver. • Expression of the genes related to bile acid secretion and reuptake was decreased. • Increased serum bile acids result from block of enterohepatic circulation of bile acids.

  10. Using 'component multiplication' in MONK to reduce pessimism in the dose rate assessment for water-filled (ullaged) transport packages

    Dean, M.H.

    2002-01-01

    The external dose rates from spent fuel packages consist of gamma ray and neutron components. The source of gamma rays is from fission products and actinides in the spent fuel and from activation products in structural components of the fuel element. Neutrons originate from spontaneous fission in actinides (for example from curium isotopes) within the spent fuel and from (alpha, n) reactions in oxide fuel. However, a significant number of neutrons are produced due to further fission within the fuel. This is known as neutron enhancement or multiplication (M). To treat the effects of enhancement, the neutron source may be scaled within the dose rate calculation. In a wet package, it has been customary to determine k effective (k eff ) for a completely water-filled package or a package with a defined water level (for the horizontal transport condition). The irradiation of the fuel is normally taken into account in calculating k eff for this purpose. The neutron enhancement is then obtained by calculating M=1/(1-k eff ), which is then applied as a source scaling factor throughout each fuel assembly. In a wet package, there is normally an ullage volume above the water level, the package only being partially flooded. The ullage volume is designed to accommodate pressure build-up within the package. Typically the top row of fuel assemblies may be partially covered and partially uncovered by water. When the above value of M is used for fuel within the dry part of the package, dose rates above the package tend to be overestimated and can limit the carrying capability of the package. (Also, a single value of M will tend to over-predict dose rate contributions from all assemblies around the periphery). Use of component multiplication (a new feature available in the MONK computer code) enables two separate values of 'k eff ' to be determined for the wet and dry parts of the package. These typically differ by a factor of three, leading to differences in the enhancement, M. Use

  11. Individual doses control in the units of ministry of defence and ministry of interior and administration in the years 1986 - 2000

    Jazwinski, J.; Nowosielska, E.M.; Janiak, M.K.

    2003-01-01

    The aim of presented work was the assessment of occupational radiation exposure and its distribution among the workers of Ministry of Defence and Ministry of Interior and Administration in the years 1986 - 2000. the research was conducted on the basis of data collected by Laboratory of Radiological Inspection and Individual Doses Control, Department of Radiation Protection and Radiobiology Military Institute of Hygiene and Epidemiology, Warsaw, Poland. The workers occupationally exposed to radiation were divided into following groups: government department (Ministry of Defence or Ministry of Interior and Administration), according to the age (below 25, 26-35, 36-45, 46-55 and above 56 years old), sex, education, (elementary, secondary, university) or job (doctors, nurses, rtg technicians, etc.). The number of workers covered with individual doses control changed in Ministry of Defence from 689 (in 1986) to 1030 (in 2000), and in Ministry of Interior and Administration from 261 to 924 in the same period. The percent of workers, who received doses below 2 mSv per year varied in Ministry of Defence from 91,6% (in 1997) to 99,4% (in 1990), and in Ministry of Interior and Administration from 96,8% (in 1993) to 99,4 (in 2000). Almost 99% of workers occupationally exposed to radiation and covered with individual doses control received doses below 15 mSv, irrespective of year or department. The analysis of collected data revealed, that for a large majority of occupationally exposed workers the risk arising from contact with ionizing radiation is minimal (over 99% of workers covered with individual doses control received doses below 2 mSv per year), however there are critical groups of workers, for which the received equivalent doses were about 30 - 50 mSv. Increased doses of radiation, however not exceeding obligatory limits, are noticed for workers taking part in surgical operations in X radiation field, urologic operations and diagnostic and or working on several

  12. Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis.

    Peyro Saint Paul, Laure; Debruyne, Danièle; Bernard, Delphine; Mock, Donald M; Defer, Gilles L

    2016-01-01

    Multiple sclerosis (MS) is a chronic, potentially highly disabling neurological disorder. No disease-modifying treatments are approved in the progressive and not active forms of the disease. High doses of biotin were tested in an open-label pilot study involving 23 patients with progressive MS and reported positive results. A randomized, double-blind, placebo-controlled trial in 154 progressive MS patients confirmed the beneficial effect of MD1003 (high-dose biotin) on reversing or stabilizing disability progression, with a good safety profile. It is proposed that MD1003 in progressive MS 1) increases energy production in demyelinated axons and/or 2) enhances myelin synthesis in oligodendrocytes. Biotin is highly bioavailable; absorption and excretion are rapid. The major route of elimination is urinary excretion. A high oral dose of biotin seems generally well tolerated but a few important safety concerns were identified: 1) teratogenicity in one species and 2) interference with some biotin-based laboratory immunoassays. The animal toxicity data are limited at such high doses. Further preclinical studies would be useful to address the mechanism of action of MD1003. Assessment of clinical benefit duration in responders will be also very important to set. Results of randomized, placebo-controlled trial are reassuring and provide hope for the treatment of progressive MS.

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

    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

  14. Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects [Corrigendum

    Cui Y

    2014-03-01

    Full Text Available Cui Y, Song Y, Wang J, et al. Clinical Pharmacology: Advances and Applications. 2013;5(1:177–184.Note that on page 182, Figure 3 should be corrected as follows, with the line for mean anti-Xa activity extended through to 72 hours post dose on Day 9, and the Day 1 plasma apixaban concentration-time profile rendering error bars and symbols more visually apparent.Read the original article

  15. Dose- and time-dependent changes in tissue levels of tetrabromobisphenol A (TBBPA and its sulfate and glucuronide conjugates following repeated administration to female Wistar Han Rats

    S.J. Borghoff

    Full Text Available Tetrabromobisphenol A (TBBPA, a nongenotoxic flame retardant, causes uterine tumors in female rats. A proposed mode of action (MoA for these tumors involves an increase in the bioavailability of estradiol as a result of TBBPA inhibiting estrogen sulfotransferases (ES, the enzymes responsible for inactivating and enhancing the elimination of estradiol. The objective of this study was to evaluate the effect of dose and repeated administration of TBBPA on the level of TBBPA, TBBPA-glucuronide (GA and TBBPA-sulfate (S conjugates in plasma, liver and uterus of female Wistar Han rats administered TBBPA (50, 100, 250, 500 or 1000 mg/kg for 28 consecutive days. In accordance with this objective, TBBPA sulfation was used as a surrogate for evaluating the potential for estradiol sulfation to be limited at high dose levels of TBBPA. Blood samples were collected at 4 and 8 h post-dosing on study day 7, 14, and 28, while liver and uterus were collected at the same time points following 28 days of dosing. Tissue samples were analyzed for TBBPA, TBBPA-GA and TBBPA-S by LC–MS/MS. A dose-related increase in the concentration of all three analytes occurred in plasma (day 7, 14, and 28 as well as liver and uterus tissue (day 28 at both 4 and 8 h post dose. The plasma concentration of TBBPA-GA and TBBPA-S was higher in animals dosed for 28 days compared to those dosed for 7 or 14 days showing an increase in systemic circulation of these conjugates with repeated administration. The balance of these conjugates was also different in tissues with TBBPA-S > TBBPA-GA at high doses in the liver and TBBPA-GA > TBBPA-S in both plasma and uterus. In all three tissues the ratio of TBBPA-S/TBBPA-GA showed a decreasing trend with dose, suggesting that at high TBBPA dose levels sulfation of TBBPA becomes limited. This effect was most apparent in the liver and plasma at 28 days of administration. Together these data show that administration of high doses of TBBPA

  16. Demonstration of a stimulating effect of natural ionizing radiation and of very low radiation doses on cell multiplication

    Planel, G.; Soleilhavoup, J.P.; Tixador, R.; Croute, F.; Richoilley, G.

    1976-01-01

    Experiments have been carried out to demonstrate a possible effect of natural ionizing radiation. Using lead shielding devices or an underground laboratory, it was shown that a decrease in background irradiation induces a decrease in cell growth rate (experiments carried out on Paramecia). On the other hand, the recovery of a normal irradiation level in shielding devices induces a quite normal cell proliferation. Moreover, small doses of γ rays from 60 Co exhibit a stimulating effect. Variations in cell radiosensitivity to these low doses are reported. Experiments carried out in the underground laboratory and at high altitude show that both telluric radioactivity and cosmic rays contribute to this stimulating effect on cell multiplication. (author)

  17. The Effect of Nicotine Administration on Physical and Psychological Signs of Withdrawal Syndrome Induced by Single or Frequent Doses of Morphine in Rats

    Mohammad Allahtavakoli

    2012-07-01

    Full Text Available Introduction. Morphine addiction and morphine withdrawal syndrome are the two main problems of today’s human society. The present study has investigated the effects of nicotine on the strength of physical and psychological dependency in single and repeated doses morphine administrated rats. Materials and methods. Male Wistar rats were subjected to morphine consumption with single or frequent dose protocols. In the single dose protocol, rats received only one dose of morphine and 24hrs later they also received one dose of nicotine 30 min prior to injection of naloxone. In the repeated dose protocol, rats received incremental doses of morphine for 7 days and 24hr after the last dose (the 8th day were given naloxone. However, the nicotine regimen of this group was injected 15 min before the morphine injection, for 4 days, from the 4th to the 7th day. Five minutes after naloxone injection, each rat′s behavior was captured for 30 min, and then physical and psychological signs of withdrawal syndrome were recorded. Data were analyzed by ANOVA followed by Tukey tests and p<0.05 was considered as significant difference. Findings. Results showed that the injection of frequent and single doses of morphine lead to morphine dependency. In single dose protocol, nicotine consumption attenuated the signs of withdrawal syndrome, especially weight of excrement and total withdrawal score. In frequent dose protocol, in addition to these effects, nicotine induced weight loss and place aversion. Conclusion. The inhibitory effects of nicotine on signs of withdrawal syndrome may involve a dopaminergic portion of the central nervous system and is mediated by central nicotinic receptors. There is also a cross-dependence between nicotine and morphine.

  18. ‌‌The effect of nicotine administration on physical and psychological signs of withdrawal syndrome induced by single or frequent doses of morphine in rats

    Ali Shamsizadeh

    2012-07-01

    Full Text Available Introduction: Morphine addiction and morphine withdrawal syndrome are the two main problems of today’s human society. The present study has investigated the effects of nicotine on the strength of physical and psychological dependency in single and repeated doses morphine administrated rats. Methods: Male Wistar rats were subjected to morphine consumption with single or frequent dose protocols. In the single dose protocol, rats received only one dose of morphine and 24hrs later they also received one dose of nicotine 30 min prior to injection of naloxone. In the repeated dose protocol, rats received incremental doses of morphine for 7 days and 24hr after the last dose (the 8th day were given naloxone. However, the nicotine regimen of this group was injected 15 min before the morphine injection, for 4 days, from the 4th to the 7th day. Five minutes after naloxone injection, each rat′s behavior was captured for 30 min, and then physical and psychological signs of withdrawal syndrome were recorded. Data were analyzed by ANOVA followed by Tukey tests and p<0.05 was considered as significant difference. Results: Results showed that the injection of frequent and single doses of morphine lead to morphine dependency. In single dose protocol, nicotine consumption attenuated the signs of withdrawal syndrome, especially weight of excrement and total withdrawal score. In frequent dose protocol, in addition to these effects, nicotine induced weight loss and place aversion. Discussion: The inhibitory effects of nicotine on signs of withdrawal syndrome may involve a dopaminergic portion of the central nervous system and is mediated by central nicotinic receptors. There is also a cross-dependence between nicotine and morphine.

  19. Steady-State Serum T3 Concentrations for 48 Hours Following the Oral Administration of a Single Dose of 3,5,3'-Triiodothyronine Sulfate (T3S).

    Santini, Ferruccio; Giannetti, Monica; Ricco, Ilaria; Querci, Giorgia; Saponati, Giorgio; Bokor, Daniela; Rivolta, Giovanni; Bussi, Simona; Braverman, Lewis E; Vitti, Paolo; Pinchera, Aldo

    2014-07-01

    Sulfate conjugation of thyroid hormones is an alternate metabolic pathway that facilitates the biliary and urinary excretion of iodothyronines and enhances their deiodination rate, leading to the generation of inactive metabolites. A desulfating pathway reverses this process, and thyromimetic effects have been observed following the parenteral administration of 3,5,3'-triiodothyronine (T3) sulfate (T3S) in rats. The present study investigated whether T3S is absorbed after oral administration in humans and if it represents a source of T3. Twenty-eight hypothyroid patients (7 men and 21 women; mean age, 44 ± 11 years) who had a thyroidectomy for thyroid carcinoma were enrolled. Replacement thyroid hormone therapy was withdrawn (42 days for thyroxine, 14 days for T3) prior to 131I remnant ablation. A single oral dose of 20, 40, 80 (4 patients/group), or 160 μg (16 patients/group) of T3S was administered 3 days before the planned administration of 131I. Blood samples for serum T3S and total T3 (TT3) concentrations were obtained at various times up to 48 hours after T3S administration. At all T3S doses, serum T3S concentrations increased, reaching a peak at 2 to 4 hours and progressively returning to basal levels within 8 to 24 hours. The T3S maximum concentration (Cmax) and area under the 0- to 48-hour concentration-time curve (AUC0-48h) were directly and significantly related to the administered dose. An increase in serum TT3 concentration was observed (significant after 1 hour), and the concentration increased further at 2 and 4 hours and then remained steady up to 48 hours after T3S administration. There was a significant direct correlation between the TT3 AUC0-48h and the administered dose of T3S. No changes in serum free thyroxine (T4) concentrations during the entire study period were observed, whereas serum thyroid-stimulating hormone levels increased slightly at 48 hours, but this was not related to the dose of T3S. No adverse events were reported. (1) T3S is

  20. Subcutaneous Administration of Bortezomib in Combination with Thalidomide and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma Patients

    Shenghao Wu

    2015-01-01

    Full Text Available Objective. To investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM patients with the therapy of subcutaneous (subQ administration of bortezomib and dexamethasone plus thalidomide (VTD regimen. Methods. A total of 60 newly diagnosed MM patients were analyzed. 30 patients received improved VTD regimen (improved VTD group with the subQ injection of bortezomib and the other 30 patients received conventional VTD regimen (VTD group.The efficacy and safety of two groups were analyzed retrospectively. Results. The overall remission (OR after eight cycles of treatment was 73.3% in the VTD group and 76.7% in the improved VTD group (P>0.05. No significant differences in time to 1-year estimate of overall survival (72% versus 75%, P=0.848 and progression-free survival (median 22 months versus 25 months; P=0.725 between two groups. The main toxicities related to therapy were leukopenia, neutropenia, thrombocytopenia, asthenia, fatigue, and renal and urinary disorders. Grade 3 and higher adverse events were significantly less common in the improved VTD group (50% than VTD group (80%, P=0.015. Conclusions. The improved VTD regimen by changing bortezomib from intravenous administration to subcutaneous injection has noninferior efficacy to standard VTD regimen, with an improved safety profile and reduced adverse events.

  1. Effective multiple oral administration of reverse genetics engineered infectious bursal disease virus in mice in the presence of neutralizing antibodies.

    Hornyák, Ákos; Lipinski, Kai S; Bakonyi, Tamás; Forgách, Petra; Horváth, Ernő; Farsang, Attila; Hedley, Susan J; Palya, Vilmos; Bakács, Tibor; Kovesdi, Imre

    2015-01-01

    Despite spectacular successes in hepatitis B and C therapies, severe hepatic impairment is still a major treatment problem. The clinically tested infectious bursal disease virus (IBDV) superinfection therapy promises an innovative, interferon-free solution to this great unmet need, provided that a consistent manufacturing process preventing mutations or reversions to virulent strains is obtained. To address safety concerns, a tissue culture adapted IBDV vaccine strain V903/78 was cloned into cDNA plasmids ensuring reproducible production of a reverse engineered virus R903/78. The therapeutic drug candidate was characterized by immunocytochemistry assay, virus particle determination and immunoblot analysis. The biodistribution and potential immunogenicity of the IBDV agent was determined in mice, which is not a natural host of this virus, by quantitative detection of IBDV RNA by a quantitative reverse transcriptase-polymerase chain reaction and virus neutralization test, respectively. Several human cell lines supported IBDV propagation in the absence of visible cytopathic effect. The virus was stable from pH 8 to pH 6 and demonstrated significant resistance to low pH and also proved to be highly resistant to high temperatures. No pathological effects were observed in mice. Single and multiple oral administration of IBDV elicited antibodies with neutralizing activities in vitro. Repeat oral administration of R903/78 was successful despite the presence of neutralizing antibodies. Single oral and intravenous administration indicated that IBDV does not replicate in mammalian liver alleviating some safety related concerns. These data supports the development of an orally delivered anti-hepatitis B virus/ anti-hepatitis C virus viral agent for human use. Copyright © 2015 John Wiley & Sons, Ltd.

  2. Low-dose metformin improves pregnancy rate in in vitro fertilization repeaters without polycystic ovary syndrome: prediction of effectiveness by multiple parameters related to insulin resistance.

    Jinno, Masao; Kondou, Kenichi; Teruya, Koji

    2010-01-01

    Insulin resistance is associated with aging and stress, both common among patients repeatedly failing to conceive with in vitro fertilization (IVF repeaters). In the present study we examined whether low-dose metformin could improve the outcome in IVF repeaters without polycystic ovary syndrome (PCOS). Study I was a preliminary clinical trial aiming at defining indications for therapy; study II was a prospective randomized study. The studies involved a university hospital and a private infertility clinic. We studied 232 women without PCOS who had failed at least twice to conceive by previous IVF. Metformin (500 mg/ day) was administered for 8 to 12 weeks before and during ovarian stimulation (metformin IVF). In study I, IVF outcomes with metformin (n = 33) were compared to outcomes without metformin of previous IVF in the same subjects. A discriminant score (DS) was determined from nine parameters assessed before metformin administration to predict achievement of ongoing pregnancy by metformin IVF. In study II (n = 199), ongoing pregnancy rates were compared prospectively between groups with/without metformin and with DS above/below 0.6647. Study I. Ongoing pregnancy rate improved significantly with metformin compared with previous IVF, and pregnancy correlated significantly with a DS at an optimal threshold of 0.6647 (sensitivity, 0.90; specificity, 0.91). Study II. Ongoing pregnancy and implantation rates were significantly higher in women with a DS above 0.6647 who received metformin (56% and 33%) compared with those having a DS below 0.6647 with metformin (14% and 11%) and those having a DS above/below 0.6647 without metformin (20% and 7.1%/15% and 11%, respectively). Low-dose metformin improved pregnancy rate in IVF repeaters without PCOS, probably by decreasing insulin resistance. Indication can be determined from insulin-resistance-related multiple parameters assessed before metformin administration.

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

    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)

  4. Bisphenol A (BPA) aggravates multiple low-dose streptozotocin-induced Type 1 diabetes in C57BL/6 mice.

    Cetkovic-Cvrlje, Marina; Thinamany, Sinduja; Bruner, Kylie A

    2017-12-01

    Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disorder characterized by destruction of insulin-producing pancreatic β-cells. Whereas epidemiological data implicate environmental factors in the increasing incidence of T1D, their identity remains unknown. Though exposure to bisphenol A (BPA) has been associated with several disorders, no epidemiologic evidence has linked BPA exposure and T1D. The goal of this study was to elucidate diabetogenic potentials of BPA and underlying mechanisms in the context of T-cell immunity, in a multiple low-dose streptozotocin (MLDSTZ)-induced autoimmune mouse T1D model. C57BL/6 mice were orally exposed to 1 or 10 mg BPA/L starting at 4 wk of age; diabetes was induced at 9 wk of age with STZ. T-cell composition, function, and insulitis levels were studied at Days 11 and 50 during diabetes development (i.e. post-first STZ injection). Results showed both BPA doses increased diabetes incidence and affected T-cell immunity. However, mechanisms of diabetogenic action appeared divergent based on dose. Low-dose BPA fits a profile of an agent that exhibits pro-diabetogenic effects via T-cell immunomodulation in the early stages of disease development, i.e. decreases in splenic T-cell subpopulations [especially CD4 + T-cells] along with a trend in elevation of splenic T-cell formation of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6). In contrast, high-dose BPA did not affect T-cell populations and led to decreased levels of IFN-γ and TNF-α. Both treatments did not affect insulitis levels at the disease early stage, but aggravated it later on. By the study end, besides decreasing T-cell proliferative capacity, low-dose BPA did not affect other T-cell-related parameters, including cytokine secretion, comparable to the effects of high-dose BPA. In conclusion, this study confirmed BPA as a potential diabetogenic compound with immunomodulatory mechanisms of action - in the context of T-cell immunity - that seemed to be dose

  5. Single and multiple dose Fluconazole in the treatment of candidia vulvovaginitis: a prospective comparative study

    Ashrafinia M

    2007-09-01

    Full Text Available  Background: Vulvovaginal candidiasis, the most common type of vaginitis, is usually caused by Candidia albicans. Patients experience a variety of symptoms. There are many types of vulvovaginal candidiasis with various microbial causes, symptoms, host circumstances, recurrence rates, and responses to treatment. The purpose of this study was to find the best method of treatment of complicated vaginitis as determined by its high prevalence, varying symptoms and signs and patient complaints.Methods: In this open clinical trial without placebo control, we studied all patients aged 18 to 65 years, suffering from vaginitis symptoms that presented at the gynecological clinic of Arash Hospital, Tehran, Iran, during the year 2004. After obtaining informed consent, we assessed the response to a treatment of single 150 mg dose of fluconazole in one group, and sequential 150 mg doses of fluconazole in the other. The analysis was performed using SPSS statistical software (version 11.Results: With regard to symptom severity, no significant difference was found between the groups. The rate of excoriation and fissure formation demonstrated significant difference between the two groups (p=0.048. Assessment of clinical and mycological response proved that patients with severe vaginitis treated with sequential doses of fluconazole had a better general status than those in the other group. The difference between the severity of vaginitis and positive response to the treatment in culture was not significant among patients with recurrent vaginitis.Conclusion: Patients with mild to moderate recurrent vaginitis show better response to treatment. The high rate of positive culture on day 35 reconfirms the limitation of fluconazole and other azoles as fungistatic drugs.

  6. Evaluation of multiple scan average dose (MSAD) levels in computerized tomography in Minas Gerais state, Brazil

    Alonso, Thessa C.; Vieira, Leandro de A.; Barbosa, Nayra V.; Oliveira, Jeyselaine R. de; Cesar, Adriana C.Z.; Silva, Teogenes A. da

    2014-01-01

    Computed Tomography (CT) grows every year and is a diagnostic method that has revolutionized radiology with advances in procedures for obtaining image. However, the indiscriminate use of this method generates relatively high doses in patients. The diagnostic reference levels (DRLs) is a practical tool to promote the evaluation of existing protocols. The optimization and the periodic review of the protocols are important to balance the risk of radiation. The present study aims to conduct a survey of levels of MSAD of Minas Gerais following the procedures recommended by current Brazilian law. (author)

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

    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

  8. Neutron/gamma dose separation by the multiple-ion-chamber technique

    Goetsch, S.J.

    1983-01-01

    Many mixed n/γ dosimetry systems rely on two dosimeters, one composed of a tissue-equivalent material and the other made from a non-hydrogenous material. The paired chamber technique works well in fields of neutron radiation nearly identical in spectral composition to that in which the dosimeters were calibrated. However, this technique is drastically compromised in phantom due to the degradation of the neutron spectrum. The three-dosimeter technique allows for the fall-off in neutron sensitivity of the two non-hydrogenous dosimeters. Precise and physically meaningful results were obtained with this technique with a D-T source in air and in phantom and with simultaneous D-T neutron and 60 Co gamma ray irradiation in air. The MORSE-CG coupled n/γ three-dimensional Monte Carlo code was employed to calculate neutron and gamma doses in a water phantom. Gamma doses calculated in phantom with this code were generally lower than corresponding ion chamber measurements. This can be explained by the departure of irradiation conditions from ideal narrow-beam geometry. 97 references

  9. Effects of ligand priming and multiple-dose injection on tissue uptake of 111In-pentetreotide in rats

    Breeman, Wout A. P.; Jong, Marion de; Bernard, Bert F.; Bakker, Willem H.; Rolleman, Edgar J.; Kwekkeboom, Kik J.; Visser, Theo J.; Krenning, Eric P.

    1997-01-01

    In patients undergoing somatostatin receptor scintigraphy, treatment with octreotide (Sandostatin[reg]) is usually discontinued 24-48 h before and after injection with the radioligand 111 In-pentetreotide ([ 111 In-DTPA o ]octreotide) (Octreoscan[reg]) because octreotide competes with radioligand for the same receptors. However, Doerr et al. and Soresi et al. reported improved visualization of carcinoid and small cell lung cancer lesions, respectively, during continued octreotide treatment. We found that intravenous administration of unlabeled octreotide to rats inhibited the binding of an optimal dose (0.5 μg) of 111 In-pentetreotide to somatostatin receptors in pancreas and adrenals in a mass- and time-dependent way. Pretreatment with unlabeled octreotide never increased receptor binding of 111 In-pentetreotide. Administration of 100 μg of octreotide decreased receptor-bound radioactivity if given simultaneously with or 10 or 20 min after injection of the radioligand, but had no effect if given 30 min after the radioligand. These findings indicate rapid processing of receptor-bound octreotide and suggest that octreotide treatment of patients undergoing 111 In-pentetreotide scintigraphy may be reinitiated as soon as 1 h after radioligand administration

  10. Estimation of the {beta}+ dose to the embryo resulting from {sup 18}F-FDG administration during early pregnancy

    Zanotti-Fregonara, P.; Trebossen, R.; Maroy, R. [CEA, DSV, I2BM, SHFJ, LIME, Orsay (France); Champion, C. [Univ Paul Verlaine Metz, Inst Phys, Lab Phys Mol et Collis, Metz (France); Hindie, E. [Univ Paris 07, IUH, Ecole Doctorale B2T, Paris (France); Hindie, E. [Hop St Louis, AP-HP, Nucl Med Serv, F-75475 Paris 10 (France)

    2008-07-01

    Although {sup 18}F-FDG examinations are widely used, data are lacking on the dose to human embryo tissues in cases of exposure in early pregnancy. Although the photon component can easily be estimated from available data on the pharmacokinetics of {sup 18}F-FDG in female organs and from phantom measurements (considering the uterus as the target organ), the intensity of embryo tissue uptake, which is essential for deriving the {beta}+ dose, is not known. We report the case of a patient who underwent {sup 18}F-FDG PET/CT for tumor surveillance and who was later found to have been pregnant at the time of the examination(embryo age, 8 wk). Methods: The patient received 320 MBq of {sup 18}F-FDG. Imaging started with an unenhanced CT scan 1 h after the injection, followed by PET acquisition. PET images were used to compute the total number of {beta}+ emissions in embryo tissues per unit of injected activity, from standardized uptake value (SUV) measurements corrected for partial-volume effects. A Monte Carlo track structure code was then used to derive the {beta}+ self-dose and the {beta}+ cross-dose from amniotic fluid. The photon and CT doses were added to obtain the final dose received by the embryo. Results: The mean SUV in embryo tissues was 2.7, after correction for the partial-volume effect. The mean corrected SUV of amniotic fluid was 1.1. Monte Carlo simulation showed that the {beta}+ dose to the embryo (self-dose plus cross-dose from amniotic fluid) was 1.8 E-2 mGy per MBq of injected {sup 18}F-FDG. Based on MIRD data for the photon dose to the uterus, the estimated photon dose to the embryo was 1.5 E-2 mGy/MBq. Thus, the specific {sup 18}F-FDG dose to the embryo was 3.3 E-2 mGy/MBq (10.6 mGy in this patient). The CT scan added a further 8.3 mGy. Conclusion: The dose to the embryo is 3.3 E-2 mGy/MBq of {sup 18}F-FDG. The {beta}+ dose contributes 55% of the total dose. This value is higher than previous estimates in late nonhuman-primate pregnancies. (authors)

  11. A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration.

    Sun, Changling; Wang, Xueling; Zheng, Zhaozhu; Chen, Dongye; Wang, Xiaoqin; Shi, Fuxin; Yu, Dehong; Wu, Hao

    2015-01-01

    This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of -26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications.

  12. Immune cell-derived c3 is required for autoimmune diabetes induced by multiple low doses of streptozotocin.

    Lin, Marvin; Yin, Na; Murphy, Barbara; Medof, M Edward; Segerer, Stephan; Heeger, Peter S; Schröppel, Bernd

    2010-09-01

    The complement system contributes to autoimmune injury, but its involvement in promoting the development of autoimmune diabetes is unknown. In this study, our goal was to ascertain the role of complement C3 in autoimmune diabetes. Susceptibility to diabetes development after multiple low-dose streptozotocin treatment in wild-type (WT) and C3-deficient mice was analyzed. Bone marrow chimeras, luminex, and quantitative reverse transcription PCR assays were performed to evaluate the phenotypic and immunologic impact of C3 in the development of this diabetes model. Coincident with the induced elevations in blood glucose levels, we documented alternative pathway complement component gene expression within the islets of the diabetic WT mice. When we repeated the experiments with C3-deficient mice, we observed complete resistance to disease, as assessed by the absence of histologic insulitis and the absence of T-cell reactivity to islet antigens. Studies of WT chimeras bearing C3-deficient bone marrow cells showed that bone marrow cell-derived C3, and not serum C3, is involved in the induction of diabetes in this model. The data reveal a key role for immune cell-derived C3 in the pathogenesis of murine multiple low-dose streptozotocin-induced diabetes and support the concept that immune cell mediated diabetes is in part complement-dependent.

  13. Bioavailibility of higher dose methotrexate comparing oral and subcutaneous route of administration in patients with rheumatoid arthritis

    Hoekstra, Monique; Hoekstra, M.; Haagsma, Cees; Neef, Cees; Proost, Johannes; van de Laar, Mart A F J; Knuif, Antonius

    2004-01-01

    OBJECTIVE: To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA). METHODS: A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (> or = 25 mg weekly). Separated by 2 weeks, a pharmacokinetic

  14. The development of a methodology to assess population doses from multiple sources and exposure pathways of radioactivity

    Hancox, J.; Stansby, S.; Thorne, M.

    2002-01-01

    The Environment Agency (EA) has new duties in accordance with the Basic Safety Standards Directive under which it is required to ensure that doses to individuals received from exposure to anthropogenic sources of radioactivity are within defined limits. In order to assess compliance with these requirements, the EA needs to assess the doses to members of the most highly exposed population groups ('critical' groups) from all relevant potential sources of anthropogenic radioactivity and all relevant potential exposure pathways to such radioactivity. The EA has identified a need to develop a methodology for the retrospective assessment of effective doses from multiple sources of radioactive materials and exposure pathways associated with those sources. Under contract to the EA, AEA Technology has undertaken the development of a suitable methodology as part of EA R and D Project P3-070. The methodology developed under this research project has been designed to support the EA in meeting its obligations under the Euratom Basic Safety Standards Directive and is consistent with UK and international approaches to radiation dosimetry and radiological protection. The development and trial application of the methodology is described in this report

  15. Effect of multiple honey doses on non-specific acute cough in children. An open randomised study and literature review.

    Miceli Sopo, S; Greco, M; Monaco, S; Varrasi, G; Di Lorenzo, G; Simeone, G

    2015-01-01

    Honey is recommended for non-specific acute paediatric cough by the Australian guidelines. Current available randomised clinical trials evaluated the effects of a single evening dose of honey, but multiple doses outcomes have never been studied. To evaluate the effects of wildflower honey, given for three subsequent evenings, on non-specific acute paediatric cough, compared to dextromethorphan (DM) and levodropropizine (LDP), which are the most prescribed over-the-counter (OTC) antitussives in Italy. 134 children suffering from non-specific acute cough were randomised to receive for three subsequent evenings a mixture of milk (90ml) and wildflower honey (10ml) or a dose of DM or LDP adjusted for the specific age. The effectiveness was evaluated by a cough questionnaire answered by parents. Primary end-point efficacy was therapeutic success. The latter was defined as a decrease in cough questionnaire score greater than 50% after treatment compared with baseline values. Three children were excluded from the study, as their parents did not complete the questionnaire. Therapeutic success was achieved by 80% in the honey and milk group and 87% in OTC medication group (p=0.25). Milk and honey mixture seems to be at least as effective as DM or LDP in non-specific acute cough in children. These results are in line with previous studies, which reported the health effects of honey on paediatric cough, even if placebo effect cannot be totally excluded. Copyright © 2014 SEICAP. Published by Elsevier Espana. All rights reserved.

  16. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.

    Sedel, Frédéric; Bernard, Delphine; Mock, Donald M; Tourbah, Ayman

    2016-11-01

    Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Estimation of effective dose for the diagnosis and follow-up of multiple myeloma using conventional radiology

    Tsalafoutas, I.; Kostopoulou, H.; Steinhauer, G.; Koukourakis, G.; Yakoumakis, E.

    2012-01-01

    Background and objective: Multiple myeloma (MM) is a haemolytic neoplasm which produces osteolytic lesions and necessitates the periodical radiological examination of the skeleton for monitoring the disease progression. This involves the acquisition of multiple radiographs every 3 to 6 months, depending on the extent and the stage of the disease. Our objective was to estimate the cumulative patient dose during the radiographic investigation of MM. Materials and methods: Sixty eight MM radiographic examinations performed with a digital X-ray unit were recorded on a CD-rom in DICOM format. The DICOM data were extracted using appropriate software (DICOM Info Extractor) and were input into a Microsoft Excel based spreadsheet, containing embedded algorithms for the identification of the radiological examination type and the estimation of entrance surface air kerma (ESAK), dose area product (DAP) and effective dose (E) in each radiograph. The DAP to E conversion coefficients for each examination type were derived using the PCXMC 2.0 Monte Carlo simulation software for the case of a standard adult patient utilizing the irradiation geometry as this was perceived from the images and the DICOM data. Results: The mean values [and ranges] were: for number of radiographs= 14 [7-23], for cumulative ESAK 13 [2-44] mGy, for cumulative DAP= 6 [1.35-16.5] Gycm 2 and for E= 0. [0.14-2.4] mSv. Conclusion: The average E value calculated is smaller than the values of 1.7 and 2.4 mSv reported in the literature and even smaller than the values of 4.8 and 4.1 mSv reported for MM diagnosis using whole-body CT. (authors)

  18. Combined administration of the GPVI-Fc fusion protein Revacept with low-dose thrombolysis in the treatment of stroke

    Andreas Reimann

    2016-04-01

    Full Text Available BackgroundThrombolytic therapy with recombinant tissue plasminogen activator (rtPA remains the only approved medication for acute ischemic stroke, but incurs significant bleeding risks. Therefore, approaches to combine lower doses of thrombolytic therapy with other effective drugs aim at improving efficacy and reducing bleeding rates. We examined the safety and therapeutic effects of various dosings of rtPA, either alone or combined with glycoprotein VI-Fc fusion protein (GPVI-Fc, Revacept on experimental stroke in mice.Methods and resultsThe effect of filament-induced intracerebral thrombus formation and embolization was investigated after a one-hour occlusion of the middle cerebral artery.In accordance with previous studies, treatment with 10 mg/kg rtPA significantly improved functional outcome, cerebral infarct size and edema, but also resulted in markedly increased intracranial bleeding volumes. In contrast, low doses of rtPA (0.1 or 0.35 mg/kg body weight did not change outcome parameters. However, addition of 1 mg/kg Revacept to 0.35 mg/kg rtPA led to improved reperfusion compared to rtPA alone. Moreover, these combined treatments resulted in improved grip strength, compared to the respective dose of rtPA alone. Infarct-surrounding edema improved after combined treatments, but not after respective single rtPA dosings. Intracranial bleeding volumes were below controls after all low-dose rtPA therapies, given either alone or combined with Revacept.ConclusionsIn contrast to using the equally effective full dose of rtPA, intracranial bleeding was not increased by low-dose rtPA combined with Revacept. Therefore, addition of Revacept to low-dose rtPA does not incur safety risks, but improves efficacy of treatment.

  19. Absorption, Distribution, and Excretion of 14C-APX001 after Single-Dose Administration to Rats and Monkeys

    Mansbach, Robert; Shaw, Karen J; Hodges, Michael R; Coleman, Samantha; Fitzsimmons, Michael E

    2017-01-01

    Abstract Background APX001 is a small-molecule therapeutic agent in clinical development for the treatment of invasive fungal infections (IFI). Methods The absorption, distribution and excretion profiles of [14C]APX001-derived radioactivity were determined in rats (albino and pigmented) and monkeys. Rats (some implanted with bile duct cannulae) were administered a single 100 mg/kg oral dose or a 30 mg/kg intravenous (IV) dose. Monkeys were administered a single 6 mg/kg IV dose. Samples of blo...

  20. Evaluation of radiation dose in 64-row whole-body CT of multiple injured patients compared to 4-row CT

    Harrieder, A.; Geyer, L.L.; Koerner, M.; Deak, Z.; Wirth, S.; Reiser, M.; Linsenmaier, U.

    2012-01-01

    Purpose: To evaluate radiation exposure in whole-body CT (WBCT) of multiple injured patients comparing 4-row multidetector computed tomography (MDCT) to 64-row MDCT. Materials and Methods: 200 WBCT studies were retrospectively evaluated: 92 4-row MDCT scans and 108 64-row MDCT scans. Each CT protocol was optimized for the particular CT system. The scan length, CT dose index (CTDI), and dose length product (DLP) were recorded and analyzed for radiation exposure. The mean effective dose was estimated based on conversion factors. Student's t-test was used for statistical analysis. Results: The mean CTDI vol values (mGy) of the thorax and abdomen were significantly reduced with 64-row MDCT (10.2 ± 2.5 vs. 11.4 ± 1.4, p < 0.001; 14.2 ± 3.7 vs. 16.1 ± 1.7, p < 0.001). The DLP values (mGy x cm) of the head and thorax were significantly increased with 64-row MDCT (1305.9 ± 201.1 vs. 849.8 ± 90.9, p < 0,001; 504.4 ± 134.4 vs. 471.5 ± 74.1, p = 0.030). The scan lengths (mm) were significantly increased with 64-row MDCT: head 223.6 ± 35.8 vs. 155.5 ± 12.3 (p < 0.001), thorax 427.4 ± 44.5 vs. 388.3 ± 57.5 (p < 0.001), abdomen 520.3 ± 50.2 vs. 490.8 ± 51.6 (p < 0.001). The estimated mean effective doses (mSv) were 22.4 ± 2.6 (4-row MDCT) and 24.1 ± 4.6 (64-row MDCT; p = 0.001), resulting in a percentage increase of 8 %. Conclusion: The radiation dose per slice of the thorax and abdomen can be significantly decreased by using 64-row MDCT. Due to the technical advances of modern 64-row MDCT systems, the scan field can be adapted to the clinical demands and, if necessary, enlarged without time loss. As a result, the estimated mean effective dose might be increased in WBCT. (orig.)

  1. Radioprotective effects in mice by a single dose of subcutaneous administration of cobaltous chloride post γ-rays irradiation with a sublethal dose

    Izumo, Yoshiro; Ogata, Hiromitsu

    1993-01-01

    Radioprotective effects were investigated in mice which received subcutaneously a single dose of each inorganic metal: Co, Cu, Rb, Sr, Mo and W 24 hours post irradiation of 60 Co γ-rays with a sublethal dose. The effects were observed in mice injected with Co at an optimum dosage of 20 mg/kg·body weight. Then to elucidate mechanisms of the effects, mice were injected with Co containing the radioactive tracer ( 60 Co) following the radiation exposure, measured elimination of the radioactivity for 7 days, then sacrificed and divided to some tissues and organs. The radioactivity in whole body during this period resulted in a markedly higher retention than that for mice injected with [ 60 Co] alone, as well as liver in the organs. These higher retentions appeared to be related to the radioprotective effects. (author)

  2. Pharmacokinetics of marbofloxacin in pigs after intravenous and intramuscular administration of a single dose of 8 mg/kg: dose proportionality, influence of the age of the animals and urinary elimination.

    Schneider, M; Paulin, A; Dron, F; Woehrlé, F

    2014-12-01

    The pharmacokinetics of marbofloxacin in pigs were evaluated as a function of dose and animal age following intravenous and intramuscular administration of a 16% solution (Forcyl(®) ). The absolute bioavailability of marbofloxacin as well as the dose proportionality was evaluated in 27-week-old fattening pigs. Blood PK and urinary excretion of marbofloxacin were evaluated after a single intramuscular dose of 8 mg/kg in 16-week-old male pigs. An additional group of 12-week-old weaned piglets was used for the evaluation of age-related kinetics. The plasma and urine concentration of marbofloxacin was determined using a HPLC method. Pharmacokinetic parameters were calculated using noncompartmental methods. After intravenous administration in 27-week-old fattening pigs, the total body clearance was 0.065 L/h·kg. After intramuscular administration to the same animals, the mean observed Cmax was 6.30 μg/mL, and the AUCINF was 115 μg·h/mL. The absolute bioavailability was 91.5%, and dose proportionality was shown within the dose range of 4-16 mg/kg. The renal clearance was about half of the value of the total clearance. The total systemic clearance values significantly decreased as a function of age, being 0.092 L/h·kg and 0.079 L/h·kg in pigs aged 12 and 16 weeks, respectively. © 2014 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

  3. Effect of administration route and dose of streptavidin or biotin on the tumor uptake of radioactivity in intraperitoneal tumor with multistep targeting

    Zhang Meili; Yao Zhengsheng; Sakahara, Harumi; Saga, Tsuneo; Nakamoto, Yuji; Sato, Noriko; Zhao Songji; Nakada, Hiroshi; Yamashina, Ikuo; Konishi, Junji

    1998-01-01

    The effect of the administration route and dose of streptavidin or biotin on the biodistribution of radioactivity in multistep targeting was studied in nude mice bearing intraperitoneal (IP) colon cancer xenograft. The multistep targeting included a two-step method using biotinylated antibody and radiolabeled streptavidin and a three-step method with radiolabeled biotin based on the two-step method. A monoclonal antibody, MLS128, which recognizes Tn antigen on mucin, was biotinylated and injected intravenously (IV) or IP in nude mice bearing human colon cancer LS180 IP xenografts for pretargeting. In the two-step method, IP-injected streptavidin showed a higher tumor uptake and tumor-to-nontumor ratios than IV-injected streptavidin regardless of administration route of pretargeting. The tumor uptake of radiolabeled streptavidin was increased with a high dose of biotinylated antibody pretargeting, but decreased with an increasing dose of streptavidin. In the three-step targeting, IP injection also gave a higher tumor uptake of radiolabeled biotin than IV injection. In conclusion, IP administration of radiolabeled streptavidin or biotin resulted in more efficient IP tumor targeting with the multistep methods

  4. Pharmacodynamics of alfaxalone after single-dose intramuscular administration in red-eared sliders (Trachemys scripta elegans): a comparison of two different doses at two different ambient temperatures.

    Shepard, Molly K; Divers, Stephen; Braun, Christina; Hofmeister, Erik H

    2013-11-01

    This study compares the pharmacodynamics of two different doses of alfaxalone administered intramuscularly (IM) to red-eared sliders at two ambient temperatures. Prospective blinded crossover experimental study. Nine adult female sliders (Trachemys scripta elegans). Following a 2-week acclimation at 22-25 °C, nine sliders were randomly assigned to receive alfaxalone, 10 mg kg(-1) (W10), or 20 mg kg(-1) (W20) IM. Each turtle received each dose, with a minimum 7-day washout period. A blinded observer evaluated heart rate (HR), palpebral and corneal reflexes, muscle relaxation, handling, and response to toe pinch at the following points: pre-injection, and 5, 12, 20, 30, 45, 60, and 120 minutes post-injection. Turtles then acclimated to 18-20 °C for 63 days, and the experiment was repeated in this lower-temperature environment, with treatment groups C10 (alfaxalone 10 mg kg(-1)) and C20 (alfaxalone 20 mg kg(-1)) subjected to the same crossover design. C10 and C20 groups had significantly lower intraanesthetic HR than W10 or W20, respectively. C10 and W20 were significantly more relaxed and easier to handle than W10. No significant differences were observed in palpebral reflex, nor responsiveness to the toe pinch stimulus. None of the turtles lost corneal reflex. W20 and C20 had prolonged recoveries, compared to low-dose groups within the same temperature environment. Recovery was also longer at C20 and C10 compared to W10. Turtles given 10 mg kg(-1) were more relaxed and easier to handle in cold than warm conditions. Warm turtles were more relaxed and easier to handle when given 20 mg kg(-1) than those given 10 mg kg(-1). Cold conditions correlated with lower HR and longer recovery time for each dose category. The turtles had dose-dependent and inconsistent responses to alfaxalone. Lower ambient temperature augmented the behavioral effects of this drug. © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  5. Intranasal Ketamine Administration for Narcotic Dose Decrement in Patients Suffering from Acute Limb Trauma in Emergency Department: a Double-Blind Randomized Placebo-Controlled Trial

    Ali Mohammadshahi

    2018-04-01

    Full Text Available Introduction: pain management is an important and challenging issue in emergency medicine. Despite the conduct of several studies on this topic, pain is still handled improperly in many cases. Objective: This study investigated the effectiveness of low-dose IN ketamine administration in reducing the need for opiates in patients in acute pain resulting from limb injury. Method: This randomized, double-blind, placebo-controlled trial was conducted to assess the possible effect of low-dose intranasal (IN ketamine administration in decreasing patients' narcotic need. Patients in emergency department suffering from acute isolated limb trauma were included. One group of patients received 0.5 mg/kg intravenous morphine sulfate and 0.02 ml/kg IN ketamine. The other group received the same dose of morphine sulfate and 0.02 ml/kg IN distilled water. Pain severity was measured using the 11 points numerical rating scale at 0, 10, 30, 60, 120, and 180 minutes. Results: Ninety-one patients with mean age of 31.62 ± 9.13 years were enrolled (54.9% male. The number of requests for supplemental medication was significantly lower in patients who received ketamine (12 patients (30% than those who received placebo (27 patients (67.5% (p = 0.001. Conclusion: It is likely that low-dose IN ketamine is effective in reducing the narcotic need of patients suffering from acute limb trauma.

  6. Efficiency of early, single-dose probiotic administration methods on performance, small intestinal morphology, blood biochemistry, and immune response of Japanese quail.

    Seifi, Kazem; Karimi Torshizi, Mohammad Amir; Rahimi, Shaban; Kazemifard, Mohammad

    2017-07-01

    The aim of the present study was to investigate the efficacy of early probiotics (single dose) administered in different ways, on quails' performance, small intestine morphology, blood biochemistry, and immune response. In total, 192 day-old chicks were used in one of the following experimental groups before being transferred to a raising room: 1) Control (no probiotic administered), 2) oral gavage, 3) spray, and 4) vent lip. Four replicates of 12 chicks per cage were considered for each treatment and birds were raised up to 35 d in the same conditions. Probiotic treated birds had higher d 1 to 35 feed intake than the control group (P birds had a higher body weight gain as compared to the control (P birds compared to control (P  0.01). None of the immune-related parameters were affected by the probiotic (P > 0.05). Single dose usage of probiotics exerts its beneficial effects on quails' body weight gain, feed intake and mortality in 1 to 35 d period, regardless of the route of administration. This work generally supports the efficacy of single-dose usage of probiotics and suggests the spray of probiotics as an early, single-dose administration method. © 2017 Poultry Science Association Inc.

  7. Doses to the hand during the administration of radiolabeled antibodies containing Y-90, Tc-99m, I-131, and Lu-177

    Barber, D.E. [Minnesota Univ., Minneapolis, MN (United States). School of Public Health; Carsten, A.L.; Kaurin, D.G.L.; Baum, J.W. [Brookhaven National Lab., Upton, NY (United States)

    1997-02-01

    Exposure of the hands of medical personnel administering radiolabeled antibodies (RABs) was evaluated on the basis of (a) observing and photo-documenting administration techniques, and (b) experimental data on doses to thermoluminescent dosimeters (TLDs) on fingers of phantom hands holding syringes, and on syringes, with radionuclides in the syringes in each case. Actual exposure data for I-131 and Lu-177 were obtained in field studies. Variations in handling and administration techniques were identified. Dose rates measured using TLDs on the surface of loaded syringes were adjusted for differences in electronic stopping power, absorption coefficients, and attenuation between dosimeters and tissue to estimate dose-to-skin averaged over 1 cm{sup 2} at 7 mg cm{sup {minus}2} depth for Y-90, Tc-99m, I-131, and Lu-177. Dose rate coefficients to the skin, if in contact with the syringe wall, were 89, 1.9, 3.8, and 0.41 {micro}Sv s{sup {minus}1} per 37 MBq (1 mCi) for Y-90, Tc-99m, I-131, and Lu-177, respectively. For dose reduction, when using Y-90 the importance was clearly indicated of (a) avoiding direct contact with syringes containing RABs, if practical, and (b) using a beta-particle shield on the syringe. In using a syringe for injection, doses can best be approximated for the geometry studied by (a) wearing a finger dosimeter on the middle finger, toward the outside of the hand, on the hand operating the plunger, and (b) wearing finger dosimeters on the inner (palm) side of the finger on the hand that supports the syringe for energetic beta-particle emitters, such as Y-90 and Re-188.

  8. Doses to the hand during the administration of radiolabeled antibodies containing Y-90, Tc-99m, I-131, and Lu-177

    Barber, D.E.

    1997-02-01

    Exposure of the hands of medical personnel administering radiolabeled antibodies (RABs) was evaluated on the basis of (a) observing and photo-documenting administration techniques, and (b) experimental data on doses to thermoluminescent dosimeters (TLDs) on fingers of phantom hands holding syringes, and on syringes, with radionuclides in the syringes in each case. Actual exposure data for I-131 and Lu-177 were obtained in field studies. Variations in handling and administration techniques were identified. Dose rates measured using TLDs on the surface of loaded syringes were adjusted for differences in electronic stopping power, absorption coefficients, and attenuation between dosimeters and tissue to estimate dose-to-skin averaged over 1 cm 2 at 7 mg cm -2 depth for Y-90, Tc-99m, I-131, and Lu-177. Dose rate coefficients to the skin, if in contact with the syringe wall, were 89, 1.9, 3.8, and 0.41 microSv s -1 per 37 MBq (1 mCi) for Y-90, Tc-99m, I-131, and Lu-177, respectively. For dose reduction, when using Y-90 the importance was clearly indicated of (a) avoiding direct contact with syringes containing RABs, if practical, and (b) using a beta-particle shield on the syringe. In using a syringe for injection, doses can best be approximated for the geometry studied by (a) wearing a finger dosimeter on the middle finger, toward the outside of the hand, on the hand operating the plunger, and (b) wearing finger dosimeters on the inner (palm) side of the finger on the hand that supports the syringe for energetic beta-particle emitters, such as Y-90 and Re-188

  9. Characterization of a Mouse Model of Emphysema Induced by Multiple Instillations of Low-Dose Elastase

    Milena V. Oliveira

    2016-10-01

    Full Text Available Many experimental models have been proposed to study the pathophysiological features of emphysema, as well as to search for new therapeutic approaches for acute or chronically injured lung parenchyma. We aimed to characterize an emphysema model induced by multiple instillations of elastase by tracking the changes in inflammation, remodeling, and cardiac function after each instillation. Forty-eight C57BL/6 mice were randomly assigned across 2 groups. Emphysema (ELA animals received 1, 2, 3, or 4 intratracheal instillations of pancreatic porcine elastase (PPE, 0.2 IU with a 1-week interval between them. Controls (C received saline following the same protocol. Before and after implementation of the protocol, animals underwent echocardiographic analysis. After the first instillation of PPE, the percentage of mononuclear cells in the lung parenchyma was increased compared to C (p = 0.0001. The second instillation resulted in hyperinflated alveoli, increased mean linear intercept, and reduced elastic fiber content in lung parenchyma compared to C (p=0.0197. Following the third instillation, neutrophils and collagen fiber content in alveolar septa and airways were increased, whereas static lung elastance was reduced compared to C (p=0.0094. After the fourth instillation, the percentage of M1 macrophages in lungs; levels of interleukin-1beta, keratinocyte-derived chemokine, hepatocyte growth factor, and vascular endothelial growth factor; and collagen fiber content in the pulmonary vessel wall were increased compared to C (p=0.0096. At this time point, pulmonary arterial hypertension was apparent, with increased diastolic right ventricular wall thickness. In conclusion, the initial phase of emphysema was characterized by lung inflammation with predominance of mononuclear cells, whereas at the late stage, impairment of pulmonary and cardiovascular functions was observed. This model enables analysis of therapies at different time points during controlled

  10. Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects.

    Munjal, Sagar; Gautam, Anirudh; Okumu, Franklin; McDowell, James; Allenby, Kent

    2016-01-01

    In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0-inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product. © 2015, The American College of Clinical Pharmacology.

  11. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Yoon-Dong Park

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development.

  12. Effects of multiple low dose radiation on the apoptosis of splenocytes and immune factor in male diabetic rats

    Li Yanbo; Guo Caixia; Dong Lihua; Wang Jianfeng; Liu Shuchun; Lu Zhe; Gong Shouliang

    2009-01-01

    Objective: To explore the effect of multiple low dose radiation (LDR) on the apoptosis of splenocytes and immune factors in diabetes mellitus (DM) rats. Methods: The rats were randomly divided into control, DM and DM + LDR groups. The irradiation doses were 25, 50 and 75 mGy, and the irradiated times were 15. At the fourth weekend after the DM rats irradiated, the apoptotic rate and TCRαβ percentage of splenocytes were detected by flow cytometry, and the content of IL-2 in both serum and supernatant of cultured splenocytes were detected by ELISA. Results: Compared with that in the control, the body weight (BW) decreased in the DM and DM + LDR groups,particularly in DM group. The blood glucose (BG) level in the DM + LDR groups was higher than that in the control, but decreased significantly as compared with that in the DM group (P < 0.01). As compared with those in the control, the apoptotic rate in DM + 50 mGy (P < 0.05) and the content of serum IL-2 in DM + 75 mGy group (P < 0.01) all increased significantly, while the content of IL-2 in supernatant of cultured splenocytes decreased significantly in the DM + LDR groups. Compared with those in the DM group, the apoptotic rate and the percentage of TCRαβ in splenocytes in the DM + LDR groups (P < 0.01-P < 0.001) and the content of IL-2 in serum in DM + 50 mGy group (P < 0.01) decreased significantly. Conclusions: The multiple LDR could weaken the loss of BW and increase of BG caused by DM, decrease the splenocyte apoptosis induced by DM, and regulate the immune factors. (authors)

  13. Impact of intra-arterial administration of boron compounds on dose-volume histograms in boron neutron capture therapy for recurrent head-and-neck tumors

    Suzuki, Minoru; Sakurai, Yoshinori; Nagata, Kenji; Kinashi, Yuko; Masunaga, Shinichiro; Ono, Koji; Maruhashi, Akira; Kato, Ituro; Fuwa, Nobukazu; Hiratsuka, Junichi; Imahori, Yoshio

    2006-01-01

    Purpose: To analyze the dose-volume histogram (DVH) of head-and-neck tumors treated with boron neutron capture therapy (BNCT) and to determine the advantage of the intra-arterial (IA) route over the intravenous (IV) route as a drug delivery system for BNCT. Methods and Materials: Fifteen BNCTs for 12 patients with recurrent head-and-neck tumors were included in the present study. Eight irradiations were done after IV administration of boronophenylalanine and seven after IA administration. The maximal, mean, and minimal doses given to the gross tumor volume were assessed using a BNCT planning system. Results: The results are reported as median values with the interquartile range. In the IA group, the maximal, mean, and minimal dose given to the gross tumor volume was 68.7 Gy-Eq (range, 38.8-79.9), 45.0 Gy-Eq (range, 25.1-51.0), and 13.8 Gy-Eq (range, 4.8-25.3), respectively. In the IV group, the maximal, mean, and minimal dose given to the gross tumor volume was 24.2 Gy-Eq (range, 21.5-29.9), 16.4 Gy-Eq (range, 14.5-20.2), and 7.8 Gy-Eq (range, 6.8-9.5), respectively. Within 1-3 months after BNCT, the responses were assessed. Of the 6 patients in the IV group, 2 had a partial response, 3 no change, and 1 had progressive disease. Of 4 patients in the IA group, 1 achieved a complete response and 3 a partial response. Conclusion: Intra-arterial administration of boronophenylalanine is a promising drug delivery system for head-and-neck BNCT

  14. Anti-CD20 Cell Therapies in Multiple Sclerosis—A Fixed Dosing Schedule for Ocrelizumab is Overkill

    Jagannadha Avasarala

    2017-10-01

    Full Text Available Anti-CD 20 therapies have found significant uses in multiple sclerosis (MS. Based singularly on the accumulated evidence with the use of rituximab (RTX; Rituxan, Genentech, and Biogen in neuroimmunological diseases, ocrelizumab (OCR; Ocrevus, Genentech was developed as a treatment option for MS and selectively targets CD20 B cells, a cell surface antigen found on pre-B cells, mature, and memory B cells, but not on lymphoid stem cells and plasma cells. On the basis of indirect evidence, elimination of the antigen-presenting capabilities and antigen nonspecific immune functions of B cells appear to be central to the therapeutic efficacy of anti-CD20 B-cell therapies. An important question is this—Why does the drug need to be dosed at fixed intervals and not based on a measurable endpoint, such as tracking peripheral CD20 cell counts? There is minimal scientific validity in infusing the drug every 6 months particularly if CD20 cell counts are negligible in the peripheral blood. In this analysis, a case is made for following CD19 cell populations as a surrogate for CD20 cells on a monthly basis to guide OCR redosing parameters and does not follow a scheduled dosing parameter.

  15. Studying the effect of administration route and treatment dose on the selection of enrofloxacin resistance in commensal Escherichia coli in broilers.

    Chantziaras, Ilias; Smet, Annemieke; Haesebrouck, Freddy; Boyen, Filip; Dewulf, Jeroen

    2017-07-01

    Factors potentially contributing to fluoroquinolone resistance selection in commensal Escherichia coli strains in poultry were studied through a series of in vivo experiments. The effect of the initial prevalence of enrofloxacin resistance in the E. coli gut microbiota, effect of the bacterial fitness of the enrofloxacin-resistant strain and effect of treatment with enrofloxacin (effect of dose and effect of route of administration) were assessed. Four in vivo studies with broiler chickens were performed. Right after hatching, the chicks were inoculated with either a bacteriologically fit or a bacteriologically non-fit fluoroquinolone-resistant strain as either a minority or the majority of the total E. coli population. Six days later, the chicks were treated for three consecutive days either orally or parenterally and using three different doses (under-, correct- and over-dose) of enrofloxacin. The faecal shedding of E. coli strains was quantified by plating on agar plates either supplemented or not supplemented with enrofloxacin. Linear mixed models were used to assess the effect of the aforementioned variables on the selection of enrofloxacin resistance. The factors that significantly contributed were treatment ( P  <   0.001), bacterial fitness of the resistant donor strain ( P  <   0.001), administration route ( P  =   0.052) and interactions between bacterial fitness and administration route ( P  <   0.001). In the currently used models, fluoroquinolone resistance selection was influenced by treatment, bacterial fitness of the inoculation strain and administration route. The use of oral treatment seems to select more for fluoroquinolone resistance, particularly in the model where a non-fit strain was used for inoculation. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high-dose melphalan in patients with multiple myeloma.

    Talamo, Giampaolo; Rakszawski, Kevin L; Rybka, Witold B; Dolloff, Nathan G; Malysz, Jozef; Berno, Tamara; Zangari, Maurizio

    2012-08-01

    High-dose melphalan (HD-Mel) is considered the current standard of care among the preparative regimens used in autologous peripheral blood stem cell transplantation (SCT) for multiple myeloma (MM), but optimal time and schedule of administration is not defined. We retrospectively analyzed outcomes and toxicities of HD-Mel administered on day -2 vs. day -1 before autologous stem cells infusion. A total of 138 consecutive MM patients treated at Penn State Hershey Cancer Institute between 2007 and 2010 were included in this study. No difference in time to hematopoietic recovery, common SCT-related toxicities, and clinical outcomes was seen between patients who received HD-Mel on day -2 (group A, n = 47), and those who received it on day -1 (group B, n = 91). Prompt and full hematopoietic recovery occurred even when stem cells were infused between 8 and 24 h after completion of chemotherapy. In the absence of prospective and randomized data, we conclude that a single I.V. infusion of HD-Mel on day -1 is a safe and effective practice, and the so-called 'day of rest' before the transplant appears not to be necessary. © 2012 John Wiley & Sons A/S.

  17. Single, 14-Day, and 13-Week Repeated Dose Toxicity Studies of Daily Oral Gelidium elegans Extract Administration to Rats.

    Choi, Jia; Ryu, Su-Jung; Kim, Kui-Jin; Kim, Hyung-Min; Chung, Hee-Chul; Lee, Boo-Yong

    2018-01-20

    Gelidium elegans extract (GEE) is derived from a red alga from the Asia-Pacific region, which has antioxidant, anti-adipogenic, and anti-hyperglycemic effects. However, detailed studies of the toxicology of GEE have not been performed. We evaluated the single oral dose toxicity of GEE in male and female Sprague-Dawley (CD) rats. GEE did not cause deaths or have toxic effects at dosages of 5000 mg/kg/day, although compound-colored stools and diarrhea were observed in both sexes, which lasted 5000 mg/kg. We next evaluated the repeated oral dose toxicity of GEE in CD rats over 14 days and 13 weeks. GEE did not induce any significant toxicological changes in either sex at 2000 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects, in terms of clinical signs, mortality, body mass, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy, organ masses, or histopathology, at dosages of 500, 1000, or 2000 mg/kg/day. The no observed adverse effect level (NOAEL) for GEE is thus likely to be >2000 mg/kg/day, and no pathology was identified in potential target organs. Therefore, this study indicates that repeated oral dosing with GEE is safe in CD rats.

  18. Single, 14-Day, and 13-Week Repeated Dose Toxicity Studies of Daily Oral Gelidium elegans Extract Administration to Rats

    Jia Choi

    2018-01-01

    Full Text Available Gelidium elegans extract (GEE is derived from a red alga from the Asia–Pacific region, which has antioxidant, anti-adipogenic, and anti-hyperglycemic effects. However, detailed studies of the toxicology of GEE have not been performed. We evaluated the single oral dose toxicity of GEE in male and female Sprague-Dawley (CD rats. GEE did not cause deaths or have toxic effects at dosages of 5000 mg/kg/day, although compound-colored stools and diarrhea were observed in both sexes, which lasted <2 days. Therefore, the LD50 of GEE is likely to be >5000 mg/kg. We next evaluated the repeated oral dose toxicity of GEE in CD rats over 14 days and 13 weeks. GEE did not induce any significant toxicological changes in either sex at 2000 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects, in terms of clinical signs, mortality, body mass, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy, organ masses, or histopathology, at dosages of 500, 1000, or 2000 mg/kg/day. The no observed adverse effect level (NOAEL for GEE is thus likely to be >2000 mg/kg/day, and no pathology was identified in potential target organs. Therefore, this study indicates that repeated oral dosing with GEE is safe in CD rats.

  19. Radiation dose to bladder wall following the administration of sup(99m)Tc-microspheres and sup(99m)Tc-DTPA

    Smith, T.

    1981-01-01

    Castronovo et al. (Health Phys. Vol. 39, p 112, 1980) reported a method of calculating the dose to the bladder wall following administration of sup(99m)Tc human albumin microspheres (sup(99m)Tc-HAM) for lung perfusion scanning. The present note comments that (1) the dosimetry is estimated for an unusual bladder voiding schedule and no indication is given of the variation of dose to be expected with different schedules, and (2) that the method assumes linear biological excretion of the radiopharmaceutical into the bladder in any particular filling period. It is shown that whilst this is a valid approximation in the case considered, it is not a generally applicable principle. Values of bladder wall dose commitments following intravenous administration of sup(99m)Tc-HAM or sup(99m)Tc DTPA are tabulated. Values for constant voiding cycles are presented for four different bladder voiding periods between 2 and 8 hr, and for three different methods of calculation:-a method described in this paper, the linear excretion method of Castronovo et al., and the method of Snyder et al. (ORNL-4584, pp. 206-208, 1970) which allows for urine flow rate. (U.K.)

  20. Intranasal administration of a therapeutic HIV vaccine (Vacc-4x induces dose-dependent systemic and mucosal immune responses in a randomized controlled trial.

    Kristin Brekke

    Full Text Available Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant.Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β.Vacc-4x proliferative T cell responses increased only among the vaccinated (p ≤ 0.031. The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037 and developed larger DTH (p = 0.005 than the adjuvant group. Rectal (distal Vacc-4x IgA and IgG antibodies also increased (p = 0.043 in this group. In contrast, the high dose generated higher nasal (local Vacc-4x IgA (p = 0.028 and serum IgG (p = 0.030 antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = -0.82, p < 0.001 and high regulation (r = 0.61, p = 0.010 at baseline.Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further investigation.ClinicalTrials.gov NCT01473810.

  1. High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma.

    Akiyama, Hiroki; Takase, Hiroshi; Kubo, Fumito; Miki, Tohru; Yamamoto, Masahide; Tomita, Makoto; Mochizuki, Manabu; Miura, Osamu; Arai, Ayako

    2016-10-01

    In order to prevent central nervous system (CNS) involvement and improve the prognosis of primary intraocular lymphoma (PIOL), we prospectively evaluated the efficacy of combined therapy using intravitreal methotrexate (MTX) and systemic high-dose MTX on treatment-naïve PIOL. Patients with newly diagnosed PIOL whose lymphoma was limited to the eyes were enrolled. The patients were treated with weekly intravitreal MTX until the ocular lesions were resolved, followed by five cycles of systemic high-dose MTX (3.5 g/m 2 ) every other week. Ten patients were enrolled in this study and completed the treatment. All patients achieved complete response for their ocular lesions with rapid decrease of intravitreal interleukin-10 concentration. Adverse events of intravitreal and systemic high-dose MTX were mild and tolerable. With a median follow-up of 29.5 months, four patients (40%) experienced the CNS disease development and the mean CNS lymphoma-free survival (CLFS) time was 51.1 months. Two-year CLFS, which was the primary end-point of the study, was 58.3% (95% confidence interval, 23.0-82.1%). In contrast, eight patients were treated with intravitreal MTX alone in our institute, and their 2-year CLFS was 37.5% (95% confidence interval, 8.7-67.4%). In conclusion, systemic high-dose MTX following intravitreal MTX is feasible and might be effective in preventing CNS involvement of PIOL. Further arrangements are worth considering in order to improve the effects. This study was registered with UMIN Clinical Trials Registry (UMIN000003921). © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  2. Therapeutic administration of 131I for differentiated thyroid cancer, radiation dose to ovaries and outcome of pregnancies

    Garsi, Jerome-Philippe; Rubino, Carole; Labbe, Martine; Vathaire, Florent de; Schlumberger, Martin; Ricard, Marcel; Ceccarelli, Claudia; Schvartz, Claire; Henri- Amar, Michel; Bardet, Stephane

    2008-01-01

    Full text: Background: Radiation is known to be mutagenic. In thyroid cancer treatment, 131 I is usually administered, for the first treatment, at a 3.7 GMBq activity, corresponding to an estimated mean radiation dose of 140 mGy to the ovaries. However data on the effects of 131 I therapy on pregnancy outcomes, especially untoward, are scarce. Methods: Data on 2673 pregnancies were obtained by interviewing female patients treated for thyroid carcinoma who had not received external radiation to the ovaries, in three French hospitals and one Italian hospital. Results: The incidence of miscarriages was 10 % before any treatment for thyroid cancer; this percentage increased after surgery for thyroid cancer, both before (20 %) and after (19 %) 131 I treatment, with no variation according to the cumulative dose. Miscarriages were not significantly more frequent in women treated with 131 I during the year before conception, even in subjects who had received more than 370 MBq during that year, as compared to women never treated with 131 I. The incidence of stillbirths, preterm births, a low birth weight, congenital malformation and death during the first year of life was not significantly different before or after 131 I therapy. The incidence of thyroid and non thyroidal cancers was similar in children born either before or after the mother's exposure to 131 I. Conclusion: In our data, we found no evidence that exposure to 131 I affects the outcome of subsequent pregnancies and offspring. Whether the number of malformations, or thyroid and non thyroidal cancers are related to gonadal irradiation remains to be established. Our findings allowed us to fuel the debate on the doubling dose: the concept is still heatedly debated and the value of 1 Gy as the doubling dose in humans should be rediscussed. (author)

  3. A multiple-dose, double-blind comparison of intramuscularly and orally administered ketorolac tromethamine and Ketogan in patients with pain following orthopaedic surgery

    Gebuhr, Peter Henrik; Soelberg, M; Strauss, W

    1994-01-01

    combination product containing the narcotic analgesic, ketobemidone, plus a spasmolytic agent) by intramuscular injection every 1-6 h as needed for pain. When patients were able to tolerate an oral diet and were expected to respond to oral analgesic medication, based on overall pain sensitivity, they were...... and at the end of each day. Both treatments were effective immediately after the first dose and during the subsequent multiple-dose phase. There were no statistically significant differences between ketorolac and Ketogan. The results show that 10-mg doses of ketorolac in intramuscular injections followed by 10......In this multiple-dose, double-blind study 100 patients with moderate, severe or very severe pain following orthopaedic surgery were randomly assigned to receive ketorolac, a non-steroidal anti-inflammatory drug with potent analgesic properties (10 mg), or the standard regimen of Ketogan (a...

  4. Effects of administration of four different doses of Escherichia coli phytase on femur properties of 16-week-old turkeys.

    Tatara, Marcin R; Krupski, Witold; Kozłowski, Krzysztof; Drażbo, Aleksandra; Jankowski, Jan

    2015-03-18

    The enzyme phytase is able to initiate the release of phosphates from phytic acid, making it available for absorption within gastrointestinal tract and following utilization. The aim of the study was to determine effects of Escherichia coli phytase administration on morphological, densitometric and mechanical properties of femur in 16-week-old turkeys. One-day-old BUT Big-6 males were assigned to six weight-matched groups. Turkeys receiving diet with standard phosphorus (P) and calcium (Ca) content belonged to the positive control group (Group I). Negative control group (Group II) consisted of birds fed diet with lowered P and Ca content. Turkeys belonging to the remaining groups have received the same diet as group II but enriched with graded levels of Escherichia coli phytase: 125 (Group III), 250 (Group IV), 500 (Group V) and 1000 (Group VI) FTU/kg. At the age of 112 days of life, the final body weights were determined and the turkeys were sacrificed to obtain right femur for analyses. Geometric and densitometric properties of femur were determined using quantitative computed tomography (QCT) technique, while mechanical evaluation was performed in three-point bending test. Phytase administration increased cross-sectional area, second moment of inertia, mean relative wall thickness, cortical bone mineral density and maximum elastic strength decreasing cortical bone area of femur (P phytase administration on geometric, densitometric and mechanical properties of femur were observed in turkeys receiving 125 and 250 FTU/kg of the diet. Phytase administration at the dosages of 500 and 1000 FTU/kg of the diet improved the final body weight in turkeys. The results obtained in this study indicate a possible practical application of Escherichia coli phytase in turkey feeding to improve skeletal system properties and function.

  5. Intravenous contrast medium administration at 128 multidetector row CT pulmonary angiography: Bolus tracking versus test bolus and the implications for diagnostic quality and effective dose

    Rodrigues, J.C.L.; Mathias, H.; Negus, I.S.; Manghat, N.E.; Hamilton, M.C.K.

    2012-01-01

    Aim: To investigate the effects of a test bolus protocol contrast medium administration on diagnostic image quality in computed tomography pulmonary angiography (CTPA). Materials and methods: Fifty patients referred for exclusion of pulmonary embolism underwent CTPA using a test bolus protocol CTPA at 120 kVp and were compared with 50 patients undergoing CTPA using a standard bolus-tracking protocol at 120 kVp, via assessment of attenuation, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) seen in the pulmonary arteries (PAs). An additional group of 10 non-obese patients who underwent CTPA using a test bolus protocol performed at 100 kVp were also analysed. Mean effective dose was calculated from the dose–length product, using standard conversion factors. Results: The test bolus protocol showed significantly higher attenuation, SNR, and CNR in the pulmonary vasculature down to the segmental level compared to bolus-tracking CTPA (p < 0.0001). There was no significant difference in effective dose between the test bolus and bolus tracking cohorts. The additional group of test bolus CTPA examinations performed at 100 kVp had a significantly reduced effective dose in comparison to both test bolus CTPA at 120 kVp and bolus-tracking CTPA at 120 kVp (p < 0.005) yet maintained mean PA attenuation to segmental level significantly better than bolus-tracking CTPA performed at 120 kVp and comparable to the test bolus cohort performed at 120 kVp. Conclusion: Test bolus contrast administration should be used as an optimal protocol. Performing test bolus CTPA at 100 kVp, as opposed to 120 kVp, significantly reduces dose without compromising PA attenuation in non-obese subjects.

  6. Method of examination of blood microcirculation in skin by multiple using of an identical dose of radioactive Xe/sup 133/ gas

    Lewandowski, J.; Bogdanowski, T.; Brzezinska-Wcislo, L. (Slaska Akademia Medyczna, Katowice (Poland))

    1981-01-01

    The introduced method of Xe/sup 133/ gas application on epidermis serves to the investigation of microcirculation of blood within skin. It consists in a single use a dose of radioactive gas which is injected under the plastic membrane adhering to the skin surface. Our method of gaseous Xe/sup 133/ contact with epidermis enabling the multiple utilization of once applied dose to further examination is described.

  7. Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus.

    Lu, P; Fleischmann, R; Curtis, C; Ignatenko, S; Clarke, S H; Desai, M; Wong, S L; Grebe, K M; Black, K; Zeng, J; Stolzenbach, J; Medema, J K

    2018-02-01

    Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.

  8. Evaluation of multiple low doses of copper oxide wire particles compared with levamisole for control of Haemonchus contortus in lambs.

    Burke, J M; Miller, J E

    2006-06-30

    High levels of anthelmintic resistance in gastrointestinal nematodes (GIN) of small ruminants have created the need for alternative approaches to parasite control. Copper oxide wire particles (COWP; 2g) have proven effective in decreasing GIN infection in lambs. However, the risk of copper toxicity has limited the usefulness of this approach. Recently, smaller doses (0.5 and 1g) have proven effective in GIN control, reducing the risk of toxicity. The objective of this study was to examine the effectiveness and risk of toxicity using multiple small doses of COWP for GIN control in lambs between weaning and market weight. Dorper crossbred ram lambs were orally administered levamisole (Levasol, 8.0mg/kg; n=8), 0.5g (n=9), or 1g COWP (n=9) at weaning (Day 0; 118+/-2 days of age; late May 2005) and again at 6-week intervals for a total of four treatments. A pooled fecal culture determined that Haemonchus contortus was the predominant gastrointestinal parasite at weaning. Lambs grazed bermudagrass pastures and were supplemented with up to 500g corn/soybean meal and free choice trace mineralized salt. Fecal egg counts (FEC), packed cell volume (PCV), and plasma aspartate aminotransferase (AST) activity were determined every 14 days and lambs weighed every 28 days. GIN infection reached a peak at Day 42 (high FEC, low PCV). COWP effectively reduced FEC on Days 0 and 42 compared with the previous week, but did not reduce FEC on Days 84 and 126 (treatment by time interaction, Pcopper in the liver on Day 155 were greater in COWP-treated lambs (Pcopper toxicity.

  9. Pharmacokinetics of Levetiracetam in Healthy Hispaniolan Amazon Parrots ( Amazona ventralis ) After Oral Administration of a Single Dose.

    Schnellbacher, Rodney; Beaufrère, Hugues; Vet, Dr Med; Arnold, Robert D; Tully, Thomas N; Mayer, Joerg; Divers, Stephen J

    2014-09-01

    Long-term anticonvulsive treatments have been poorly described in birds, and few pharmacokinetic studies have been performed, with mixed results. Levetiracetam, a new anticonvulsive drug, has shown good efficacy for monotherapy or adjunctive treatment of seizures in both human and veterinary medicine. To determine pharmacokinetics of levetiracetam in Hispaniolan Amazon parrots ( Amazona ventralis ), 20 healthy birds were randomly divided into 2 groups and administered either a 50 mg/kg (n = 10) or a 100 mg/kg (n = 10) oral dose of levetiracetam with no observable adverse effects. Blood samples were collected at baseline and at 12 time intervals (6 per group) for 16 hours. The concentration-time profiles resembled characteristic absorption, with maximum plasma concentrations of 61.0 μg/mL and 95.1 μg/mL at 60 minutes; terminal half-lives at 2.38 and 2.37 hours; volumes of distribution of 0.807 and 0.773 L/kg, with an area under the curve at 14 100 and 28 820 mg × min/L; and clearance rates of 3.65 and 3.60 mL/min per kg, respectively. Plasma concentrations were greater than 5.5 mg/L for up to 9.4 and 12 hours, suggesting an 8- and 12-hour oral dosing at 50 and 100 mg/kg, respectively, would be sufficient to maintain targeted values. Clinically, doses and frequencies may need escalation based on differences in species and individuals, and drug levels should be monitored.

  10. Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs.

    Fish, Brian L; Gao, Feng; Narayanan, Jayashree; Bergom, Carmen; Jacobs, Elizabeth R; Cohen, Eric P; Moulder, John E; Orschell, Christie M; Medhora, Meetha

    2016-11-01

    The NIAID Radiation and Nuclear Countermeasures Program is developing medical agents to mitigate the acute and delayed effects of radiation that may occur from a radionuclear attack or accident. To date, most such medical countermeasures have been developed for single organ injuries. Angiotensin converting enzyme (ACE) inhibitors have been used to mitigate radiation-induced lung, skin, brain, and renal injuries in rats. ACE inhibitors have also been reported to decrease normal tissue complication in radiation oncology patients. In the current study, the authors have developed a rat partial-body irradiation (leg-out PBI) model with minimal bone marrow sparing (one leg shielded) that results in acute and late injuries to multiple organs. In this model, the ACE inhibitor lisinopril (at ~24 mg m d started orally in the drinking water at 7 d after irradiation and continued to ≥150 d) mitigated late effects in the lungs and kidneys after 12.5-Gy leg-out PBI. Also in this model, a short course of saline hydration and antibiotics mitigated acute radiation syndrome following doses as high as 13 Gy. Combining this supportive care with the lisinopril regimen mitigated overall morbidity for up to 150 d after 13-Gy leg-out PBI. Furthermore, lisinopril was an effective mitigator in the presence of the growth factor G-CSF (100 μg kg d from days 1-14), which is FDA-approved for use in a radionuclear event. In summary, by combining lisinopril (FDA-approved for other indications) with hydration and antibiotics, acute and delayed radiation injuries in multiple organs were mitigated.

  11. [Experience with high-dose immunosuppressive therapy followed by transplantation of autologous stem hematopoietic cells in patients with multiple sclerosis].

    Rossiev, V A; Makarov, S V; Aleksandrova, I Ia; Dolgikh, G T; Lipshina, S R; Stukalova, T A; Trushina, O A; Fedorova, E Iu; Lipina, L N; Sivak, V F; Korenev, P P; Murashov, B F

    2002-01-01

    To assess efficiency of immunosuppressive therapy and subsequent autologous transplantation of stem blood cells (SBC) in patients with multiple sclerosis. The trial enrolled 23 patients (4 men and 19 women) with multiple sclerosis (MS) lasting for 3 to 12 years. The age of the patients ranged from 18 to 44 years. The index of the progression was above 1 in all the patients. A remitting, primary-progredient, secondary-progredient course was diagnosed in 3, 3 and 17 patients, respectively. Posttransplantation follow-up was 1 to 1.5 years. The degree of the neurological deficiency (0-6 scores) was estimated by the scale of functional systems damage. Lymphocyte subpopulations were evaluated by enzyme immunoassay according to expression of membrane antigens CD3, CD4, CD8, CD16, CD20, CD25, CD56, CD95 using monoclonal antibodies ICO (Biomedspectr), humoral immunity--by serum levels of IgA, IgM and IgG. SBC mobilization was conducted for 5 days by subcutaneous introduction of neipogen (Roche) in a dose 8.7-10 mcg/kg. Preparation of SBC was made on Haemonetics blood separator on mobilization day 4-5. Cryopreservation was carried out in programmed freezer (Cryomed) with 7% dimethylsulphoxide as a cryoprotector. Pretransplantation conditioning was conducted according to the schemes BEAM + antilymphocytic globulin (protocol N 1) and fludar + melfalan + ALG (protocol N 2). In posttransplantation period most of the patients achieved a fall in intensity of motor and coordination disorders. No recovery of cranial nerve function was observed. The protocols of pretransplantation preparation were compared by efficiency and organic toxicity. Indications to immunosuppressive therapy in MS patients were defined, pathogenetic validation of the immunosuppressive therapy was attempted.

  12. Microdose gonadotropin-releasing hormone agonist flare-up protocol versus multiple dose gonadotropin-releasing hormone antagonist protocol in poor responders undergoing intracytoplasmic sperm injection-embryo transfer cycle.

    Kahraman, Korhan; Berker, Bulent; Atabekoglu, Cem Somer; Sonmezer, Murat; Cetinkaya, Esra; Aytac, Rusen; Satiroglu, Hakan

    2009-06-01

    To compare the efficacy of microdose GnRH agonist (GnRH-a) flare-up and multiple dose GnRH antagonist protocols in patients who have a poor response to a long luteal GnRH-a protocol. Prospective, randomized, clinical study. University hospital. Forty-two poor responder patients undergoing intracytoplasmic sperm injection (ICSI)-embryo transfer cycle. Twenty-one patients received microdose leuprolide acetate (LA) (50 microg twice daily) starting on the second day of withdrawal bleeding. The other 21 patients received 0.25 mg of cetrorelix daily when the leading follicle reached 14 mm in diameter. Serum E(2) levels, number of growing follicles and mature oocytes, embryo quality, dose of gonadotropin used, cancellation, fertilization, implantation rate and pregnancy rate (PR). The mean serum E(2) concentration on the day of hCG administration was significantly higher in the microdose GnRH-a group than in the GnRH antagonist group (1,904 vs. 1,362 pg/mL). The clinical PRs per started cycle of microdose GnRH-a and GnRH antagonist groups were 14.2% and 9.5%, respectively. There were no statistically significant differences in the other ovulation induction characteristics, fertilization and implantation rates. Microdose GnRH-a flare-up protocol and multiple dose GnRH antagonist protocol seem to have similar efficacy in improving treatment outcomes of poor responder patients.

  13. Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU.

    Ji, Zhiying; LeBaron, Matthew J; Schisler, Melissa R; Zhang, Fagen; Bartels, Michael J; Gollapudi, B Bhaskar; Pottenger, Lynn H

    2016-05-01

    The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P agents. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order.

    Levi Bolin, B; Alcorn, Joseph L; Lile, Joshua A; Rush, Craig R; Rayapati, Abner O; Hays, Lon R; Stoops, William W

    2017-09-01

    Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study

    Conte, Giorgio; Minotti, Marta; De Piano, Francesca [Universita degli Studi di Milano, Postgraduation School in Radiodiagnostics, Milan (Italy); Preda, Lorenzo [Universita degli Studi di Pavia, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, Pavia (Italy); National Center of Oncological Hadrontherapy (CNAO Foundation), Division of Radiology, Pavia (Italy); Cocorocchio, Emilia; Ferrucci, Pier Francesco [European Institute of Oncology, Melanoma and Sarcoma Medical Oncology Division, Milan (Italy); Raimondi, Sara [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Giannitto, Caterina; Petralia, Giuseppe [European Institute of Oncology, Division of Radiology, Milan (Italy); Bellomi, Massimo [European Institute of Oncology, Division of Radiology, Milan (Italy); Universita degli Studi di Milano, Oncology and Haematology/Oncology Department, Milan (Italy)

    2017-10-15

    To investigate whether there is an increased signal intensity (SI) of dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted magnetic resonance imaging (MRI), in patients who had undergone multiple administrations of gadoxetate disodium. We retrospectively included stage III melanoma patients, who had been previously enrolled in a trial of adjuvant therapy and who had undergone whole-body contrast-enhanced MRIs with gadoxetate disodium every three months for their follow-up. The SI ratios of DN-to-pons and GP-to-thalamus on unenhanced T1-weighted images were calculated. The difference in SI ratios between the first and the last MRI examinations was assessed and a linear mixed model was performed to detect how SI ratios varied with the number of administrations. Eighteen patients were included in our study. The number of gadoxetate disodium administrations ranged from 2 to 18. Paired t-test did not show any significant difference in DN-to-pons (p=0.21) and GP-to-thalamus (p=0.09) SI ratios by the end of the study. DN-to-pons SI ratio and GP-to-thalamus SI ratio did not significantly increase with increasing the number of administrations (p=0.14 and p=0.06, respectively). Multiple administrations of gadoxetate disodium are not associated with increased SI in DN and GP in the brain. (orig.)

  16. A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration

    Sun CL

    2015-05-01

    Full Text Available Changling Sun,1,3,* Xueling Wang,1,* Zhaozhu Zheng,2 Dongye Chen,1 Xiaoqin Wang,2 Fuxin Shi,1 Dehong Yu,1 Hao Wu11Department of Otolaryngology–Head and Neck Surgery, Xinhua Hospital, Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, 2National Engineering Laboratory for Modern Silk, Soochow University, Suzhou, 3Department of Otolaryngology–Head and Neck Surgery, Affiliated Hospital of Jiangnan University, The Fourth People’s Hospital of Wuxi City, Wuxi, People’s Republic of China*These authors have contributed equally to this workAbstract: This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA stealth nanoparticles loaded with dexamethasone (DEX. DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of -26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4, 5 days in artificial perilymph (pH 7.4, and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8

  17. Submillisievert standard-pitch CT pulmonary angiography with ultra-low dose contrast media administration: A comparison to standard CT imaging.

    Suntharalingam, Saravanabavaan; Mikat, Christian; Stenzel, Elena; Erfanian, Youssef; Wetter, Axel; Schlosser, Thomas; Forsting, Michael; Nassenstein, Kai

    2017-01-01

    To evaluate the image quality and radiation dose of submillisievert standard-pitch CT pulmonary angiography (CTPA) with ultra-low dose contrast media administration in comparison to standard CTPA. Hundred patients (56 females, 44 males, mean age 69.6±15.4 years; median BMI: 26.6, IQR: 5.9) with suspected pulmonary embolism were examined with two different protocols (n = 50 each, group A: 80 kVp, ref. mAs 115, 25 ml of contrast medium; group B: 100 kVp, ref. mAs 150, 60 ml of contrast medium) using a dual-source CT equipped with automated exposure control. Objective and subjective image qualities, radiation exposure as well as the frequency of pulmonary embolism were evaluated. There was no significant difference in subjective image quality scores between two groups regarding pulmonary arteries (p = 0.776), whereby the interobserver agreement was excellent (group A: k = 0.9; group B k = 1.0). Objective image analysis revealed that signal intensities (SI), signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the pulmonary arteries were equal or significantly higher in group B. There was no significant difference in the frequency of pulmonary embolism (p = 0.65). Using the low dose and low contrast media protocol resulted in a radiation dose reduction by 71.8% (2.4 vs. 0.7 mSv; pcontrast agent volume can obtain sufficient image quality to exclude or diagnose pulmonary emboli while reducing radiation dose by approximately 71%.

  18. Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers.

    Tildesley, N T J; Kennedy, D O; Perry, E K; Ballard, C G; Wesnes, K A; Scholey, A B

    2005-01-17

    Members of the Sage family, such as Salvia officinalis and Salvia lavandulaefolia, have a long history of use as memory-enhancing agents coupled with cholinergic properties that may potentially be relevant to the amelioration of the cognitive deficits associated with Alzheimer's disease. The current study utilised a placebo-controlled, double-blind, balanced, crossover design in order to comprehensively assess any mood and cognition modulation by S. lavandulaefolia. Twenty-four participants received single doses of placebo, 25 microl and 50 microl of a standardised essential oil of S. lavandulaefolia in an order dictated by a Latin square. Doses were separated by a 7-day washout period. Cognitive performance was assessed prior to the day's treatment and at 1, 2.5, 4 and 6 h thereafter using the Cognitive Drug Research (CDR) computerised test battery. Subjective mood ratings were measured using Bond-Lader visual analogue scales. The primary outcome measures were scores on the five cognitive factors that can be derived by factor analysis of the task outcomes from the CDR battery. The results showed that administration of S. lavandulaefolia resulted in a consistent improvement for both the 25- and 50-microl dose on the 'Speed of Memory' factor. There was also an improvement on the 'Secondary Memory' factor for the 25-microl dose. Mood was consistently enhanced, with increases in self-rated 'alertness', 'calmness' and 'contentedness' following the 50-microl dose and elevated 'calmness' following 25 microl. These results represent further evidence that Salvia is capable of acute modulation of mood and cognition in healthy young adults. The data also suggest that previous reports of memory enhancement by Salvia may be due to more efficient retrieval of target material.

  19. The effects of oral and intramuscular administration and dose escalation of enrofloxacin on the selection of quinolone resistance among Salmonella and coliforms in pigs

    Wiuff, C.; Lykkesfeldt, J.; Svendsen, O.

    2003-01-01

    The effect of route of administration and dose of enrofloxacin (Baytril(R)) on the development of fluoroquinolone resistance in Salmonella and Escherichia coli in the intestinal tract of pigs was investigated. Healthy pigs at the age of 8-10 weeks were infected with a mixture of susceptible wild......-type (MICciprofloxacin = 0.03 mug/ml) and a mutant Salmonella typhimurium with reduced susceptibility to fluoroquinolones (MICciprofloxacin 0.5 mug/ml) (in the ratio 99: 1) and treated with 2.5 mg/kg bwt enrofloxacin by either intramuscular (i.m.) or oral (p.o.) administration at time points either 4 or 24 It after....... The Salmonella infection was cleared in all cases during the 2 weeks independent of frequency of resistance. The study showed that resistance is very easily selected by treatment with enrofloxacin at the recommended dose 2.5 mg/kg bwt, but also that the intensity of selection can be reduced by using...

  20. Sequential gadolinium-enhanced magnetic resonance angiography of the aortoiliac and the femoropopliteal arteries with repetitive administration of low-dose contrast agent

    Ito, Koichiro; Kumazaki, Tatsuo

    2000-01-01

    To obtain a wide-range contrast MR angiography in a single examination, we performed two sequential administrations of low-dose (0.08 mmol/kg) gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) with three dimensional inversion recovery prepared fast spoiled gradient recalled acquisition in the steady-state (3D IR-fast SPGR) sequence. Signal characteristics of the sequence were estimated by computed simulations and an in vitro study. A clinical study of 19 examinations was done with sequential MR angiography of the aortoiliac and femoropopliteal arteries. Great signal differences were observed between the high and low Gd concentrations. Higher Gd concentrations generated significantly stronger signals. Greater signals were produced at TIs of longer than 150 msec than at shorter than 100 msec. In the clinical study, the arteries were visualized with sufficient signals even with a small amount of contrast agent. Contrast-to-noise ratios between the arteries and surrounding skeletal muscles or fat tissues ranged from 10.5±9.6 to 4.7±2.2 and 6.6±2.8 to -3.1±11.2, respectively. No venous enhancement was found with diluted contrast agent on the second MR angiography. Two consecutive contrast MR angiographies can be obtained with repetitive administration of low-dose contrast agent. (author)

  1. Sequential gadolinium-enhanced magnetic resonance angiography of the aortoiliac and the femoropopliteal arteries with repetitive administration of low-dose contrast agent

    Ito, Koichiro [Nippon Medical School, Inba, Chiba (Japan). Chiba Hokusoh Hospital; Kumazaki, Tatsuo

    2000-12-01

    To obtain a wide-range contrast MR angiography in a single examination, we performed two sequential administrations of low-dose (0.08 mmol/kg) gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) with three dimensional inversion recovery prepared fast spoiled gradient recalled acquisition in the steady-state (3D IR-fast SPGR) sequence. Signal characteristics of the sequence were estimated by computed simulations and an in vitro study. A clinical study of 19 examinations was done with sequential MR angiography of the aortoiliac and femoropopliteal arteries. Great signal differences were observed between the high and low Gd concentrations. Higher Gd concentrations generated significantly stronger signals. Greater signals were produced at TIs of longer than 150 msec than at shorter than 100 msec. In the clinical study, the arteries were visualized with sufficient signals even with a small amount of contrast agent. Contrast-to-noise ratios between the arteries and surrounding skeletal muscles or fat tissues ranged from 10.5{+-}9.6 to 4.7{+-}2.2 and 6.6{+-}2.8 to -3.1{+-}11.2, respectively. No venous enhancement was found with diluted contrast agent on the second MR angiography. Two consecutive contrast MR angiographies can be obtained with repetitive administration of low-dose contrast agent. (author)

  2. The pharmacokinetics of peginterferon lambda-1a following single dose administration to subjects with impaired renal function.

    Hruska, Matthew W; Adamczyk, Robert; Colston, Elizabeth; Hesney, Michael; Stonier, Michele; Myler, Heather; Bertz, Richard

    2015-09-01

    This open label study was conducted to assess the effect of renal impairment (RI) on the pharmacokinetics (PK) of peginterferon lambda-1a (Lambda). Subjects (age 18-75 years, BMI 18-35 kg m(-2) ) were enrolled into one of five renal function groups: normal (n = 12), mild RI (n = 8), moderate RI (n = 8), severe RI (n = 7), end-stage renal disease (ESRD, n = 8) based on estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) equation. Subjects received a single dose of Lambda (180 µg) subcutaneously on day 1 followed by PK serum sample collections through day 29. Safety, tolerability and immunogenicity data were collected through day 43. PK parameters were estimated and summarized by group. Geometric mean ratios (GMR) and 90% confidence intervals (CIs) were calculated between normal and RI groups. With decreasing eGFR, Lambda exposure (Cmax , AUC) increased while apparent clearance (CL/F) and apparent volume of distribution (V/F) decreased. Relative to subjects with normal renal function (geometric mean AUC = 99.5 ng ml(-1) h), Lambda exposure estimates (AUC) were slightly increased in the mild RI group (geometric mean [90% CI]: 1.20 [0.82, 1.77]) and greater in the moderate (1.95 [1.35, 2.83]), severe RI (1.95 [1.30, 2.93]) and ESRD (1.88 [1.30, 2.73]) groups. Lambda was generally well tolerated. The results demonstrated that RI reduces the clearance of Lambda and suggests that dose modifications may not be required in patients with mild RI but may be required in patients with moderate to severe RI or ESRD. © 2015 The British Pharmacological Society.

  3. Effect of the dose and route of administration of butylscopolamine on the reduction of the artifacts associated with intestinal peristalsis in abdominal magnetic resonance

    Dosda, R.; Marti-Bonmati, L.; Ronchera-Oms, C.

    1999-01-01

    To compare the effect of the route of administration (intravenous and oral) and the dose (40 mg and 80 mg) of butylscopolamine, determining its efficacy in reducing the noise associated with gastrointestinal movement in magnetic resonance (MR) images and the incidence and severity of associated adverse reactions. The present prospective, controlled, double-blind study included 80 patients who underwent abdominal MR. All the patients were given oral, high-density barium sulfate and were divided randomly into 4 groups of 20 patients each: a control group and 3 groups treated with 40 mg or 80 mg of oral butylscopolamine or 40 mg of intravenous butylscopolamine. Both the barium and the oral solutions were administered 25 to 30 minutes before the examination. the MR images were obtained with a STIR sequence (1487/100/44), and qualitative analysis of the noise was carried out using regions of interest situated in the background. The gastrointestinal noise was defined both by the mean and the standard deviation of the signal intensity of the air front of an behind the patient. The standard deviation of the air beside the patient was determined to confirm the absence of variations in noise inherent to MR. The adverse reactions to MR after 2 hours (immediate) and one day (late) were recorded. There were no significant differences among the groups with respect to sex, age or time interval between administration of the oral solution and the start of the sequence. The noise inherent to MR was not significantly different from one group to another (Student-Newman-Keuls test, p=0.71). Both the mean and the standard deviation of the intensity of the air situated in anteroposterior phase-encoding direction were significantly lower in the butylscopolamine groups than in the control group (Student-Newman-Keuls test, p=0.008). The most marked reduction was observed after the oral dose of 80 mg, followed by intravenous injection of 40 mg and the oral dose of 40 mg. Adverse reaction

  4. An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

    Liu, Hongzhong; Wu, Runhui; Hu, Pei; Sun, Feifei; Xu, Lihong; Liang, Yali; Nepal, Sunil; Qu, Peng Roger; Huard, Francois; Korth-Bradley, Joan M

    2017-07-01

    Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported with recombinant FVIII products in studies with a predominantly white population; younger patients had reduced exposure to FVIII:C. The single doses of moroctocog alfa (AF-CC) were well tolerated; 2 cases of transient, low-titer FVIII inhibitor development were observed. ClinicalTrials.gov identifier: NCT02461992. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

  5. The effects of the administration of two different doses of manganese on short-term spatial memory and anxiety-like behavior in rats

    Hogas M.

    2011-01-01

    Full Text Available Manganese is a very well known neurotoxic agent. It has been mainly linked to impaired motor skills and disturbed psychomotor development. However, very few aspects are known about the cognitive deficits and behavioral consequences of chronic manganese exposure. In this context, we report herein our findings regarding short-term spatial memory, motor and anxiety-like behavior assessments in male Wistar rats exposed for 45 days to two different doses (3 mg/kg b.w., i.p. and 10 mg/kg b.w., i.p. of manganese. Behavior testing (Y-maze task and elevated plus maze was performed after 45 days of manganese administration. Chronic manganese exposure in Wistar rats led to behavioral alterations consisting of cognitive deficiencies in the Y-maze task and anxiety/compulsive-like behaviors in the elevated plus maze, but no motor disturbances as tested by the number of arm entries in the Y-maze. Additional work is necessary to understand the longterm effects of different doses and dosing regimens of manganese on cognitive/affective and motor functioning.

  6. Isavuconazole absorption following oral administration in healthy subjects is comparable to intravenous dosing, and is not affected by food, or drugs that alter stomach pH.

    Schmitt-Hoffmann, Anne; Desai, Amit; Kowalski, Donna; Pearlman, Helene; Yamazaki, Takao; Townsend, Robert

    2016-08-01

    Two openlabel, single-dose, randomized crossover studies and one open-label, multiple-dose, parallel group study in healthy volunteers were conducted with the prodrug, isavuconazonium sulfate, to determine absolute bioavailability of the active triazole, isavuconazole (EudraCT 2007-004949-15; n = 14), and the effect of food (EudraCT 2007- 004940-63; n = 26), and pH (NCT02128893; n = 24) on the absorption of isavuconazole. Isavuconazonium sulfate 744 mg designed to deliver 400 mg of the active triazole isavuconazole was administered in the absolute bioavailability (oral or intravenous (IV) (2-hour infusion)) and food-effect studies (oral). In the pH-effect study, isavuconazonium sulfate 372 mg designed to deliver 200 mg of isavuconazole was administered orally three times daily (t.i.d.) for 2 days, followed by a single daily oral dose for 3 days, in the presence of steady state esomeprazole dosed orally at 40 mg/day. Isavuconazole was well tolerated in each study. Bioavailability: Geometric least squares mean ratios (GLSMR; oral/IV) for isavuconazole AUC∞, and Cmax were 98% (90% confidence interval (CI): 94, 101) and 78% (90% CI: 72, 85), respectively. Food-effect: GLSMR (fed/fasted) for AUC∞ and Cmax of isavuconazole in plasma were 110% (90% CI: 102, 118) and 92% (90% CI: 86, 98), respectively. Median tmax was 5 hours with food and 3 hours under fasted conditions. pH-effect: GLSMR for isavuconazole AUCtau and Cmax were 108% (90% CI: 89, 130) and 105% (90% CI: 89, 124), respectively. Orally administered isavuconazonium sulfate effectively delivers isavuconazole, as evidenced by the fact that oral isavuconazole is bioequivalent to the IV formulation. Dose adjustments are not required when switching between oral and IV formulations, regardless of food or drugs that increase gastric pH.

  7. Effects of lead administration at low doses by different routes on rat spleens. Study of response of splenic lymphocytes and tissue lysozyme

    Teijon, Cesar; Olmo, Rosa; Dolores Blanco, Maria; Romero, Arturo; Maria Teijon, Jose

    2003-09-30

    The aim of this study was to evaluate the effects of low doses of lead (200 ppm of PbAc{sub 2} for 4 weeks) on rat spleens using different routes of administration. The study has been carried out at different levels: a histological evaluation has been made, and alterations of cell proliferation, B and T lymphocyte subpopulations, and CD4{sup +} and CD8{sup +} T cell subpopulations have been evaluated. Apoptosis and necrosis of lymphoid cells were also analysed. Furthermore, lysozyme activity was measured. Results indicate a large increase in spleen size when lead is administered by intraperitoneal injection, being this route in which lead causes larger modifications in all of the parameters measured. Lead administered orally causes histological modifications, such as an increase in the number of lymphocytes as well as edema. However, significant alterations in other parameters studied have not been detected. Lead administration by intraperitoneal route causes more evident histological modifications as well as an increase in the number of lymphocytes, and also induces a decrease in the percentage of B{sup +}, T{sup +} and CD4{sup +} cells, and an increase in CD8{sup +} cells. Cell death of splenic lymphocytes is not altered by lead. With regard to the immune innate response, lead behaves as an immunomodulator as can be deduced from data on lysozyme activity in tissue. Therefore, it is possible to affirm that the effect of low doses of lead depends on the route of administration. Thus, the intraperitoneal route, through which lead goes directly to the bloodstream, causes drastic effects, generating important immunological alterations.

  8. Effects of lead administration at low doses by different routes on rat spleens. Study of response of splenic lymphocytes and tissue lysozyme

    Teijon, Cesar; Olmo, Rosa; Dolores Blanco, Maria; Romero, Arturo; Maria Teijon, Jose

    2003-01-01

    The aim of this study was to evaluate the effects of low doses of lead (200 ppm of PbAc 2 for 4 weeks) on rat spleens using different routes of administration. The study has been carried out at different levels: a histological evaluation has been made, and alterations of cell proliferation, B and T lymphocyte subpopulations, and CD4 + and CD8 + T cell subpopulations have been evaluated. Apoptosis and necrosis of lymphoid cells were also analysed. Furthermore, lysozyme activity was measured. Results indicate a large increase in spleen size when lead is administered by intraperitoneal injection, being this route in which lead causes larger modifications in all of the parameters measured. Lead administered orally causes histological modifications, such as an increase in the number of lymphocytes as well as edema. However, significant alterations in other parameters studied have not been detected. Lead administration by intraperitoneal route causes more evident histological modifications as well as an increase in the number of lymphocytes, and also induces a decrease in the percentage of B + , T + and CD4 + cells, and an increase in CD8 + cells. Cell death of splenic lymphocytes is not altered by lead. With regard to the immune innate response, lead behaves as an immunomodulator as can be deduced from data on lysozyme activity in tissue. Therefore, it is possible to affirm that the effect of low doses of lead depends on the route of administration. Thus, the intraperitoneal route, through which lead goes directly to the bloodstream, causes drastic effects, generating important immunological alterations

  9. Administrative Data Repository (ADR)

    Department of Veterans Affairs — The Administrative Data Repository (ADR) was established to provide support for the administrative data elements relative to multiple categories of a person entity...

  10. Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

    San Miguel, Jesus F.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine; Renner, Christoph; Bahlis, Nizar Jacques; Yu, Xin; Teasdale, Terri; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Dimopoulos, Meletios A.

    2015-01-01

    Pomalidomide is a distinct oral IMiD® immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. PMID:26160879

  11. Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.

    Lerman, Tamara; Depenbusch, Marion; Schultze-Mosgau, Askan; von Otte, Soeren; Scheinhardt, Markus; Koenig, Inke; Kamischke, Axel; Macek, Milan; Schwennicke, Arne; Segerer, Sabine; Griesinger, Georg

    2017-05-01

    The incidence of low (18 oocytes) ovarian response to 150 µg corifollitropin alfa in relation to anti-Müllerian hormone (AMH) and other biomarkers was studied in a multi-centre (n = 5), multi-national, prospective, investigator-initiated, observational cohort study. Infertile women (n = 212), body weight >60 kg, underwent controlled ovarian stimulation in a gonadotrophin-releasing hormone-antagonist multiple-dose protocol. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle day 2 or 3 of a spontaneous menstruation before the administration of 150 µg corifollitropin alfa. Serum AMH showed the best correlation with the number of oocytes obtained among all predictor variables. In receiver-operating characteristic analysis, AMH at a threshold of 0.91 ng/ml showed a sensitivity of 82.4%, specificity of 82.4%, positive predictive value 52.9%and negative predictive value 95.1% for predicting low response (area under the curve [AUC], 95% CI; P-value: 0.853, 0.769-0.936; <0.0001). For predicting high response, the optimal threshold for AMH was 2.58 ng/ml, relating to a sensitivity of 80.0%, specificity 82.1%, positive predictive value 42.5% and negative predictive value 96.1% (AUC, 95% CI; P-value: 0.871, 0.787-0.955; <0.0001). In conclusion, patients with serum AMH concentrations between approximately 0.9 and 2.6 ng/ml were unlikely to show extremes of response. Copyright © 2017. Published by Elsevier Ltd.

  12. Short-term, high-dose glucocorticoid treatment does not contribute to reduced bone mineral density in patients with multiple sclerosis

    Olsson, A.; Oturai, D B; Sørensen, P S

    2015-01-01

    BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). OBJECTIVES: The objective of this paper is to assess bone mass in patients with MS and evaluate...... the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. METHODS: A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference...... population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. RESULTS: Osteopenia was present in 38...

  13. Perioperative single high dose ATG-Fresenius S administration as induction immunosuppressive therapy in cadaveric renal transplantation--preliminary results.

    Samsel, R; Chmura, A; Włodarczyk, Z; Wyzgał, J; Cieciura, T; Lagiewska, B; Pliszczyński, J; Korczak, G; Lazowski, T; Paczek, L; Wałaszewski, J; Lao, M; Rowiński, W

    1999-01-01

    Monoclonal and polyclonal antilymphocyte antibodies have been used successfully in organ transplantation as induction therapy and in the treatment of acute graft rejection. Used for induction the medication is generally given for the first 7-10 days. The aim of this study was to assess the safety and efficacy of single high dose (9 mg/kg) ATG Fresenius S given perioperatively, before revascularization, to kidney allograft recipients. During last twelve months seventy six, first cadaveric kidney adult recipients were included into the study in two centers (center A-64, center B-12). All patients received triple drug immunosuppression (Neoral, steroids and Cellcept which was replaced by azathioprine after 4 months), and were randomized to receive ATG or not. The follow-up period ranged from 1 month up to 1 year. The preliminary results are very promising, the rejection rate in bolus group was significantly lower than in control. No significant side effects or serious adverse events in both groups were observed.

  14. Helical Tomotherapy for Whole-Brain Irradiation With Integrated Boost to Multiple Brain Metastases: Evaluation of Dose Distribution Characteristics and Comparison With Alternative Techniques

    Levegrün, Sabine; Pöttgen, Christoph; Wittig, Andrea; Lübcke, Wolfgang; Abu Jawad, Jehad; Stuschke, Martin

    2013-01-01

    Purpose: To quantitatively evaluate dose distribution characteristics achieved with helical tomotherapy (HT) for whole-brain irradiation (WBRT) with integrated boost (IB) to multiple brain metastases in comparison with alternative techniques. Methods and Materials: Dose distributions for 23 patients with 81 metastases treated with WBRT (30 Gy/10 fractions) and IB (50 Gy) were analyzed. The median number of metastases per patient (N mets ) was 3 (range, 2-8). Mean values of the composite planning target volume of all metastases per patient (PTV mets ) and of the individual metastasis planning target volume (PTV ind met ) were 8.7 ± 8.9 cm 3 (range, 1.3-35.5 cm 3 ) and 2.5 ± 4.5 cm 3 (range, 0.19-24.7 cm 3 ), respectively. Dose distributions in PTV mets and PTV ind met were evaluated with respect to dose conformity (conformation number [CN], RTOG conformity index [PITV]), target coverage (TC), and homogeneity (homogeneity index [HI], ratio of maximum dose to prescription dose [MDPD]). The dependence of dose conformity on target size and N mets was investigated. The dose distribution characteristics were benchmarked against alternative irradiation techniques identified in a systematic literature review. Results: Mean ± standard deviation of dose distribution characteristics derived for PTV mets amounted to CN = 0.790 ± 0.101, PITV = 1.161 ± 0.154, TC = 0.95 ± 0.01, HI = 0.142 ± 0.022, and MDPD = 1.147 ± 0.029, respectively, demonstrating high dose conformity with acceptable homogeneity. Corresponding numbers for PTV ind met were CN = 0.708 ± 0.128, PITV = 1.174 ± 0.237, TC = 0.90 ± 0.10, HI = 0.140 ± 0.027, and MDPD = 1.129 ± 0.030, respectively. The target size had a statistically significant influence on dose conformity to PTV mets (CN = 0.737 for PTV mets ≤4.32 cm 3 vs CN = 0.848 for PTV mets >4.32 cm 3 , P=.006), in contrast to N mets . The achieved dose conformity to PTV mets , assessed by both CN and PITV, was in all investigated volume strata

  15. Enhancing the Predictive Potential of Personality: Isolating Multiple Components of Trait Expression via a Single Administration Design

    2015-03-01

    109 8.0 Arts, Design, Entertainment, Media, Sports , and Recreation 100 7.4 Information Technology 86 6.3 Office and Administrative Support 74 5.5...55 4.1 Government and Public Administration 35 2.6 Community and Social Service 29 2.1 Manufacturing 29 2.1 Hospitality and Tourism 25 1.8...playing a sport ; exercising; or doing yard work or housework. % Not descriptive of me % Somewhat descriptive of me % Very descriptive of me N/A

  16. Tamoxifen Forms DNA Adducts In Human Colon After Administration Of A Single [14C]-Labeled Therapeutic Dose.

    Brown, K; Tompkins, E M; Boocock, D J; Martin, E A; Farmer, P B; Turteltaub, K W; Ubick, E; Hemingway, D; Horner-Glister, E; White, I H

    2007-05-23

    Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the U.S. for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated but much interest has focussed on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to ten women as a single [{sup 14}C]-labeled therapeutic (20 mg) dose, {approx}18 h prior to undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with HPLC separation of enzymatically digested DNA, a peak corresponding to authentic dG-N{sup 2}-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1-7 adducts/10{sup 9} nucleotides. No [{sup 14}C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests this tissue has the potential to activate tamoxifen to {alpha}-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of inter-individual variability, when present it was {approx}10-100 times higher than that reported for other suspect human colon carcinogens such as PhIP. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

  17. GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice.

    Wang, Z; Gleichmann, H

    1998-01-01

    In mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both beta-cell toxicity and T-cell-dependent immune reactions. The target molecule(s) of MLD-STZ-induced beta-cell toxicity are not known, however. In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. Significant reduction of both GLUT2 protein and mRNA expression was first noted 1 day after the third STZ injection, clearly preceding the onset of hyperglycemia. The extent of reduction increased with the number of STZ injections administered and increased over time, after the last, i.e., fifth, STZ injection. The STZ-induced reduction of GLUT2 protein and mRNA was not due to an essential loss of beta-cells, because ex vivo, not only the total RNA yield and protein content in isolated islets, but also proinsulin mRNA expression, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction of both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells.

  18. Development of a flattening filter free multiple source model for use as an independent, Monte Carlo, dose calculation, quality assurance tool for clinical trials.

    Faught, Austin M; Davidson, Scott E; Popple, Richard; Kry, Stephen F; Etzel, Carol; Ibbott, Geoffrey S; Followill, David S

    2017-09-01

    The Imaging and Radiation Oncology Core-Houston (IROC-H) Quality Assurance Center (formerly the Radiological Physics Center) has reported varying levels of compliance from their anthropomorphic phantom auditing program. IROC-H studies have suggested that one source of disagreement between institution submitted calculated doses and measurement is the accuracy of the institution's treatment planning system dose calculations and heterogeneity corrections used. In order to audit this step of the radiation therapy treatment process, an independent dose calculation tool is needed. Monte Carlo multiple source models for Varian flattening filter free (FFF) 6 MV and FFF 10 MV therapeutic x-ray beams were commissioned based on central axis depth dose data from a 10 × 10 cm 2 field size and dose profiles for a 40 × 40 cm 2 field size. The models were validated against open-field measurements in a water tank for field sizes ranging from 3 × 3 cm 2 to 40 × 40 cm 2 . The models were then benchmarked against IROC-H's anthropomorphic head and neck phantom and lung phantom measurements. Validation results, assessed with a ±2%/2 mm gamma criterion, showed average agreement of 99.9% and 99.0% for central axis depth dose data for FFF 6 MV and FFF 10 MV models, respectively. Dose profile agreement using the same evaluation technique averaged 97.8% and 97.9% for the respective models. Phantom benchmarking comparisons were evaluated with a ±3%/2 mm gamma criterion, and agreement averaged 90.1% and 90.8% for the respective models. Multiple source models for Varian FFF 6 MV and FFF 10 MV beams have been developed, validated, and benchmarked for inclusion in an independent dose calculation quality assurance tool for use in clinical trial audits. © 2017 American Association of Physicists in Medicine.

  19. Comparison of sedation and mechanical antinociception induced by intravenous administration of acepromazine and four dose rates of dexmedetomidine in donkeys.

    Lizarraga, Ignacio; Castillo-Alcala, Fernanda; Robinson, Lauren S

    2017-05-01

    To assess and compare the sedative and antinociceptive effects of four dosages of dexmedetomidine in donkeys. Randomized, controlled, crossover, Latin-square, blinded study. Six healthy, castrated, adult, standard donkeys. Dexmedetomidine (2, 3, 4 and 5 μg kg -1 ; D2, D3, D4 and D5), acepromazine (0.1 mg kg -1 ) and saline were administered intravenously to each donkey and a 1 week interval was allowed between successive trials on each animal. Sedation scores (SS) and head heights above ground (HHAG) were used to assess sedation and mechanical nociceptive threshold (MNT) testing to assess antinociception over 120 minutes post-treatment. Areas under the curve (AUC) for 0-30, 30-60 and 60-120 minutes were computed to compare the effect of treatments. SS-AUC 0-30 values were larger for D4 and D5, and SS-AUC 30-60 values were larger for D5 than for saline. All dexmedetomidine treatments produced lower HHAG-AUC 0-30 and HHAG-AUC 30-60 values, and acepromazine produced lower HHAG AUC 60-120 values than did saline. For MNT, D3, D4 and D5 increased AUC 0-30 and AUC 30-60 values compared with saline and also AUC 0-30 values compared with D2 and acepromazine. Smaller MNT-AUC 30-60 values were obtained with D2 than with D4 and D5, with D3 than with D5, and with acepromazine than with D4 and D5. Dexmedetomidine induced sedation and dosage-dependent mechanical antinociception. Larger dexmedetomidine dose rates were required to induce antinociception than sedation. Furthermore, the antinociception induced by dexmedetomidine was of shorter duration than its sedation. For minor painful procedures on standing donkeys, D5 may be clinically useful to provide sedation and analgesia. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

  20. Estimation of lung tissue doses following exposure to low-LET radiation in the Canadian study of cancer following multiple fluoroscopies

    Howe, G.R.; Yaffe, M.

    1992-02-01

    Lung tissue doses from exposure to external low-LET radiation have been estimated for each year between 1930 and 1960 for 92,707 tuberculosis patients first treated in Canadian institutions between 1930 and 1952. Many of these patients received multiple chest fluoroscopies together with treatment by artificial pneumothorax, and thus accumulated doses up to 15.7 grays. The estimated doses have been used in a statistical analysis of lung cancer mortality between 1950 and 1987 occurring among 64,698 patients known to be alive at the start of 1950, and followed by linkage to the Canadian national mortality data base. There were substantial variations in the total cumulative lung tissue dose received by the cohort, with 2,490 individuals having doses in excess of 1.7 grays. A total of 1,156 lung cancer deaths was observed in the cohort, and these have been used to estimate relative risks. The most appropriate risk model appears to be a simple linear relative risk function, with an excess relative risk coefficient of 0.089 for an absorbed dose of 1 gray. This contrasts with estimates of relative risk based on the atomic bomb survivors study, for which the excess relative risk coefficient for males 20 years after the first exposure is estimated to be 0.64. The difference is statistically significant. It is postulated that fractionation and dose rate effectiveness factors may account for some of the discrepancy. (Modified author abstract) (14 refs., 20 tabs.)

  1. Optimizing dose and administration regimen of a high-relaxivity contrast agent for myocardial MRI late gadolinium enhancement

    Secchi, Francesco; Di Leo, Giovanni; Papini, Giacomo D.E. [Universita degli Studi di Milano, Dipartimento di Scienze Medico-Chirurgiche, Milan (Italy); IRCCS Policlinico San Donato, Radiology Unit, Via Morandi 30, 20097 San Donato Milanese, Milan (Italy); Giacomazzi, Francesca [IRCCS Policlinico San Donato, Unit of Cardiac Surgery, Via Morandi 30, 20097 San Donato Milanese, Milan (Italy); Di Donato, Marisa [University of Florence, Department of Critical Care Medicine, IRCCS Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese, Milan (Italy); Sardanelli, Francesco, E-mail: francesco.sardanelli@unimi.it [Universita degli Studi di Milano, Dipartimento di Scienze Medico-Chirurgiche, Milan (Italy); IRCCS Policlinico San Donato, Radiology Unit, Via Morandi 30, 20097 San Donato Milanese, Milan (Italy)

    2011-10-15

    Objectives: To investigate the time-course of late gadolinium enhancement of infarcted myocardium using gadobenate dimeglumine at different dosages and administration regimens. Materials and methods: After institutional review board approval and informed consent, we studied 13 patients (aged 63 {+-} 11 years) with chronic myocardial infarction. They underwent two gadobenate dimeglumine-enhanced MR examinations (interval 24-48 h) using short-axis inversion-recovery gradient-echo sequences, with the following two different protocols, in randomized order: 0.05 mmol/kg and imaging at the 2.5th, 5th, 7.5th and 10th minute plus 0.05 mmol/kg and imaging at the 12.5th, 15th, 17.5th and 20th minute; the same as before but using 0.1 mmol/kg for both contrast injections. Contrast-to-noise ratios (CNRs) between infarcted myocardium, non-infarcted myocardium and left ventricle cavity were calculated for each time-point (2.5-min steps). Friedman ANOVA was used for comparing the CNR time-course; Wilcoxon test for comparing CNR at the 10th and the 20th minute. Results: The CNR between infarcted and non-infarcted myocardium obtained at the 20th minute with 0.05 plus 0.05 mmol/kg resulted significantly higher than that obtained at the 10th minute with 0.05 mmol/kg (P = 0.033) while not significantly different from that obtained at the 10th (0.1 mm/kg) or at the 20th minute with 0.1 plus 0.1 mmol/kg. The CNR between infarcted myocardium and the left ventricle cavity obtained at the 20th minute with 0.05 plus 0.05 mmol/kg resulted significantly higher than all other measured values (P {<=} 0.017). Conclusion: Using gadobenate dimeglumine, 0.05 plus 0.05 mmol/kg allows for a higher CNR between infarcted myocardium and the left ventricle cavity allowing for reliable assessment of the sub-endocardial infarctions.

  2. The stimulatory effect of single-dose pre-irradiation administration of indomethacin and diclofenac on haemopoietic recovery in the spleen of gamma-irradiated mice

    Kozubik, A.; Pospisil, M.; Netikova, J.

    1989-01-01

    The aim of the work was to examine the effect of the single-dose pre-irradiation administration of non-steroid anti-inflammatory drugs, i.e. indomethacin (0.15 mg/mouse) and diclofenac (0.6 mg/mouse) on the recovery of haemopoiesis in the spleen of whole-body irradiated male mice (CBA x C57BL/10)F 1 . It was shown that the administation of these substances 1-24 h prior to sublethal irradiation stimulates the recovery of the proliferation activity of the spleen and the formation of endogenous spleen colonies. These results can be explained as the inhibitory effect of the substances administered on biosynthesis of prostaglandins. (author)

  3. Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers.

    Oh, Minkyung; Park, Sung-Eun; Ghim, Jong-Lyul; Choi, Young-Kyung; Shim, Eon-Jeong; Shin, Jae-Gook; Kim, Eun-Young

    2017-01-01

    This study compared the pharmacokinetic (PK) and safety profiles of a fixed-dose combination (FDC) formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs. This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S-amlodipine and were also coadministered the same dose of both drugs given separately. The crossover study design included a 14-day washout period between the two treatments. Blood samples were collected up to 168 h following drug administration. The plasma concentrations of telmisartan and S-amlodipine were determined by liquid chromatography tandem mass spectrometry. PK parameters and plasma concentration-time curves were compared. Safety was assessed by measuring vital signs, clinical laboratory tests, physical examinations, and patient interviews. The geometric mean ratios and 90% CIs for the maximum plasma concentration (C max ) and area under the curve from time zero to the last sampling time (AUC t ) were 0.8782 (0.8167-0.9444) and 0.9662 (0.9210-1.0136) for telmisartan and 1.0069 (0.9723-1.0427) and 1.0324 (0.9969-1.0690) for S-amlodipine, respectively. A total of 36 adverse events (AEs) were reported by 23 subjects, but no statistical differences were observed between the two treatments. The most frequently reported AE was a mild-to-moderate headache that was generally self-limiting. For both telmisartan and S-amlodipine, the C max and AUC t 90% CIs were between ln (0.8) and ln (1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile to the coadministration of these drugs.

  4. A new method for synthesizing radiation dose-response data from multiple trials applied to prostate cancer

    Diez, Patricia; Vogelius, Ivan S; Bentzen, Søren M

    2010-01-01

    A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high).......A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high)....

  5. Characterisation of Population Pharmacokinetics and Endogenous Follicle Stimulating Hormone (FSH) Levels after Multiple Dosing of a Recombinant Human FSH, FE 999049, in Healthy Women

    Rose, Trine Høyer; Röshammer, Daniel; Erichsen, Lars

    2016-01-01

    : Longitudinal measurements of FSH, luteinising hormone, progesterone, estradiol, and inhibin B levels were collected after repeated subcutaneous dosing with 225 IU of FE 999049 in 24 gonadotropin downregulated healthy women. The FSH data were described using nonlinear mixed-effects modelling. Results...... increased with body weight in accordance with an allometrically scaled power exponent of 0.75 and 1, respectively. Endogenous FSH levels were lower in individuals with higher progesterone levels at baseline and were further suppressed over time with increasing inhibin B levels. Conclusions......: This characterisation of FE 999049 population pharmacokinetics after repeated dosing is in line with previous findings after single-dose administration. The results provide a basis for study design and data evaluation in the future development of recombinant FSH products, and show it can be of importance to account...

  6. Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti-hyperalgesic effects, in patients with sciatica.

    Okkerse, Pieter; Hay, Justin L; Versage, Eve; Tang, Yongqiang; Galluppi, Gerald; Ravina, Bernard; Verma, Ajay; Williams, Leslie; Aycardi, Ernesto; Groeneveld, Geert Jan

    2016-07-01

    BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica. This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ). Safety and efficacy assessments were used as endpoints. The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 μg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen. The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica. © 2016 The British Pharmacological Society.

  7. Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers

    Oh M

    2017-12-01

    Full Text Available Minkyung Oh,1,2,* Sung-Eun Park,3,* Jong-Lyul Ghim,1–3 Young-Kyung Choi,1 Eon-Jeong Shim,1–3 Jae-Gook Shin,1–3 Eun-Young Kim1–3 1Department of Pharmacology, 2PharmacoGenomics Research Center, Inje University College of Medicine, Busan, 3Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea *These authors contributed equally to this work Objective: This study compared the pharmacokinetic (PK and safety profiles of a fixed-dose combination (FDC formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs.Materials and methods: This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S-amlodipine and were also coadministered the same dose of both drugs given separately. The crossover study design included a 14-day washout period between the two treatments. Blood samples were collected up to 168 h following drug administration. The plasma concentrations of telmisartan and S-amlodipine were determined by liquid chromatography tandem mass spectrometry. PK parameters and plasma concentration–time curves were compared. Safety was assessed by measuring vital signs, clinical laboratory tests, physical examinations, and patient interviews.Results: The geometric mean ratios and 90% CIs for the maximum plasma concentration (Cmax and area under the curve from time zero to the last sampling time (AUCt were 0.8782 (0.8167–0.9444 and 0.9662 (0.9210–1.0136 for telmisartan and 1.0069 (0.9723–1.0427 and 1.0324 (0.9969–1.0690 for S-amlodipine, respectively. A total of 36 adverse events (AEs were reported by 23 subjects, but no statistical differences were observed between the two treatments. The most frequently reported AE was a mild-to-moderate headache that was generally self-limiting.Conclusion: For both telmisartan and S-amlodipine, the Cmax and AUCt 90% CIs

  8. Epidemiology of two large measles virus outbreaks in Catalonia: what a difference the month of administration of the first dose of vaccine makes.

    Torner, Núria; Anton, Andres; Barrabeig, Irene; Lafuente, Sara; Parron, Ignasi; Arias, César; Camps, Neus; Costa, Josep; Martínez, Ana; Torra, Roser; Godoy, Pere; Minguell, Sofia; Ferrús, Glòria; Cabezas, Carmen; Domínguez, Ángela; Spain

    2013-03-01

    Measles cases in the European Region have been increasing in the last decade; this illustrates the challenge of what we are now encountering in the form of pediatric preventable diseases. In Catalonia, autochthonous measles was declared eliminated in the year 2000 as the result of high measles-mumps-rubella vaccine (MMR) coverage for first and second dose (15 mo and 4 y) since the mid-1990s. From then on, sporadic imported cases and small outbreaks appeared, until in 2006-2007 a large measles outbreak affecting mostly unvaccinated toddlers hit the Barcelona Health Region. Consequently, in January 2008, first dose administration of MMR was lowered from 15 to 12 mo of age. A new honeymoon period went by until the end of 2010, when several importations of cases triggered new sustained transmission of different wild measles virus genotypes, but this time striking young adults. The aim of this study is to show the effect of a change in MMR vaccination schedule policy, and the difference in age incidence and hospitalization rates of affected individuals between both outbreaks.   Epidemiologic data were obtained by case interviews and review of medical records. Samples for virological confirmation and genotyping of cases were collected as established in the Measles Elimination plan guidelines. Incidence rate (IR), rate ratio (RR) and their 95% CI and hospitalization rate (HR) by age group were determined. Statistic z was used for comparing proportions. Total number of confirmed cases was 305 in the 2010 outbreak and 381 in the 2006-2007 outbreak; mean age 20 y (SD 14.8 y; 3 mo to 51 y) vs. 15 mo (SD 13.1 y; 1 mo to 50 y). Highest proportion of cases was set in ≥ 25 y (47%) vs. 24.2% in 2006 (p < 0.001). Differences in IR for ≤ 15 mo (49/100,000 vs. 278.2/100,000; RR: 3,9; 95%CI 2,9-5.4) and in overall HR 29.8% vs. 15.7% were all statistically significant (p < 0.001). The change of the month of age for the administration of the first MMR dose proved successful to

  9. A quality improvement project to reduce the intraoperative use of single-dose fentanyl vials across multiple patients in a pediatric institution.

    Buck, David; Subramanyam, Rajeev; Varughese, Anna

    2016-01-01

    The use of a single-dose vial across multiple patients presents a risk to sterility and is against CDC guidelines. We initiated a quality improvement (QI) project to reduce the intraoperative use of single-dose vials of fentanyl across multiple patients at Cincinnati Children's Hospital Medical Center (CCHMC). The initial step of the improvement project was the development of a Key Driver Diagram. The diagram has the SMART aim of the project, key drivers inherent to the process we are trying to improve, and specific interventions targeting the key drivers. The number of patients each week receiving an IV dose of fentanyl, from a vial previously accessed for another patient was tracked in a high turnover operating room (OR). The improvement model used was based on the concept of building Plan-Do-Study-Act (PDSA) cycles. Tests of change included provider education, provision of an increased number of fentanyl vials, alternate wasting processes, and provision of single-use fentanyl syringes by the pharmacy. Prior to initiation of this project, it was common for a single fentanyl vial to be accessed for multiple patients. Our data showed an average percentage of failures of just over 50%. During the end of the project, after 7 months, the mean percentage failures had dropped to 5%. Preparation of 20 mcg single-use fentanyl syringes by pharmacy, combined with education of providers on appropriate use, was successful in reducing failures to below our goal of 25%. Appropriately sized fentanyl syringes prepared by pharmacy, education on correct use of single-dose vials, and reminders in the OR, reduced the percentage of patients receiving a dose of fentanyl from a vial previously accessed for another patient in a high-volume otolaryngology room. © 2015 John Wiley & Sons Ltd.

  10. Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US Department of Defense administrative claims database.

    Capkun, Gorana; Dahlke, Frank; Lahoz, Raquel; Nordstrom, Beth; Tilson, Hugh H; Cutter, Gary; Bischof, Dorina; Moore, Alan; Simeone, Jason; Fraeman, Kathy; Bancken, Fabrice; Geissbühler, Yvonne; Wagner, Michael; Cohan, Stanley

    2015-11-01

    Data are limited for mortality and comorbidities in patients with multiple sclerosis (MS). Compare mortality rates and event rates for comorbidities in MS (n=15,684) and non-MS (n=78,420) cohorts from the US Department of Defense (DoD) database. Comorbidities and all-cause mortality were assessed using the database. Causes of death (CoDs) were assessed through linkage with the National Death Index. Cohorts were compared using mortality (MRR) and event (ERR) rate ratios. All-cause mortality was 2.9-fold higher in the MS versus non-MS cohort (MRR, 95% confidence interval [CI]: 2.9, 2.7-3.2). Frequent CoDs in the MS versus non-MS cohort were infectious diseases (6.2, 4.2-9.4), diseases of the nervous (5.8, 3.7-9.0), respiratory (5.0, 3.9-6.4) and circulatory (2.1, 1.7-2.7) systems and suicide (2.6, 1.3-5.2). Comorbidities including sepsis (ERR, 95% CI: 5.7, 5.1-6.3), ischemic stroke (3.8, 3.5-4.2), attempted suicide (2.4, 1.3-4.5) and ulcerative colitis (2.0, 1.7-2.3), were higher in the MS versus non-MS cohort. The rate of cancers was also higher in the MS versus the non-MS cohort, including lymphoproliferative disorders (2.2, 1.9-2.6) and melanoma (1.7, 1.4-2.0). Rates of mortality and several comorbidities are higher in the MS versus non-MS cohort. Early recognition and management of comorbidities may reduce premature mortality and improve quality of life in patients with MS. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Bismuth adjuvant ameliorates adverse effects of high-dose chemotherapy in patients with multiple myeloma and malignant lymphoma undergoing autologous stem cell transplantation

    Hansen, Per Boye; Penkowa, Milena

    2017-01-01

    show for the first time that bismuth significantly reduces grade 2 stomatitis, febrile neutropenia and infections caused by melphalan in multiple myeloma, where adverse effects also were significantly linked to gender. In lymphoma patients, bismuth significantly reduces diarrhoea relative to placebo......PURPOSE: High-dose chemotherapy prior to autologous stem cell transplantation (ASCT) leads to adverse effects including mucositis, neutropenia and bacteremia. To reduce the toxicity, we treated myeloma and lymphoma patients with peroral bismuth as an adjuvant to chemotherapy to convey...

  12. The atypical excretion profile of meldonium: Comparison of urinary detection windows after single- and multiple-dose application in healthy volunteers.

    Görgens, Christian; Guddat, Sven; Bosse, Christina; Geyer, Hans; Pop, Valentin; Schänzer, Wilhelm; Thevis, Mario

    2017-05-10

    Following a one-year monitoring program providing unequivocal analytical evidence for a high prevalence in international elite sports, meldonium has been included in the World Anti-Doping Agency's (WADA) list of prohibited substances that came into effect on 1 January 2016. Despite of the polar and hydrophilic nature of the molecule, an unusual long detection window was observed in pilot elimination studies. Consequently, in the present study, urinary excretion profiles after single-dose (5 volunteers, 1×500mg) and multiple-dose oral application (5 volunteers; 2×500mg/day for 6days) were determined in order to facilitate the result management concerning meldonium findings in doping controls. Particularly the option to differentiate between recent use and tapering concentrations was studied. Urinary meldonium concentrations were determined using an analytical approach based on hydrophilic interaction liquid chromatography and high resolution tandem mass spectrometry. The study corroborates the hypothesis of a non-linear, dose-depended and biphasic excretion profile after oral application of meldonium and demonstrates that urinary detection windows are of considerable extent with up to 65 and 117days (concentrations>LOQ of 10ng/mL) following single- and multiple-dose applications, respectively. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Short-term, high-dose glucocorticoid treatment does not contribute to reduced bone mineral density in patients with multiple sclerosis.

    Olsson, A; Oturai, D B; Sørensen, P S; Oturai, P S; Oturai, A B

    2015-10-01

    Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). The objective of this paper is to assess bone mass in patients with MS and evaluate the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. Osteopenia was present in 38% and osteoporosis in 7% of the study population. Mean Z-score was significantly below zero, indicating a decreased BMD in our MS patients. Multiple linear regression analysis showed no significant association between GCs and BMD. In contrast, age, BMI and disease severity were independently associated with both lumbar and femoral BMD. Reduced BMD was prevalent in patients with MS. GC treatment appears not to be the primary underlying cause of secondary osteoporosis in MS patients. © The Author(s), 2015.

  14. Thermally assisted OSL application for equivalent dose estimation; comparison of multiple equivalent dose values as well as saturation levels determined by luminescence and ESR techniques for a sedimentary sample collected from a fault gouge

    Şahiner, Eren, E-mail: sahiner@ankara.edu.tr; Meriç, Niyazi, E-mail: meric@ankara.edu.tr; Polymeris, George S., E-mail: gspolymeris@ankara.edu.tr

    2017-02-01

    Highlights: • Multiple equivalent dose estimations were carried out. • Additive ESR and regenerative luminescence were applied. • Preliminary SAR results employing TA-OSL signal were discussed. • Saturation levels of ESR and luminescence were investigated. • IRSL{sub 175} and SAR TA-OSL stand as very promising for large doses. - Abstract: Equivalent dose estimation (D{sub e}) constitutes the most important part of either trap-charge dating techniques or dosimetry applications. In the present work, multiple, independent equivalent dose estimation approaches were adopted, using both luminescence and ESR techniques; two different minerals were studied, namely quartz as well as feldspathic polymineral samples. The work is divided into three independent parts, depending on the type of signal employed. Firstly, different D{sub e} estimation approaches were carried out on both polymineral and contaminated quartz, using single aliquot regenerative dose protocols employing conventional OSL and IRSL signals, acquired at different temperatures. Secondly, ESR equivalent dose estimations using the additive dose procedure both at room temperature and at 90 K were discussed. Lastly, for the first time in the literature, a single aliquot regenerative protocol employing a thermally assisted OSL signal originating from Very Deep Traps was applied for natural minerals. Rejection criteria such as recycling and recovery ratios are also presented. The SAR protocol, whenever applied, provided with compatible D{sub e} estimations with great accuracy, independent on either the type of mineral or the stimulation temperature. Low temperature ESR signals resulting from Al and Ti centers indicate very large D{sub e} values due to bleaching in-ability, associated with large uncertainty values. Additionally, dose saturation of different approaches was investigated. For the signal arising from Very Deep Traps in quartz saturation is extended almost by one order of magnitude. It is

  15. Amphetamine concentrations in human urine following single-dose administration of the calcium antagonist prenylamine-studies using fluorescence polarization immunoassay (FPIA) and GC-MS.

    Kraemer, Thomas; Roditis, Susanne K; Peters, Frank T; Maurer, Hans H

    2003-03-01

    Prenylamine (R,S-N-(3,3-diphenylpropyl-methyl-2-phenethylamine), a World Health Organization class V calcium antagonist, is known to be metabolized to amphetamine. In this study, amphetamine concentrations after a single-dose administration of prenylamine were determined to check if they reached values that could be of analytical and/or pharmacological importance in clinical and forensic toxicology. Enantiomeric composition of amphetamine was also studied. Five volunteers received a single 120-mg oral dose of prenylamine. Urine samples were analyzed using the Abbott TDx immunoassay Amphetamine/Methamphetamine II and using our routine systematic toxicological analysis (STA) gas chromatography-mass spectrometry (GC-MS) procedure. For quantitation purposes, GC-MS was used in the selected-ion monitoring (SIM) mode (ions m/z 118, 122, 240, 244) after solid-phase extraction (Isolute Confirm HCX) and derivatization (heptafluorobutyric anhydride). Amphetamine-d5 was used as internal standard (IS). Chiral separation of the heptafluorobutyrated amphetamine enantiomers was achieved using an Astec Chiraldex G-PN column. The TDx results showed a great variability for the different volunteers. A urine sample of one volunteer showed results as high as 3200 ng/mL, whereas the urine samples of another volunteer never gave results greater than the TDx detection limit (100 ng/mL). Using the STA procedure, the presence of amphetamine could be confirmed in all urine samples with TDx results greater than the cutoff value (300 ng/mL). Using the GC-MS SIM method, amphetamine concentrations up to 1280 ng/mL were determined. Chiral analysis revealed that both enantiomers of amphetamine were present in the samples with a surplus of the S(+)-enantiomer in the early phase of excretion. Forensic implications are discussed.

  16. Adverse event management in patients with relapsed and refractory multiple myeloma taking pomalidomide plus low-dose dexamethasone: A pooled analysis.

    Moreau, Philippe; Dimopoulos, Meletios A; Richardson, Paul G; Siegel, David S; Cavo, Michele; Corradini, Paolo; Weisel, Katja; Delforge, Michel; O'Gorman, Peter; Song, Kevin; Chen, Christine; Bahlis, Nizar; Oriol, Albert; Hansson, Markus; Kaiser, Martin; Anttila, Pekka; Raymakers, Reinier; Joao, Cristina; Cook, Gordon; Sternas, Lars; Biyukov, Tsvetan; Slaughter, Ana; Hong, Kevin; Herring, Jennifer; Yu, Xin; Zaki, Mohamed; San-Miguel, Jesus

    2017-09-01

    Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care. Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Acute, low-dose methamphetamine administration improves attention/information processing speed and working memory in methamphetamine-dependent individuals displaying poorer cognitive performance at baseline.

    Mahoney, James J; Jackson, Brian J; Kalechstein, Ari D; De La Garza, Richard; Newton, Thomas F

    2011-03-30

    Abstinent methamphetamine (Meth) dependent individuals demonstrate poorer performance on tests sensitive to attention/information processing speed, learning and memory, and working memory when compared to non-Meth dependent individuals. The poorer performance on these tests may contribute to the morbidity associated with Meth-dependence. In light of this, we sought to determine the effects of acute, low-dose Meth administration on attention, working memory, and verbal learning and memory in 19 non-treatment seeking, Meth-dependent individuals. Participants were predominantly male (89%), Caucasian (63%), and cigarette smokers (63%). Following a four day, drug-free washout period, participants were given a single-blind intravenous infusion of saline, followed the next day by 30 mg of Meth. A battery of neurocognitive tasks was administered before and after each infusion, and performance on measures of accuracy and reaction time were compared between conditions. While acute Meth exposure did not affect test performance for the entire sample, participants who demonstrated relatively poor performance on these tests at baseline, identified using a median split on each test, showed significant improvement on measures of attention/information processing speed and working memory when administered Meth. Improved performance was seen on the following measures of working memory: choice reaction time task (p≤0.04), a 1-back task (p≤0.01), and a 2-back task (p≤0.04). In addition, those participants demonstrating high neurocognitive performance at baseline experienced similar or decreased performance following Meth exposure. These findings suggest that acute administration of Meth may temporarily improve Meth-associated neurocognitive performance in those individuals experiencing lower cognitive performance at baseline. As a result, stimulants may serve as a successful treatment for improving cognitive functioning in those Meth-dependent individuals experiencing

  18. TLD-300 detectors for separate measurement of total and gamma absorbed dose distributions of single, multiple, and moving-field neutron treatments

    Rassow, J.

    1984-01-01

    Fast neutron therapy requirements, because of the poor depth dose characteristic of present therapeutical sources, are at least as complex in treatment plans as photon therapy. The physical part of the treatment planning is very important; however, it is much more complicated than for photons or electrons owing to the need for: Separation of total and gamma absorbed dose distributions (Dsub(T) and Dsub(G)); and more stringent tissue-equivalence conditions of phantoms than in photon therapy. Therefore, methods of clinical dosimetry for the separate determination of total and gamma absorbed dose distributions in irregularly shaped (inhomogeneous) phantoms are needed. A method using TLD-300 (CaF 2 :Tm) detectors is described, which is able to give an approximate solution of the above-mentioned dosimetric requirements. The two independent doses, Dsub(T) and Dsub(G), can be calculated by an on-line computer analysis of the digitalized glow curve of TLD-300 detectors, irradiated with d(14)+Be neutrons of the cyclotron isocentric neutron therapy facility CIRCE in Essen. Results are presented for depth and lateral absorbed dose distributions (Dsub(T) and Dsub(G)) for fixed neutron beams of different field sizes compared with measurements by standard procedures (TE-TE ionization chamber, GM counter) in an A-150 phantom. The TLD-300 results for multiple and moving-field treatments (with and without wedge filters) in a patient simulating irregularly shaped (inhomogeneous) phantoms, are shown together with computer calculations of these dose distributions. The probable causes for some systematic deviations are discussed, which lead to open problems for further investigations owing to features of the detector material and the evaluation method, but mainly to differences in the composition of phantom materials used for the calculations (standard dose distributions) and TLD-300 measurements. (author)

  19. Dose evaluation using multiple-aliquot quartz OSL: Test of methods and a new protocol for improved accuracy and precision

    Jain, M.; Bøtter-Jensen, L.; Singhvi, A.K.

    2003-01-01

    -dose-dependent sensitivity changes during the pre-heat, and fundamental variability in the shapes of quartz OSL (blue-green or blue-light stimulated luminescence) decay forms. A new protocol using a combination of 'elevated temperature IR cleaning' (ETIR) and 'component-specific dose normalisation' (CSDN) has been developed....... CSDN accounts for variability in the OSL decay forms and absorbs such sensitivity changes. A combination of ETIR and CSDN protocol increased palaeodose precision from +/-100% to +/-4% in quartz separates from the fluvially transported sands in the Thar desert. A comparison with palaeodose estimates...

  20. [Treatment of Chemotherapy Related Leukocytopenia by Oral Administration of Multiple Leucogenic Drugs Combined with G-CSF: an Experimental Study].

    Zhang, Xi-ping; Zhang, Xiang; Yang, Hong-jian; Zou, De-hong; He, Xiang-ming; Yu, Xing-fei; Li, Yong-feng

    2015-07-01

    To evaluate efficacies of three commonly used oral drugs including Berbamine Hydrochloride Tablet (B), Qijiao Shengbai Capsule (Q), and Leucogen Tablet (L) (by single drug, two drugs or three drugs) combined with granulocyte colony-stimulating factor (G-CSF) for treat ment of chemotherapy related leukocytopenia in mice. Totally 156 Kunming male mice were divided into the normal control group (A, n=24), the model group (B, n=24), the G-CSF group (C, n =24), the G-CSF+Q group (D, n=12), G-CSF+ B (E, n=12), the G-CSF+L group (F, n=12), the G-CSF + Q + B group (G, n=12), the G-CSF + Q + L group (H, n=12), the G-CSF + L + B group (I, n=12), and the G-CSF + L + Q + B (J, n=12). Mouse models of chemotherapy related leukocytopenia were established by intraperitoneal injection of cyclophosphamide (CTX). A G-CSF group was set up as a positive control. Mice were treated by a single oral drug, a single oral drug combined with G-CSF, and two or three drugs combined with G-CSF respectively, and the death rate calculated. Hemocytes [such as white blood cells (WBC) and its classification, red blood cells (RBC), platelet (PLT), hemoglobin (Hb)] were calculated by hematology analyzer. Mice were anatomized and important organs weighed. Organ indices were calculated. There was no statistical difference in the mortality rate among all groups (P > 0.05). Compared with Group B, WBC was elevated in all other groups (P drug B and L (P chemotherapy related leukopenia or decreased three blood series was to administrate three commonly oral drugs combined with G-CSF. Authors speculated that G-CSF and Q might have a certain effect on CTX induced immune inhibition.

  1. Reduced lung lesions in pigs challenged 25 weeks after the administration of a single dose of Mycoplasma hyopneumoniae vaccine at approximately 1 week of age.

    Reynolds, S C; St Aubin, L B; Sabbadini, L G; Kula, J; Vogelaar, J; Runnels, P; Peters, A R

    2009-09-01

    Two independent studies assessed the duration of immunity of an inactivated adjuvanted Mycoplasma hyopneumoniae vaccine against mycoplasmal pneumonia in seronegative (study A, n=52) and seropositive (study B, n=52) pigs. The pigs were allocated randomly to treatment and were then injected with a single dose of either the vaccine or a placebo at approximately 1 week of age. Twenty-five weeks after treatment administration, the pigs were challenged with a virulent strain (LI 36, Strain 232) of M. hyopneumoniae and the extent of lung lesions consistent with mycoplasmal pneumonia was assessed 4 weeks later. In study A, the geometric mean lung lesion score (expressed as least squares mean percentages of lung lesions) was significantly (P=0.0001) lower in vaccinated (0.3%, n=20) than in control pigs (5.9%, n=24) seronegative to M. hyopneumoniae at enrolment; similarly, in study B, the extent of lung lesions was significantly reduced (P=0.0385) in seropositive vaccinated pigs (2.0%, n=22) compared to controls (4.5%, n=26). At the end of the investigation period, 4 weeks after challenge, mean antibody sample-to-positive (S/P) ratios were significantly higher both in seronegative (P=0.0012) and seropositive (P=0.0001) vaccinated pigs (mean values=0.77 and 0.81, respectively) than in controls (mean values=0.51 and 0.38, respectively).

  2. Optimized computational method for determining the beta dose distribution using a multiple-element thermoluminescent dosimeter system

    Shen, L.; Levine, S.H.; Catchen, G.L.

    1987-01-01

    This paper describes an optimization method for determining the beta dose distribution in tissue, and it describes the associated testing and verification. The method uses electron transport theory and optimization techniques to analyze the responses of a three-element thermoluminescent dosimeter (TLD) system. Specifically, the method determines the effective beta energy distribution incident on the dosimeter system, and thus the system performs as a beta spectrometer. Electron transport theory provides the mathematical model for performing the optimization calculation. In this calculation, parameters are determined that produce calculated doses for each of the chip/absorber components in the three-element TLD system. The resulting optimized parameters describe an effective incident beta distribution. This method can be used to determine the beta dose specifically at 7 mg X cm-2 or at any depth of interest. The doses at 7 mg X cm-2 in tissue determined by this method are compared to those experimentally determined using an extrapolation chamber. For a great variety of pure beta sources having different incident beta energy distributions, good agreement is found. The results are also compared to those produced by a commonly used empirical algorithm. Although the optimization method produces somewhat better results, the advantage of the optimization method is that its performance is not sensitive to the specific method of calibration

  3. Evaluation of the effect of multiple doses of lansoprazole on the pharmacokinetics and safety of ponatinib in healthy subjects.

    Narasimhan, Narayana I; Dorer, David J; Davis, Jeffrey; Turner, Christopher D; Sonnichsen, Daryl

    2014-10-01

    In vitro studies have demonstrated that the aqueous solubility of the tyrosine kinase inhibitor ponatinib decreases as pH increases. The primary aim of this study was to assess the effects of the gastric proton pump inhibitor lansoprazole on the pharmacokinetics of ponatinib. The single-dose safety profile of ponatinib with and without coadministration of lansoprazole was also characterized. This was a phase I, open-label, non-randomized, two-period crossover study in 20 healthy subjects aged 18-55 years. Subjects received a single oral dose of ponatinib 45 mg alone on day 1, an oral dose of lansoprazole 60 mg on day 14, and ponatinib 45 mg plus lansoprazole 60 mg on day 15. Lansoprazole coadministration resulted in a 1-h increase in the time to maximum plasma concentration (t max) of ponatinib (6 vs. 5 h post-dose; P lansoprazole versus ponatinib alone (40.67 vs. 53.96 ng/mL). Importantly, lansoprazole did not decrease the overall ponatinib systemic exposure as assessed by the ponatinib area under the plasma concentration-time curve from time zero to infinity (AUC∞ 1,153 ng·h/mL for lansoprazole + ponatinib vs. 1,222 ng·h/mL for ponatinib alone). The safety profile was considered acceptable when ponatinib was administered alone or with lansoprazole. Although coadministration of lansoprazole led to a modest, albeit statistically significant, reduction in ponatinib C max, overall systemic exposure to ponatinib did not change. The findings suggest that no dose adjustment is necessary when ponatinib is administered with drugs that increase gastric pH.

  4. Pharmacokinetic Properties of Three Forms of Vaginal Progesterone Administered in Either Single Or Multiple Dose Regimen in Healthy Post-menopausal Chinese Women

    Jianzhong Shentu

    2017-04-01

    Full Text Available Objective: A generic vaginal progesterone gel has recently been developed in China. Little is known about its pharmacokinetic properties in Chinese subjects. The purpose of our study was to investigate the pharmacokinetics of three forms of vaginal progesterone gel (test formulations at 4 and 8% strength vs. a reference formulation: Crinone 8% in Chinese healthy post-menopausal women.Methods: This study consisted of two parts study. The part 1 study was a single-center, open-label, 3-period study. Twelve healthy post-menopausal women were to evaluate the safety and pharmacokinetics of 45 mg vaginal progesterone gel (Test 4% following single dose and multiple doses administered once every other day (q.o.d. for six times or once daily (q.d. for 6 days. The part 2 study was a randomized, open-label, 3-stage crossover study. Twelve post-menopausal women received 90 mg vaginal progesterone gel (Test 8% or 90 mg Crinone (Reference 8% following single dose and multiple doses (q.o.d. or q.d.. Plasma concentrations of progesterone were measured up to 72 h by using a validated liquid chromatography tandem-mass spectrometry method. The primary pharmacokinetic parameters, maximum plasma concentration (Cmax and area under the plasma concentration–time curve (AUC from time zero to last measurable concentration (AUC0-t and extrapolated to infinity (AUC0-∞ were compared by an analysis of variance using log-transformed data.Results: Totally 24 subjects were enrolled in and completed the study. Following single dose, The geometric mean Cmax values for Test 4%, Test 8%, and Crinone 8% were 6.35, 10.34, 10.45 ng/mL, and their geometric mean AUC0-t (AUC0-∞ were 113.73 (118.00, 169.39 (173.98, and 190.07 (201.13 ng⋅h/mL, respectively. The mean T1/2 values of progesterone were 11.00, 10.92, and 11.40 h, respectively. For 8% test formulation vs. reference, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0-t, and AUC0-∞ were 78.32–124

  5. Simultaneous quantification of multiple components in rat plasma by UPLC-MS/MS and pharmacokinetic study after oral administration of Huangqi decoction.

    Zeng, Jia-Kai; Li, Yuan-Yuan; Wang, Tian-Ming; Zhong, Jie; Wu, Jia-Sheng; Liu, Ping; Zhang, Hua; Ma, Yue-Ming

    2018-05-01

    A rapid, sensitive and accurate UPLC-MS/MS method was developed for the simultaneous quantification of components of Huangqi decoction (HQD), such as calycosin-7-O-β-d-glucoside, calycosin-glucuronide, liquiritin, formononetin-glucuronide, isoliquiritin, liquiritigenin, ononin, calycosin, isoliquiritigenin, formononetin, glycyrrhizic acid, astragaloside IV, cycloastragenol, and glycyrrhetinic acid, in rat plasma. After plasma samples were extracted by protein precipitation, chromatographic separation was performed with a C 18 column, using a gradient of methanol and 0.05% acetic acid containing 4mm ammonium acetate as the mobile phase. Multiple reaction monitoring scanning was performed to quantify the analytes, and the electrospray ion source polarity was switched between positive and negative modes in a single run of 10 min. Method validation showed that specificity, linearity, accuracy, precision, extraction recovery, matrix effect and stability for 14 components met the requirements for their quantitation in biological samples. The established method was successfully applied to the pharmacokinetic study of multiple components in rats after intragastric administration of HQD. The results clarified the pharmacokinetic characteristics of multiple components found in HQD. This research provides useful information for understanding the relation between the chemical components of HQD and their therapeutic effects. Copyright © 2017 John Wiley & Sons, Ltd.

  6. A multiple-dose, double-blind comparison of intramuscularly and orally administered ketorolac tromethamine and Ketogan in patients with pain following orthopaedic surgery

    Gebuhr, Peter Henrik; Soelberg, M; Strauss, W

    1994-01-01

    In this multiple-dose, double-blind study 100 patients with moderate, severe or very severe pain following orthopaedic surgery were randomly assigned to receive ketorolac, a non-steroidal anti-inflammatory drug with potent analgesic properties (10 mg), or the standard regimen of Ketogan (a combin......-mg doses of oral ketorolac are as effective as Ketogan for the treatment of pain following orthopaedic surgery. Ketorolac appears to be better tolerated than Ketogan since significantly fewer patients reported adverse events (P = 0.004) when taking ketorolac.......In this multiple-dose, double-blind study 100 patients with moderate, severe or very severe pain following orthopaedic surgery were randomly assigned to receive ketorolac, a non-steroidal anti-inflammatory drug with potent analgesic properties (10 mg), or the standard regimen of Ketogan (a...... combination product containing the narcotic analgesic, ketobemidone, plus a spasmolytic agent) by intramuscular injection every 1-6 h as needed for pain. When patients were able to tolerate an oral diet and were expected to respond to oral analgesic medication, based on overall pain sensitivity, they were...

  7. SU-E-T-79: Comparison of Doses Received by the Hippocampus in Patients Treated with Single Vs Multiple Isocenter Based Stereotactic Radiation Therapy to the Brain for Multiple Brain Metastases

    Algan, O; Giem, J; Young, J; Ali, I; Ahmad, S; Hossain, S [University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)

    2014-06-01

    Purpose: To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiotherapy utilizing a single isocenter (SI) versus multiple isocenter (MI) in patients with multiple intracranial metastases. Methods: Seven patients imaged with MRI including SPGR sequence and diagnosed with 2–3 brain metastases were included in this retrospective study. Two sets of stereotactic IMRT treatment plans, (MI vs SI), were generated. The hippocampus was contoured on SPGR sequences and doses received by the hippocampus and whole brain were calculated. The prescribed dose was 25Gy in 5 fractions. The two groups were compared using t-test analysis. Results: There were 17 lesions in 7 patients. The median tumor, right hippocampus, left hippocampus and brain volumes were: 3.37cc, 2.56cc, 3.28cc, and 1417cc respectively. In comparing the two treatment plans, there was no difference in the PTV coverage except in the tail of the DVH curve. All tumors had V95 > 99.5%. The only statistically significant parameter was the V100 (72% vs 45%, p=0.002, favoring MI). All other evaluated parameters including the V95 and V98 did not reveal any statistically significant differences. None of the evaluated dosimetric parameters for the hippocampus (V100, V80, V60, V40, V20, V10, D100, D90, D70, D50, D30, D10) revealed any statistically significant differences (all p-values > 0.31) between MI and SI plans. The total brain dose was slightly higher in the SI plans, especially in the lower dose regions, although this difference was not statistically significant. Utilizing brain-sub-PTV volumes did not change these results. Conclusion: The use of SI treatment planning for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain compared to MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.

  8. SU-E-T-79: Comparison of Doses Received by the Hippocampus in Patients Treated with Single Vs Multiple Isocenter Based Stereotactic Radiation Therapy to the Brain for Multiple Brain Metastases

    Algan, O; Giem, J; Young, J; Ali, I; Ahmad, S; Hossain, S

    2014-01-01

    Purpose: To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiotherapy utilizing a single isocenter (SI) versus multiple isocenter (MI) in patients with multiple intracranial metastases. Methods: Seven patients imaged with MRI including SPGR sequence and diagnosed with 2–3 brain metastases were included in this retrospective study. Two sets of stereotactic IMRT treatment plans, (MI vs SI), were generated. The hippocampus was contoured on SPGR sequences and doses received by the hippocampus and whole brain were calculated. The prescribed dose was 25Gy in 5 fractions. The two groups were compared using t-test analysis. Results: There were 17 lesions in 7 patients. The median tumor, right hippocampus, left hippocampus and brain volumes were: 3.37cc, 2.56cc, 3.28cc, and 1417cc respectively. In comparing the two treatment plans, there was no difference in the PTV coverage except in the tail of the DVH curve. All tumors had V95 > 99.5%. The only statistically significant parameter was the V100 (72% vs 45%, p=0.002, favoring MI). All other evaluated parameters including the V95 and V98 did not reveal any statistically significant differences. None of the evaluated dosimetric parameters for the hippocampus (V100, V80, V60, V40, V20, V10, D100, D90, D70, D50, D30, D10) revealed any statistically significant differences (all p-values > 0.31) between MI and SI plans. The total brain dose was slightly higher in the SI plans, especially in the lower dose regions, although this difference was not statistically significant. Utilizing brain-sub-PTV volumes did not change these results. Conclusion: The use of SI treatment planning for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain compared to MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment

  9. 21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

    2010-04-01

    ... vivo bioavailability study. 320.27 Section 320.27 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products § 320.27...

  10. Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study.

    Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Schachtel, Emily

    2014-07-03

    The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Adults (n=198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n=101) or matching placebo lozenges (n=97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (Pflurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all Pflurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010.

  11. MO-F-CAMPUS-T-01: Radiosurgery of Multiple Brain Metastases with Single-Isocenter VMAT: Optimizing Treatment Geometry to Reduce Normal Brain Dose

    Wu, Q; Snyder, K; Liu, C; Huang, Y; Li, H; Chetty, I; Wen, N

    2015-01-01

    Purpose: To develop an optimization algorithm to reduce normal brain dose by optimizing couch and collimator angles for single isocenter multiple targets treatment of stereotactic radiosurgery. Methods: Three metastatic brain lesions were retrospectively planned using single-isocenter volumetric modulated arc therapy (VMAT). Three matrices were developed to calculate the projection of each lesion on Beam’s Eye View (BEV) by the rotating couch, collimator and gantry respectively. The island blocking problem was addressed by computing the total area of open space between any two lesions with shared MLC leaf pairs. The couch and collimator angles resulting in the smallest open areas were the optimized angles for each treatment arc. Two treatment plans with and without couch and collimator angle optimization were developed using the same objective functions and to achieve 99% of each target volume receiving full prescription dose of 18Gy. Plan quality was evaluated by calculating each target’s Conformity Index (CI), Gradient Index (GI), and Homogeneity index (HI), and absolute volume of normal brain V8Gy, V10Gy, V12Gy, and V14Gy. Results: Using the new couch/collimator optimization strategy, dose to normal brain tissue was reduced substantially. V8, V10, V12, and V14 decreased by 2.3%, 3.6%, 3.5%, and 6%, respectively. There were no significant differences in the conformity index, gradient index, and homogeneity index between two treatment plans with and without the new optimization algorithm. Conclusion: We have developed a solution to the island blocking problem in delivering radiation to multiple brain metastases with shared isocenter. Significant reduction in dose to normal brain was achieved by using optimal couch and collimator angles that minimize total area of open space between any of the two lesions with shared MLC leaf pairs. This technique has been integrated into Eclipse treatment system using scripting API

  12. MO-F-CAMPUS-T-01: Radiosurgery of Multiple Brain Metastases with Single-Isocenter VMAT: Optimizing Treatment Geometry to Reduce Normal Brain Dose

    Wu, Q [Wayne State University, Detroit, MI (United States); Snyder, K; Liu, C; Huang, Y; Li, H; Chetty, I; Wen, N [Henry Ford Health System, Detroit, MI (United States)

    2015-06-15

    Purpose: To develop an optimization algorithm to reduce normal brain dose by optimizing couch and collimator angles for single isocenter multiple targets treatment of stereotactic radiosurgery. Methods: Three metastatic brain lesions were retrospectively planned using single-isocenter volumetric modulated arc therapy (VMAT). Three matrices were developed to calculate the projection of each lesion on Beam’s Eye View (BEV) by the rotating couch, collimator and gantry respectively. The island blocking problem was addressed by computing the total area of open space between any two lesions with shared MLC leaf pairs. The couch and collimator angles resulting in the smallest open areas were the optimized angles for each treatment arc. Two treatment plans with and without couch and collimator angle optimization were developed using the same objective functions and to achieve 99% of each target volume receiving full prescription dose of 18Gy. Plan quality was evaluated by calculating each target’s Conformity Index (CI), Gradient Index (GI), and Homogeneity index (HI), and absolute volume of normal brain V8Gy, V10Gy, V12Gy, and V14Gy. Results: Using the new couch/collimator optimization strategy, dose to normal brain tissue was reduced substantially. V8, V10, V12, and V14 decreased by 2.3%, 3.6%, 3.5%, and 6%, respectively. There were no significant differences in the conformity index, gradient index, and homogeneity index between two treatment plans with and without the new optimization algorithm. Conclusion: We have developed a solution to the island blocking problem in delivering radiation to multiple brain metastases with shared isocenter. Significant reduction in dose to normal brain was achieved by using optimal couch and collimator angles that minimize total area of open space between any of the two lesions with shared MLC leaf pairs. This technique has been integrated into Eclipse treatment system using scripting API.

  13. Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study.

    Rex, Douglas K; Katz, Philip O; Bertiger, Gerald; Vanner, Stephen; Hookey, Lawrence C; Alderfer, Vivian; Joseph, Raymond E

    2013-07-01

    New bowel cleansers for colonoscopy that lead to improved efficacy, safety, and tolerability are needed. This study evaluated a nonphosphate, dual-action, low-volume, orange-flavored preparation containing sodium picosulfate and magnesium citrate (P/MC). Multicenter, assessor-blinded, randomized, noninferiority study. University hospitals, academic medical centers, and private clinics across the United States. Adults preparing for colonoscopy. P/MC versus 2 L of polyethylene glycol solution (2L PEG-3350) and two 5-mg bisacodyl tablets. This phase 3 study investigated the efficacy, safety, and tolerability of split-dose administration of P/MC versus day-before dosing of 2L PEG-3350 and two 5-mg bisacodyl tablets (SEE CLEAR I study). Efficacy was evaluated by using the Aronchick and Ottawa scales; noninferiority and superiority analyses were performed. Safety was assessed by monitoring adverse events (AEs). Tolerability was measured via a patient questionnaire. The intent-to-treat population consisted of 601 patients who self-administered P/MC (n = 304) or 2L PEG-3350 and bisacodyl tablets (n = 297). P/MC was superior to 2L PEG-3350 and bisacodyl tablets in overall colon cleansing (84.2% vs 74.4%; 1-sided 97.5% confidence interval [CI], 3.4) (Aronchick scores of excellent or good) and in cleansing of the ascending (89.5% vs 78.8%; 1-sided 97.5% CI, 4.9), mid (transverse and descending) (92.4% vs 85.9%; 1-sided 97.5% CI, 1.6), and rectosigmoid (92.4% vs 87.2%; 1-sided 97.5% CI, 0.4) segments of the colon (Ottawa scores of excellent, good, or fair). Commonly reported AEs related to the bowel preparations were nausea, vomiting, headache, and chills. Patient-reported tolerability, including ease of consumption and taste, was significantly higher for P/MC than 2L PEG-3350 and bisacodyl tablets (P PEG-3350 and bisacodyl tablets. Copyright © 2013 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

  14. Comparison of the Concentrations of Lidocaine in Different Body Fluids/Tissues after Subarachnoid Space and Intravenous Administration of a Lethal Dose of Lidocaine

    Nan Zhang

    2015-01-01

    Full Text Available The objective of the study was to compare the concentration of lidocaine in different body fluids/tissues after subarachnoid space and intravenous administrations of a lethal dose of lidocaine. Totally 18 dogs were used in the experiment. Six dogs were given subarachnoid anesthesia, another were given an intravenous injection of a dose of 75 mg/kg weight of lidocaine hydrochloride in 5 min and the last 6 dogs were used as the blank control dogs and given a subarachnoid space injection or a femoral artery injection of the same volume of sodium chloride. As soon as its vital signs disappeared, each dog was dissected and the specimen, such as brain, cerebrospinal fluid (CSF in lateral ventricle, CSF in subarachnoid space, spinal cord (cervical spinal cord, thoracic spinal cord, lumbar spinal cord, and waist spinal cord, heart, lung, liver, spleen, kidney, bile, urine, heart blood, peripheral blood, muscle in injection location, and muscle in no injection location, were collected for analysis of lidocaine immediately. Analysis was performed with gas chromatography-mass spectrometry (GC-MS. From the maximum to the minimum, the order of lidocaine concentration detected in the subarachnoid space-administered dogs was as follows: CSF in subarachnoid space, waist spinal cord, thoracic spinal cord, CSF in lateral ventricle, lumbar spinal cord, cervical spinal cord, lung, kidney, muscle in injection location, heart, brain, spleen, heart blood, liver, peripheral blood, bile, muscle in no injection location, and urine. The order of lidocaine concentration detected in the intravenously administered dogs was as followed: Kidney, heart, lung, spleen, brain, liver, peripheral blood, bile, heart blood, cervical spinal cord, thoracic spinal cord, muscle in injection location, lumbar spinal cord, muscle in no injection location, CSF in subarachnoid space, urine, and CSF in lateral ventricle. The maximum concentration of lidocaine was detected in the subarachnoid

  15. Pharmacodynamic consequences of administration of VLA-4 antagonist CDP323 to multiple sclerosis subjects: a randomized, double-blind phase 1/2 study.

    Christian Wolf

    Full Text Available Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS.Investigate the effect of CDP323, an oral α4-integrin inhibitor, on lymphocyte biomarkers in RMS.Seventy-one RMS subjects aged 18-65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid, 500 mg bid, 1000 mg once daily (qd, 1000 mg bid, or placebo.Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1 and the expression of α4-integrin on VCAM-1-binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions.CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes.ClinicalTrials.gov NCT00726648.

  16. ß-cell specific overexpression of suppressor of cytokine signalling-3 does not protect against multiple low dose streptozotocin induced type 1 diabetes in mice

    Börjesson, A; Rønn, S G; Karlsen, A E

    2011-01-01

    We investigated the impact of ß-cell specific overexpression of suppressor of cytokine signalling-3 (SOCS-3) on the development of multiple low dose streptozotocin (MLDSTZ) induced Type 1 diabetes and the possible mechanisms involved. MLDSTZ treatment was administered to RIP-SOCS-3 transgenic......RNA in islet cells and secretion of IL-1Ra into culture medium. MLDSTZ treatment caused gradual hyperglycemia both in the wt mice and in the transgenic mice with the latter tending to be more sensitive. In vitro experiments on wt and transgenic islets did not reveal any differences in sensitivity to damaging...

  17. Comparison of the deviation distribution in the doses administrated with and without mask in radiotherapeutic procedures; Comparacion de la distribucion de los desvios en las dosis administradas con y sin mascara en procedimientos radioterapicos

    Santos Junior, S. dos; Ghilardi N, T. [Departamento de Fisica e Matematica FFCLRP-USP, Av. Bandeirantes, 3900 CEP 14040-901, Cidade Universitari, Ribeirao Preto, SP (Brazil)

    1998-12-31

    In order to guarantee that the error limit in the dose administration is inside of the recommended limit by the ICRU (the ICRU recommends that the doses administrated in radiotherapy must be inside of a total deviation {+-} 5 %), the radiotherapy services are maintaining quality control programs and dosimetry which guarantee that the equipment yield or source should be known with precision. The Quality Control Programs foresee moreover the radiation beam calibration dosimetry, the In vivo dosimetry for obtaining a greater control of the administered doses. At present it counts on greater devices for maintaining the deviations inside this margin, and one of them is the u se of masks. The present work was carried out on a Siemens equipment model Gammatron S-80 (Co-60) in the Radiotherapy Service of the Sao Paulo University Hospital where teletherapy procedures are realized. (Author)

  18. Early infections in patients undergoing high-dose treatment with stem cell support: a comparison of patients with non-Hodgkin lymphoma and multiple myeloma

    Gang, A O; Arpi, M.; Gang, U.J.O.

    2010-01-01

    Background: Infections are life-threatening complications in patients undergoing high-dose chemotherapy with stem cell support (HDT). Knowledge of the infectious pathogens is essential to make a safe outpatient setting. Methods: We conducted a retrospective study of 208 patients treated with HDT...... related mortality was similar between the groups. Conclusion: The frequency of isolated pathogens, positive blood cultures, and the diversity of pathogens were higher in MM patients as compared to NHL patients. However, this did not translate into higher transplantation-related mortality, probably because....... The population included non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) patients. No patients received prophylactic antibacterial treatment. Results: Pathogens were isolated from 44% of all patients. MM patients more frequently had multiple pathogens in blood cultures (38% versus 25%). Transplantation...

  19. Effect of Low Dose Lead (Pb) Administration on Tail Immersion Test and Formalin-induced Pain in Wistar Rats: Possible Modulatory Role of Cobalt (II) Chloride.

    Umar, A H; Suleiman, I; Muhammed, H

    2017-03-06

    Lead (Pb) is cheap and there is a long tradition of its use, but its toxic effects have also been recognized. There is increased public health concern regarding the hazards of low dose Pb exposure to adults and children. Studies have shown the risks for hypertension, decrements in renal function, subtle decline in cognitive function, and adverse reproductive outcome at low blood Pb level. In this study, the possible modulatory role of cobalt (II) chloride (CoCl2) on low level Pb exposure on tail immersion test and formalin induced pain was investigated. Twenty adult Wistar rats of both sexes (weight 150g to 200g) were used. The animals were divided into four groups (n = 5) and administered Pb (5mg/kg), Pb (5mg/kg) + CoCl2 (50mg/kg) and CoCl2 (50mg/kg) orally for twenty-eight days. The last group served as control and were given distilled water only. In the tail immersion test, there was no significant change in reaction time for all three groups when compared to the control. In the formalin-induced pain, pain score after five and forty-five minutes also do not show significant change for all the three groups when compared to control. This work suggested that exposure to 5mg/kg Pb for twenty-eight days do not significantly impair reaction time in tail immersion test and pain score in formalin induced pain in Wistar rats. Also, administration of 50mg/kg CoCl2 do not improve performance of the animals in the experiments.

  20. Dose-Dependent Effects of Multiple Acute Cocaine Injections on Maternal Behavior and Aggression in Sprague-Dawley Rats

    Johns, Josephine M.; Nelson, Christina J.; Meter, Kathleen E.; Lubin, Deborah A.; Couch, C. Destine; Ayers, Andy; Walker, Cheryl H.

    1998-01-01

    Rat dams, which had no prior drug treatment, were either nontreated controls or were injected subcutaneously 4 times during a 10-day period with a single dose of 30, 15 or 7.5 mg/kg of cocaine hydrochloride HCl, or normal saline. Injections were given immediately postpartum following delivery of their final pup (PPD 1), and again on postpartum day 3 (PPD 3), postpartum day 6 (PPD 6) and postpartum day 10 (PPD 10). Dams were observed 30 min following injections for maternal behavior (MB) towar...

  1. Mammalian Toxicity of Munition Compounds. Phase II. Effects of Multiple Doses. Part III. 2,6-Dinitrotoluene

    1976-07-01

    and the neuromuscular effects in these dogs were not due to hypocalcemia . The lowest serum calcium concen- tration in these dogs was 4.2 meq/liter...motor end plate might produce a local hypocalcemia . Such a mechanism is purely speculative. Qualitatively and quantitavely, most of the effects of 2,6...I ýNw,- -MIM I/ MIDWEST RESEARCH INS14ITUTE H0q .3L I LU -_ MAMMALIAN TOXICITY OF MUNITIONS COMPOUlNDSPHASE II: EFFECTS OF MiULTIPLE DOSES C* •PART

  2. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types.

    Iliopoulos, Dimitrios; Hirsch, Heather A; Struhl, Kevin

    2011-05-01

    Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy resistant subpopulation of cancer stem cells (CSC) in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin, indicating that metformin works together with a variety of standard chemotherapeutic agents. In addition, metformin has comparable effects on tumor regression and preventing relapse when combined with a four-fold reduced dose of doxorubicin that is not effective as a monotherapy. Finally, the combination of metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the CSC hypothesis for cancer relapse, an experimental rationale for using metformin as part of combinatorial therapy in a variety of clinical settings, and for reducing the chemotherapy dose in cancer patients.

  3. Pharmacokinetic comparison of controlled-release and immediate-release oral formulations of simvastatin in healthy Korean subjects: a randomized, open-label, parallel-group, single- and multiple-dose study.

    Jang, Seong Bok; Lee, Yoon Jung; Lim, Lay Ahyoung; Park, Kyung-Mi; Kwon, Bong-Ju; Woo, Jong Soo; Kim, Yong-Il; Park, Min Soo; Kim, Kyung Hwan; Park, Kyungsoo

    2010-01-01

    A controlled-release (CR) formulation of simvastatin was recently developed in Korea. The formulation is expected to yield a lower C(max) and similar AUC values compared with the immediate-release (IR) formulation. The goal of this study was to compare the pharmacokinetics of the new CR formulation and an IR formulation of simvastatin after single- and multiple-dose administration in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. This was a randomized, open-label, parallelgroup, 2-part study. Eligible subjects were healthy male or female volunteers between the ages of 19 and 55 years and within 20% of their ideal weight. In part I, each subject received a single dose of the CR or IR formulation of simvastatin 40 mg orally (20 mg x 2 tablets) after fasting. In part II, each subject received the same dose of the CR or IR formulation for 8 consecutive days. Blood samples were obtained for 48 hours after the dose in part I and after the first and the last dose in part II. Pharmacokinetic parameters were determined for both simvastatin (the inactive prodrug) and simvastatin acid (the active moiety). An adverse event (AE) was defined as any unfavorable sign (including an abnormal laboratory finding) or symptom, regardless of whether it had a causal relationship with the study medication. Serious AEs were defined as any events that are considered life threatening, require hospitalization or prolongation of existing hospitalization, cause persistent or significant disability or incapacity, or result in congenital abnormality, birth defect, or death. AEs were determined based on patient interviews and physical examinations. Twenty-four healthy subjects (17 men, 7 women; mean [SD] age, 29 [7] years; age range, 22-50 years) were enrolled in part I, and 29 subjects (17 men, 12 women; mean age, 33 [9] years; age range, 19-55 years) were enrolled in part II. For simvastatin acid, C

  4. Microarray analysis of the transcriptional response to single or multiple doses of ionizing radiation in human subcutaneous fibroblasts

    Rødningen, Olaug Kristin; Overgaard, Jens; Alsner, Jan

    2005-01-01

    cell lines after various ionizing radiation (IR) schemes in order to provide information on potential targets for prevention and to suggest candidate genes for SNP association studies aimed at predicting individual risk of radiation-induced morbidity. PATIENTS AND METHODS: Thirty different human......BACKGROUND AND PURPOSE: Transcriptional profiling of fibroblasts derived from breast cancer patients might improve our understanding of subcutaneous radiation-induced fibrosis. The aim of this study was to get a comprehensive overview of the changes in gene expression in subcutaneous fibroblast...... fibroblast cell lines were included in the study, and two different radiation schemes; single dose experiments with 3.5 Gy or fractionated with 3 x 3.5 Gy. Expression analyses were performed on unexposed and exposed cells after different time points. The IR response was analyzed using the statistical method...

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

    Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu

    2005-07-01

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

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

    Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu

    2005-01-01

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

  7. Non-randomized study on the effects of preoperative radiotherapy and daily administration of low-dose cisplatin against those of radiotherapy alone for oral cancer. Effects on local control, control of metastases, and overall survival

    Kurita, Hiroshi; Ohtsuka, Akiko; Kobayashi, Hiroichi; Kurashina, Kenji; Shikama, Naoto; Oguchi, Masahiko

    2000-01-01

    Cisplatin is a known radiation modifier. Our previous study suggested that daily administration of low-dose cisplatin enhanced the efficacy of radiotherapy against primary oral squamous carcinoma. In this paper, we follow the patients who participated in the previous study and survey the benefit of combination low-dose cisplatin in improving local control, prevention of metastases, and overall survival. This study included patients with surgically resectable advanced oral tumors. Ten patients underwent preoperative radiotherapy of 30-40 Gy/15-20 days with concomitant daily administration of low-dose cisplatin (5 mg/body or 5 mg/m 2 ). Ten other patients received external radiotherapy alone. All patients then underwent a planned radical tumor resection. No significant difference was see in loco-regional control rates (primary: 86 vs. 88%, neck: 83 vs. 78% at 48 months) or incidence of metastasis (70 vs. 64%) between the two groups. Nor was there a significant difference in the overall survival rate (60 vs. 66%). The results of this study suggest that the concomitant use of daily administration of low-dose cisplatin with preoperative radiation brings no statistically significant benefit in improving local control and survival rate in patients with advanced resectable oral cancer. (author)

  8. Impact of Genomics Platform and Statistical Filtering on Transcriptional Benchmark Doses (BMD and Multiple Approaches for Selection of Chemical Point of Departure (PoD.

    A Francina Webster

    Full Text Available Many regulatory agencies are exploring ways to integrate toxicogenomic data into their chemical risk assessments. The major challenge lies in determining how to distill the complex data produced by high-content, multi-dose gene expression studies into quantitative information. It has been proposed that benchmark dose (BMD values derived from toxicogenomics data be used as point of departure (PoD values in chemical risk assessments. However, there is limited information regarding which genomics platforms are most suitable and how to select appropriate PoD values. In this study, we compared BMD values modeled from RNA sequencing-, microarray-, and qPCR-derived gene expression data from a single study, and explored multiple approaches for selecting a single PoD from these data. The strategies evaluated include several that do not require prior mechanistic knowledge of the compound for selection of the PoD, thus providing approaches for assessing data-poor chemicals. We used RNA extracted from the livers of female mice exposed to non-carcinogenic (0, 2 mg/kg/day, mkd and carcinogenic (4, 8 mkd doses of furan for 21 days. We show that transcriptional BMD values were consistent across technologies and highly predictive of the two-year cancer bioassay-based PoD. We also demonstrate that filtering data based on statistically significant changes in gene expression prior to BMD modeling creates more conservative BMD values. Taken together, this case study on mice exposed to furan demonstrates that high-content toxicogenomics studies produce robust data for BMD modelling that are minimally affected by inter-technology variability and highly predictive of cancer-based PoD doses.

  9. Development of 99mTc imaging method using multiple imaging plates for reduction of patient's dose

    Ito, Shigeki; Nishizawa, Kunihide; Ariga, Eiji; Saze, Takuya

    2008-01-01

    A system for taking static thyroid 99m Tc images was devised by using multiple imaging plates (IPs) and a low energy high resolution collimator. Sensitivity was represented by using lower detection limits (LDL). The sensitivity and resolution of IP systems using a collimator and 9 IPs were determined by using a 20 ml thyroid phantom, and compared with the sensitivity of gamma cameras. The sensitivity of the IP systems increased in proportion to the number of IPs. The sensitivity and resolution of a probe using 9 IPs and a high resolution collimator were equivalent to or superior to the gamma camera for taking static thyroid 99m Tc images. IP systems can be applied clinically as static nuclear imaging devices as same as a gamma camera. (author)

  10. Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases. Local tumour control and survival

    Oehlke, Oliver; Wucherpfennig, David; Prokic, Vesna [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); Fels, Franziska [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); St. Josefs Hospital, Department of Radiation Oncology, Offenburg (Germany); Frings, Lars [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); University Hospital Freiburg, Department of Geriatrics and Gerontology, Freiburg (Germany); University Medical Center Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Egger, Karl [University Medical Center Freiburg, Department of Neuroradiology, Freiburg (Germany); Weyerbrock, Astrid [University Medical Center Freiburg, Department of Neurosurgery, Freiburg (Germany); Nieder, Carsten [Nordland Hospital, Department of Oncology and Palliative Medicine, Bodoe (Norway); University of Tromsoe, Institute of Clinical Medicine, Faculty of Health Sciences, Tromsoe (Norway); Grosu, Anca-Ligia [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); German Cancer Consortium (DKTK), Freiburg (Germany); German Cancer Research Center (DKFZ), Heidelberg (Germany)

    2015-01-16

    Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) for multiple brain metastases may prevent treatment-related cognitive decline, compared to standard WBRT. Additionally, simultaneous integrated boost (SIB) on individual metastases may further improve the outcome. Here, we present initial data concerning local tumour control (LTC), intracranial progression-free survival (PFS), overall survival (OS), toxicity and safety for this new irradiation technique. Twenty patients, enrolled between 2011 and 2013, were treated with HA-WBRT (30 Gy in 12 fractions, D{sub 98} {sub %} to hippocampus ≤ 9 Gy) and a SIB (51 Gy) on multiple (2-13) metastases using a volumetric modulated arc therapy (VMAT) approach based on 2-4 arcs. Metastases were evaluated bidimensionally along the two largest diameters in contrast-enhanced three-dimensional T1-weighed MRI. Median follow-up was 40 weeks. The median time to progression of boosted metastases has not been reached yet, corresponding to a LTC rate of 73 %. Median intracranial PFS was 40 weeks, corresponding to a 1-year PFS of 45.3 %. Median OS was 71.5 weeks, corresponding to a 1-year OS of 60 %. No obvious acute or late toxicities grade > 2 (NCI CTCAE v4.03) were observed. D{sub mean} to the bilateral hippocampi was 6.585 Gy ± 0.847 (α/β = 2 Gy). Two patients developed a new metastasis in the area of hippocampal avoidance. HA-WBRT (simultaneous integrated protection, SIP) with SIB to metastases is a safe and tolerable regime that shows favorable LTC for patients with multiple brain metastases, while it has the potential to minimize the side-effect of cognitive deterioration. (orig.) [German] Die Hippocampus-schonende Ganzhirnbestrahlung (HS-GHB) kann im Vergleich zur Standard-GHB die Verschlechterung der neurokognitiven Funktion verhindern. Zusaetzlich vermag ein simultan integrierter Boost (SIB) auf die Metastasen die Prognose der betroffenen Patienten weiter zu verbessern. In dieser Studie praesentieren wir erste Ergebnisse

  11. Analgesic efficacy of lysine clonixinate plus tramadol versus tramadol in multiple doses following impacted third molar surgery.

    Perez-Urizar, J; Martínez-Rider, R; Torres-Roque, I; Garrocho-Rangel, A; Pozos-Guillen, A

    2014-03-01

    This study compared the analgesic and anti-inflammatory efficacy, trismus control, and tolerability of the combination of lysine clonixinate and tramadol (LCT) versus tramadol (T) alone after surgical removal of impacted mandibular third molars. This study was a double-blind, randomized clinical trial, including two study groups of 20 patients each, who exhibited acute pain subsequent to surgical extraction of two mandibular third molars. Pain intensity was quantified over a 96-h period using a visual analogue scale and a 5-point verbal rating scale. Secondary indicators of analgesic and anti-inflammatory efficacy, trismus control, and tolerability were determined. Patients administered LCT exhibited better therapeutic effects that those administered T. Fifty percent of patients in the LCT group rated this therapy as 'excellent analgesia' compared with only 10% in the T group. The onset of the analgesic effect of LCT was significantly faster, without any therapeutic failures. There were no significant differences between the groups with regard to anti-inflammatory effect or trismus. The results of this study suggest that the postsurgical analgesic efficacy of LCT in combination (LC 125 mg + T 25 mg) is superior to that obtained with T alone, administered at the standard dose of 50 mg, for up to 96 h after the extraction of both impacted mandibular third molars. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  12. Comparison of Thromboemboli Prophylactic Effect of Aspirin and Low Dose Warfarin in Standard Risk Multiple Myeloma Patients that Treated with Regimens Containing Thalidomide

    Seyed Amir Dadkhahi

    2017-05-01

    Full Text Available Abstract Background: Most of the current regimens in the treatment of multiple myeloma include thalidomide. Thalidomide is a modulator of the immune system and according to several studies, its main complication is thromboembolism. The aim of this study is to compare the thromboemboli prophylactic effect of aspirin and low dose warfarin in standard risk multiple myeloma patients that treated with regimens containing thalidomide. Materials and Methods: In this double- blind clinical trial study, sixty-six patients with multiple myeloma under treatment with thalidomide-containing regimens with standard risk for thromboembolism who were admitted to Khansari hospital, entered the study according to inclusion and exclusion criteria. The incidence of thromboembolism in these patients was evaluated. Results: Five patients in the warfarin group and 2 patients in the aspirin group had thromboemboli. Chi square analyses showed no significant difference between groups (p=0.635. Conclusion: The results showed that both drugs are effective in preventing thromboembolism and can be used as a prophylactic treatment.

  13. Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice

    Ikebe, E; Kawaguchi, A; Tezuka, K; Taguchi, S; Hirose, S; Matsumoto, T; Mitsui, T; Senba, K; Nishizono, A; Hori, M; Hasegawa, H; Yamada, Y; Ueno, T; Tanaka, Y; Sawa, H; Hall, W; Minami, Y; Jeang, K T; Ogata, M; Morishita, K; Hasegawa, H; Fujisawa, J; Iha, H

    2013-01-01

    In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90's ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression

  14. Preemptive intravenous immunoglobulin allows safe and timely administration of antineoplastic therapies in patients with multiple myeloma and parvovirus B19 disease.

    Katragadda, L; Shahid, Z; Restrepo, A; Muzaffar, J; Alapat, D; Anaissie, E

    2013-08-01

    Parvovirus B19 (B19) disease is a rare cause of anemia in cancer patients and often goes unrecognized, causing delays in anticancer therapy. A retrospective review was carried out of the records of patients with multiple myeloma who underwent melphalan-based autologous stem cell transplantation (MEL-ASCT) and developed B19 infection (January 2009-December 2011). Cases were defined by the presence of clinical and laboratory findings consistent with B19 disease in patients with repeatedly positive plasma quantitative polymerase chain reaction for parvovirus. Six patients qualified as cases; 5 presented with trilineage cytopenias (chronic in 1) and 1 with anemia later progressing to pancytopenia. Transfusion-dependent thrombocytopenia led to testing in 5 patients. Two of these patients also had manifestations of autoimmune disease. Therapy with intravenous immunoglobulin (IVIG) resulted in clinical and hematologic response in all; however, 1 patient, whose white blood cell counts and serum hemoglobin levels improved, required splenectomy for persistent thrombocytopenia. All patients required additional IVIG for recurrent B19 disease. Although viral load at diagnosis did not correlate with the severity of cytopenia, its decrease was associated with response during 17 of 20 evaluable episodes (P = 0.02). Preemptive IVIG allowed the safe administration of chemotherapy in 3 patients, including MEL-ASCT in 1. Parvovirus B19 can cause severe disease in myeloma patients including ASCT recipients. Thrombocytopenia - not anemia - was the leading presentation and may be associated with autoimmune conditions. Patients with unexplained cytopenias, particularly when prolonged, should undergo testing for circulating parvovirus. A reduction in viral load was associated with response to IVIG, although additional therapy was needed for recurrent disease. Most importantly, preemptive IVIG allowed for safe and timely administration of antineoplastic therapy in patients with ongoing B

  15. Low dose of donepezil improves gabapentin analgesia in the rat spared nerve injury model of neuropathic pain

    Folkesson, Anna; Honoré, Per Hartvig; Andersen, Lene Munkholm

    2010-01-01

    the effect of the cholinesterase inhibitor donepezil when administered (1) alone and (2) as low-dose in combination with the first-line recommendation gabapentin. The co-administration studies were performed following single and multiple dosing. Single, parenteral dosing of donepezil (1, 1.5 and 3 mg...

  16. Probability distribution of dose rates in the body tissue as a function of the rhytm of Sr90 administration and the age of animals

    Rasin, I.M.; Sarapul'tsev, I.A.

    1975-01-01

    The probability distribution of tissue radiation doses in the skeleton were studied in experiments on swines and dogs. When introducing Sr-90 into the organism from the day of birth till 90 days dose rate probability distribution is characterized by one, or, for adult animals, by two independent aggregates. Each of these aggregates correspond to the normal distribution law

  17. Systematic literature review comparing rapid 3-dose administration of the GSK tick-borne encephalitis vaccine with other primary immunization schedules.

    Galgani, Ilaria; Bunge, Eveline M; Hendriks, Lisa; Schludermann, Christopher; Marano, Cinzia; De Moerlooze, Laurence

    2017-09-01

    Tick-borne encephalitis (TBE), which is endemic across large regions of Europe and Asia, is most effectively prevented through vaccination. Three-dose primary TBE vaccination schedules are either rapid (0,7,21-days) or conventional (0,28-84-days, 9-12-months). The second dose can also be administered at 14 days for faster priming and sero-protection). Areas covered: We used a three-step selection process to identify 21 publications comparing the immunogenicity and/or safety of different schedules. Expert commentary: Priming with two or three TBE vaccine doses was highly immunogenic. After conventional priming (0-28 days), 95% adults and ≥95% children had neutralization test (NT) titers ≥10 at 14 days post-dose-2 compared with 92% adults and 99% children at 21 days post-dose-3 (rapid schedule). Most subjects retained NT titers ≥10 at day 300. A single booster dose induced a strong immune response in all subjects irrespective of primary vaccination schedule or elapsed time since priming. GMT peaked at 42 days post-dose-1 (i.e., 21 days post-dose 3 [rapid-schedule], or 14-28 days post-dose-2 [conventional-schedule]), and declined thereafter. Adverse events were generally rare and declined with increasing doses. In the absence of data to recommend one particular schedule, the regimen choice will remain at the physician's discretion, based on patient constraints and availability.

  18. Sustainability Instruction in High Doses: Results From Incorporation of Multiple InTeGrate Modules Into an Environmental Science Class

    Rademacher, L. K.

    2017-12-01

    The Interdisciplinary Teaching about Earth for a Sustainable Future (InTeGrate) community has developed extensive courses and modules designed for broad adoption into geoscience classrooms in diverse environments. I participated in a three-semester research project designed to test the efficacy of incorporating "high doses" (minimum 3 modules or 18 class periods) of InTeGrate materials into a course, in my case, an introductory environmental science class. InTeGrate materials were developed by groups of instructors from a range of institutions across the US. These materials include an emphasis on systems thinking, interdisciplinary approaches, and sustainability, and those themes are woven throughout the modules. The three semesters included a control in which no InTeGrate materials were used, a pilot in which InTeGrate materials were tested, and a treatment semesters in which tested materials were modified as needed and fully implemented into the course. Data were collected each semester on student attitudes using the InTeGrate Attitudinal Instrument (pre and post), a subset of Geoscience Literacy Exam questions (pre and post), and a series of assessments and essay exam questions (post only). Although results suggest that learning gains were mixed, changes in attitudes pre- and post-instruction were substantial. Changes in attitudes regarding the importance of sustainable employers, the frequency of self-reported individual sustainable actions, and motivation level for creating a sustainable society were observed in the control and treatment semesters, with the treatment semester showing the greatest gains. Importantly, one of the biggest differences between the control and treatment semesters is the reported impact that the course had on influencing students' sustainable behaviors. The treatment semester course impacted students' sustainable behaviors far more than the control semester.

  19. Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison.

    Van Sanden, Suzy; Ito, Tetsuro; Diels, Joris; Vogel, Martin; Belch, Andrew; Oriol, Albert

    2018-03-01

    Daratumumab (a human CD38-directed monoclonal antibody) and pomalidomide (an immunomodulatory drug) plus dexamethasone are both relatively new treatment options for patients with heavily pretreated multiple myeloma. A matching adjusted indirect comparison (MAIC) was used to compare absolute treatment effects of daratumumab versus pomalidomide + low-dose dexamethasone (LoDex; 40 mg) on overall survival (OS), while adjusting for differences between the trial populations. The MAIC method reduces the risk of bias associated with naïve indirect comparisons. Data from 148 patients receiving daratumumab (16 mg/kg), pooled from the GEN501 and SIRIUS studies, were compared separately with data from patients receiving pomalidomide + LoDex in the MM-003 and STRATUS studies. The MAIC-adjusted hazard ratio (HR) for OS of daratumumab versus pomalidomide + LoDex was 0.56 (95% confidence interval [CI], 0.38-0.83; p  = .0041) for MM-003 and 0.51 (95% CI, 0.37-0.69; p  < .0001) for STRATUS. The treatment benefit was even more pronounced when the daratumumab population was restricted to pomalidomide-naïve patients (MM-003: HR, 0.33; 95% CI, 0.17-0.66; p  = .0017; STRATUS: HR, 0.41; 95% CI, 0.21-0.79; p  = .0082). An additional analysis indicated a consistent trend of the OS benefit across subgroups based on M-protein level reduction (≥50%, ≥25%, and <25%). The MAIC results suggest that daratumumab improves OS compared with pomalidomide + LoDex in patients with heavily pretreated multiple myeloma. This matching adjusted indirect comparison of clinical trial data from four studies analyzes the survival outcomes of patients with heavily pretreated, relapsed/refractory multiple myeloma who received either daratumumab monotherapy or pomalidomide plus low-dose dexamethasone. Using this method, daratumumab conferred a significant overall survival benefit compared with pomalidomide plus low-dose dexamethasone. In the absence of head-to-head trials, these

  20. Defining Persistent Hotspots: Areas That Fail to Decrease Meaningfully in Prevalence after Multiple Years of Mass Drug Administration with Praziquantel for Control of Schistosomiasis.

    Kittur, Nupur; Binder, Sue; Campbell, Carl H; King, Charles H; Kinung'hi, Safari; Olsen, Annette; Magnussen, Pascal; Colley, Daniel G

    2017-12-01

    Preventive chemotherapy with praziquantel for schistosomiasis morbidity control is commonly done by mass drug administration (MDA). MDA regimen is usually based on prevalence in a given area, and effectiveness is evaluated by decreases in prevalence and/or intensity of infection after several years of implementation. Multiple studies and programs now find that even within well-implemented, multiyear, annual MDA programs there often remain locations that do not decline in prevalence and/or intensity to expected levels. We term such locations "persistent hotspots." To study and address persistent hotspots, investigators and neglected tropical disease (NTD) program managers need to define them based on changes in prevalence and/or intensity. But how should the data be analyzed to define a persistent hotspot? We have analyzed a dataset from an operational research study in western Tanzania after three annual MDAs using four different approaches to define persistent hotspots. The four approaches are 1) absolute percent change in prevalence; 2) percent change in prevalence; 3) change in World Health Organization guideline categories; 4) change (absolute or percent) in both prevalence and intensity. We compare and contrast the outcomes of these analyses. Our intent is to show how the same dataset yields different numbers of persistent hotspots depending on the approach used to define them. We suggest that investigators and NTD program managers use the approach most suited for their study or program, but whichever approach is used, it should be clearly stated so that comparisons can be made within and between studies and programs.

  1. 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

    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% (...

  2. Efficacy and Safety of Multiple Doses of Exenatide Once-Monthly Suspension in Patients With Type 2 Diabetes: A Phase II Randomized Clinical Trial.

    Wysham, Carol H; MacConell, Leigh; Hardy, Elise

    2016-10-01

    This study investigated the efficacy and safety of multiple exenatide once-monthly suspension (QMS) doses of exenatide-containing microspheres in Miglyol referenced against the clinical dose of exenatide once-weekly (QW) microspheres in aqueous solution. In this phase II, randomized, controlled, single-blind study, 121 adults (∼30/arm) with type 2 diabetes and HbA1c 7.1-11.0% (54-97 mmol/mol) were randomized 1:1:1:1 to subcutaneous exenatide QW 2 mg (self-administered) or exenatide QMS 5, 8, or 11 mg (caregiver-administered) for 20 weeks. The primary end point was change in HbA1c. At baseline, mean age was 50 years, HbA1c was 8.5% (69 mmol/mol), fasting plasma glucose (FPG) was 184 mg/dL, and body weight was 98 kg. At week 20, mean ± SD HbA1c reductions were -1.54% ± 1.26% with exenatide QW and -1.29% ± 1.07%, -1.31% ± 1.66%, and -1.45% ± 0.93% with exenatide QMS 5, 8, and 11 mg, respectively (evaluable population: n = 110). There were no significant differences in HbA1c reductions among the exenatide QMS doses. FPG reductions were -34 ± 48 mg/dL with exenatide QW and -25 ± 43, -30 ± 52, and -49 ± 49 mg/dL with exenatide QMS 5, 8, and 11 mg, respectively. Weight decreased with all treatments. For exenatide QMS, nausea (16.7-23.3%) and headache (16.7-26.7%) were the most common adverse events. No major or minor hypoglycemia occurred. All doses of exenatide QMS resulted in efficacy and tolerability profiles consistent with exenatide QW. These results combined with pharmacokinetic and pharmacodynamic modeling could inform dose selection for further development. © 2016 by the American Diabetes Association.

  3. Assessment of pulmonary function using pixel indexes of multiple-slice spiral CT low-dose two-phase scanning in chronic obstructive pulmonary disease

    Zhang Lihua; Wang Yunhua; Jiang Zhongbiao; Zhang Lejun; Sun Wanli; Zhang Chunming

    2012-01-01

    Objective: To explore the values of pixel indexes (PI) with multiple-slice spiral CT low-dose two-phase scanning for assessing the pulmonary function in chronic obstructive pulmonary disease (COPD). Methods: Thirty-six patients with COPD (COPD group)and 30 healthy people (control group)underwent pulmonary function test (PFT). Chest 64-MSCT low-dose (50 mAs) scanning at full inspiration and expiration, routine scanning (100 mAs) at inspiration were performed. The effective dose (ED) was calculated. The lung was divided into three regions (upper, middle, lower). PI of lung were divided into five groups: -960--1024, -910--960, -800--910, -700--800, -400--700. The PI -910 (sum of the PI under -910 HU) of low-dose scanning at each region were measured and calculated using pulmo software. All PI included PIin -910 , PIiex -910 , PIin -910 -PIiex -910 , PIiex -910 /PIin -910 and (PIin -910 -PIiex -910 )/PIin -910 . All patients underwent PFT within 3 days after 64-MSCT canning, FEV1% and FEV1/FVC were selected for comparison. Results: The PIin in three regions (-960 - -1024, -910 - -960, -800 - -910) were statistically significant between normal and COPD groups (U=0.00, 57.00, 20.50, P<0.01). The PIex in all regions were statistically significant (U=0.00, 0.00, 71.52, 191.00, 6.00, P<0.01). PI -910--1024 at expiration and inspiration were correlated with FEV1% and FEV1/FVC (r=-0.548, -0.664, -0.752, -0.781, P<0.01). PIin -910 , PIex -910 ,PIiex -910 /PIin -910 , (PIin -910 -PIex -910 )/PIin -910 had a good correlation with FEV1% and FEV1/FVC (r=-0.548, -0.664, -0.752, -0.781, -0.674, -0.642, 0.674, 0.642, P<0.01). Conclusion: Pixel indexes of 64-MSCT low-dose two-phase scanning can be used to evaluate pulmonary function in COPD patients. (authors)

  4. Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

    Alkharusi, Amira; Mirecki-Garrido, Mercedes; Ma, Zuheng

    2016-01-01

    Background: Diabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can...... prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity. Methodology: The elevated sensitivity of SOCS2-/- mice to GH and possibly to PRL was the rationale to analyze the effects of multiple low dose streptozotocin (MLDSTZ)-induced diabetes...... in SOCS2-/- mice. Results: We show that 6-month-old SOCS2-/- mice, but not 2-month-old mice, were less sensitive to MLDSTZ-induced diabetes, compared to controls. MLDSTZ treatment induced glucose intolerance in both SOCS2+/+ and SOCS2-/- mice, as shown by glucose tolerance tests, with SOCS2+/+ mice...

  5. Diagnostic value of whole-body low-dose computed tomography (WBLDCT) in bone lesions detection in patients with multiple myeloma (MM)

    Ippolito, Davide, E-mail: davide.atena@tiscalinet.it [School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza (MB) (Italy); Department of Diagnostic Radiology, H. San Gerardo, Via Pergolesi 33, 20900 Monza (MB) (Italy); Besostri, Valeria, E-mail: valeriabesostri@gmail.com [School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza (MB) (Italy); Department of Diagnostic Radiology, H. San Gerardo, Via Pergolesi 33, 20900 Monza (MB) (Italy); Bonaffini, Pietro Andrea, E-mail: pa.bonaffini@gmail.com [School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza (MB) (Italy); Department of Diagnostic Radiology, H. San Gerardo, Via Pergolesi 33, 20900 Monza (MB) (Italy); Rossini, Fausto, E-mail: valeriabesostri@hotmail.it [Department of Hematology, H. San Gerardo, Via Pergolesi 33, 20900 Monza (MB) (Italy); Di Lelio, Alessandro, E-mail: valebeso@libero.it [Department of Diagnostic Radiology, H. San Gerardo, Via Pergolesi 33, 20900 Monza (MB) (Italy); Sironi, Sandro, E-mail: sandrosironi@libero.it [School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza (MB) (Italy); Department of Diagnostic Radiology, H. San Gerardo, Via Pergolesi 33, 20900 Monza (MB) (Italy)

    2013-12-01

    Purpose: To assess the role of whole-body low-dose computed tomography (WBLDCT) in the diagnosis and staging of patients with suspicion of multiple myeloma (MM). Materials and methods: A total of 138 patients (76 male and 62 female; mean age 63.5 years, range 50–81 years), with early MM, underwent WBLDCT protocol study, performed on 16-slice scanner (Brilliance, Philips Medical System, Eindhoven, The Netherlands): tube voltage 120 kV; tube current time product 40 mAs. Diagnosis of osteolytic lesions was performed on the basis of axial and multiplanar reformatted images, whereas the assessment of spinal misalignment and fracture was done by using multiplanar reformatted images. The overall dose delivered to each patient was 4.2 mSv. Every patient gave personal informed consent, as required by our institution guidelines. Results: The diagnosis was established either by histopathology or imaging follow-up (size increase of over a period time). In all 138 patients, image resolution was diagnostic, enabling correct classification of multiple myeloma patients. WBLDCT showed a total of 328 pathologic bone findings in 81/138 patients. CT scanning resulted in complete evaluation of the bone lesions in these areas of the skeleton: skull (42), humerus (15), femur (20), ribs (7), scapulae (13), pelvis (35), clavicle (13), sternum (10), cervical (39), dorsal (65), lombar (48) and sacral rachis (21). In 40/81 bone involvement detected by CT was the only CRAB criterion present. Furthermore, WBLDCT demonstrated pleuro-pulmonary lesions in 20 patients (11 infective, 9 as MM localizations) and 1 renal neoplasia. Conclusion: WBLDCT, detecting bone marrow localizations and demonstrating extra-osseous findings, with a fast scanning time and high resolution images, is a reliable imaging-based tool for a proper management of MM patients.

  6. A murine model of type 2 diabetes mellitus developed using a combination of high fat diet and multiple low doses of streptozotocin treatment mimics the metabolic characteristics of type 2 diabetes mellitus in humans.

    Nath, Sayantan; Ghosh, Sankar Kumar; Choudhury, Yashmin

    A murine model of type 2 diabetes mellitus was used to compare the antidiabetic effects of the dipeptidyl peptidase-4 (DPP4) inhibitor vildagliptin and biguanide, metformin. Swiss albino mice (n=20 males; n=25 females) were given high fat diet (HFD) ad libitum for 3weeks followed by low dose (40mgkg -1 body weight, bw daily) of streptozotocin (STZ) intraperitoneally five times from the 22nd day of treatment onwards, with HFD continued up to 26th day. Controls (n=15 males; n=15 females) were fed normal balanced diet without administration of STZ. Successful induction of diabetes mellitus was confirmed by testing for fasting blood glucose, intraperitoneal glucose tolerance and intraperitoneal insulin sensitivity. Diabetic mice were administered vildagliptin (10mgkg -1 bw daily) and metformin (50mgkg -1 bw daily) orally for 4weeks. Control, diabetic, vildagliptin and metformin-treated diabetic mice were evaluated for alterations in lipid profile using blood serum and histopathology and oxidative stress using tissues including liver, kidney and heart. Diabetic mice showed significant alterations in lipid profile, tissue histopathology, impaired glucose tolerance, lower insulin sensitivity and elevated lipid peroxidation and protein carbonylation, with depressed catalase activity, when compared to age and gender-matched controls. Metformin and vildagliptin ameliorated the abovementioned diabetic conditions, with vildagliptin found to be more effective. A murine model developed by the combination of HFD and multiple low dose of STZ mimics the metabolic characteristics of type 2 diabetes mellitus in humans, and may be useful for antidiabetic drug screening. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Clinical and prognostic significance of bone marrow abnormalities in the appendicular skeleton detected by low-dose whole-body multidetector computed tomography in patients with multiple myeloma

    Nishida, Y; Matsue, Y; Suehara, Y; Fukumoto, K; Fujisawa, M; Takeuchi, M; Ouchi, E; Matsue, K

    2015-01-01

    Clinical significance of medullary abnormalities in the appendicular skeleton (AS) detected by low-dose whole-body multidetector computed tomography (MDCT) in patients with multiple myeloma (MM) was investigated. A total of 172 patients with monoclonal gammopathy of undetermined significance (MGUS) (n=17), smoldering MM (n=47) and symptomatic MM (n=108) underwent low-dose MDCT. CT values (CTv) of medullary density of AS⩾0 Hounsfield unit (HU) was considered as abnormal. Percentage of medullary abnormalities and the mean CTv of AS in patients with MGUS, smoldering MM and symptomatic MM were 18, 55 and 62% and −44.5 , −20.3 and 11.2 HU, respectively (P<0.001 and P<0.001). Disease progression of MM was independently associated with high CTv on multivariate analysis. In symptomatic MM, the presence of abnormal medullary lesions was associated with increased incidence of high-risk cytogenetic abnormalities (34.4% vs 7.7% P=0.002) and extramedullary disease (10.4% vs 0% P=0.032). It was also an independent poor prognostic predictor (hazard ratio 3.546, P=0.04). This study showed that CTv of AS by MDCT is correlated with disease progression of MM, and the presence of abnormal medullary lesions is a predictor for poor survival

  8. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma. Final results of phase III US Intergroup Trial S9321

    Kim, Sung-Won; Tobinai, Kensei

    2007-01-01

    The outline of the title trial is described in comparison with outcomes of other randomized controlled trials. The S9321 trial in US started in 1993 by Southwest Oncology Group, Eastern Cooperative Oncology Group and Cancer and Leukemia Group B, including 11 institutions for performance status 0-2 untreated patients of symptomatic multiple myeloma (MM). Patients were randomized to either group receiving the standard dose therapy (SDT) or high-dose therapy with autologous heamatopoietic stem cell transplantation group (HDT). The former essentially underwent the chemotherapy with vincristine, carmustine, melphalan (MEL) and predonisolone after the remission treatment and the latter, whole body irradiation of total 12 Gy (8 fractions/4 days) as well. An appropriate part of the latter group also received the transplantation of allogenic heamatopoietic stem cells previously treated with MEL and 12-Gy radiation. Patients younger than 70 y of age, 899 cases, were registered in the trial, 86 of whom were eliminated before the remission treatment and 248, at that treatment end. No statistical significance was seen between SDT and HDT in efficacy. It is concluded that, despite the present outcome, HDT should be taken into consideration because novel medicals are being under development and MM is a symptomatic disease originated from different molecular bases. (T.I.)

  9. Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma.

    Mateos, María-Victoria; Granell, Miguel; Oriol, Albert; Martinez-Lopez, Joaquin; Blade, Joan; Hernandez, Miguel T; Martín, Jesus; Gironella, Mercedes; Lynch, Mark; Bleickardt, Eric; Paliwal, Prashni; Singhal, Anil; San-Miguel, Jesus

    2016-11-01

    Elotuzumab is an immunostimulatory, humanized immunoglobulin G1 monoclonal antibody that selectively targets and kills signalling lymphocytic activation molecule family member 7-expressing myeloma cells. We evaluated the safety and tolerability of elotuzumab 10 mg/kg combined with thalidomide 50-200 mg and dexamethasone 40 mg (with/without cyclophosphamide 50 mg) in patients with relapsed/refractory multiple myeloma (RRMM). The primary endpoint was the proportion of grade ≥3 non-haematological adverse events (AEs); other endpoints included the number of dose reductions/discontinuations and efficacy. Forty patients were treated, who had a median of three previous therapies, including bortezomib (98%) and lenalidomide (73%). Grade ≥3 non-haematological AEs were reported in 63% of patients, most commonly asthenia (35%) and peripheral oedema (25%). Six (15%) patients had an infusion reaction. Twenty-six (65%) patients had ≥1 dose reduction/discontinuation due to an AE, none related to elotuzumab. Overall response rate was 38%; median progression-free survival was 3·9 months. Median overall survival was 16·3 months and the 1-year survival rate was 63%. Minimal incremental toxicity was observed with addition of elotuzumab to thalidomide/dexamethasone with or without cyclophosphamide, and efficacy data suggest clinical benefit in a highly pre-treated population. Elotuzumab combined with thalidomide may provide an additional treatment option for patients with RRMM. © 2016 John Wiley & Sons Ltd.

  10. Gamma knife radiosurgery for acoustic schwannomas. An analysis of the method of low dose and conformal multiple shots with smaller collimator

    Fukuoka, Seiji; Takanashi, Masami; Hojo, Atsufumi; Konishi, Masanori; Nakamura, Hirohiko

    2003-01-01

    The purpose of this study was to analyze tumor control and possible complications of gamma knife radiosurgery (GKRS) in patients with acoustic schwannomas treated using low marginal dose and conformal multiple shots with smaller collimators to fit irregular tumor shapes. The authors evaluated 183 patients with follow-up periods ranging from 3 to 11 years. Marginal doses were 9 to 15 Gy (median 12 Gy), with corresponding treatment volumes being between 0.1 and 18.7 ml (median 1.8 ml). The number of isocenter varied from 2 to 24 shots (median 9 shots). The actuarial tumor control rate (resection-free survival) was 96.5%. Useful hearing, trigeminal and facial functions were preserved at 75%, 97.4%, and 100%, respectively. Hydrocephalus was recognized in 5.7% of all patients, and seems to occur in cases with medium sized tumors where mild ventricular enlargement is evident prior to treatment. GKRS proves to be a safe and effective therapy for small to medium sized tumors. However, the indication for larger sized tumors (diameter 3+ cm) should be carefully considered, larger tumors being less easy to control and liable to cause ataxia due to transient expansion. (author)

  11. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 22). Effects of 2- and 4-week administration of theobromine on the testis.

    Funabashi, H; Fujioka, M; Kohchi, M; Tateishi, Y; Matsuoka, N

    2000-10-01

    The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity. Theobromine was administered orally to male Sprague-Dawley rats at dose levels of 250 and 500 mg/kg for 2 weeks starting at the age of 6 or 8 weeks, and for 4 weeks from the age of 6 weeks. Histopathological examination of reproductive organs revealed toxic findings in the testis at 500 mg/kg after 2 weeks of dosing at both ages, and at 250 and 500 mg/kg after 4 weeks of dosing. The primary findings were degeneration/necrosis and desquamation of spermatids and spermatocytes, vacuolization of seminiferous tubules, and multinucleated giant cell formation. These findings were present mainly in stages I-VI and XII-XIV. From these results, it is concluded that the toxic effects of theobromine on the testis can be detected by repeated dosing for 2 weeks as well as for 4 weeks.

  12. A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor.

    Abbas, Richat; Hug, Bruce A; Leister, Cathie; Sonnichsen, Daryl

    2012-07-01

    Neratinib, a potent, low-molecular-weight, orally administered, irreversible, pan-ErbB receptor tyrosine kinase inhibitor has antitumor activity in ErbB2 + breast cancer. The objective of this study was to characterize the onset, severity, and duration of diarrhea after administration of neratinib 240 mg once daily (QD) and 120 mg twice daily (BID) for ≤14 days in healthy subjects. A randomized, double-blind, parallel-group, inpatient study was conducted in 50 subjects given oral neratinib either 240 mg QD or 120 mg BID with food for ≤14 days. The primary endpoint was the proportion of subjects with diarrhea of at least moderate severity (grade 2; 5-7 loose stools/day). In subjects with grade 2 diarrhea, fecal analytes were determined. Pharmacokinetic profiles were characterized for neratinib on Days 1 and 7. No severe (grade 3) diarrhea was reported. By Day 4, all subjects had grade 1 diarrhea. Grade 2 diarrhea occurred in 11/22 evaluable subjects (50 % [90 % confidence interval (CI): 28-72 %]) in the QD group and 17/23 evaluable subjects (74 % [90 % CI: 52-90 %]) in the BID group (P = 0.130). In fecal analyses, 18 % tested positive for hemoglobin and 46 % revealed fecal lactoferrin. Specimen pH was neutral to slightly alkaline. In pharmacokinetic analyses, Day 1 peak plasma concentration and Day 7 steady-state exposure were higher with the QD regimen than the BID regimen. In an exploratory analysis, ABCG2 genotype showed no correlation with severity or onset of diarrhea. Incidences and onsets of at least grade 1 and at least grade 2 diarrhea were not improved on BID dosing compared with QD dosing.

  13. Continued Benefit to Androgen Deprivation Therapy for Prostate Cancer Patients Treated With Dose-Escalated Radiation Therapy Across Multiple Definitions of High-Risk Disease

    Stenmark, Matthew H.; Blas, Kevin; Halverson, Schuyler; Sandler, Howard M.; Feng, Felix Y.; Hamstra, Daniel A.

    2011-01-01

    Purpose: To analyze prognostic factors in patients with high-risk prostate cancer treated with dose-escalated external-beam radiation therapy (EBRT) and androgen deprivation (ADT). Methods and Materials: Between 1998 and 2008 at University of Michigan Medical Center, 718 men were consecutively treated with EBRT to at least 75 Gy. Seven definitions of high-risk prostate cancer, applying to 11–33% of patients, were evaluated. Biochemical failure (BF), salvage ADT use, metastatic progression, and prostate cancer–specific mortality (PCSM) were estimated by the Kaplan-Meier method and Cox proportional hazards regression. Results: Each high-risk definition was associated with increased BF (hazard ratio [HR] 2.8–3.9, p < 0.0001), salvage ADT use (HR 3.9–6.3, p < 0.0001), metastasis (HR 3.7–6.6, p < 0.0001), and PCSM (HR 3.7–16.2, p < 0.0001). Furthermore, an increasing number of high-risk features predicted worse outcome. Adjuvant ADT yielded significant reductions in both metastases (HR 0.19–0.38, p < 0.001) and PCSM (HR 0.38–0.50, p < 0.05) for all high-risk definitions (with the exception of clinical Stage T3–4 disease) but improved BF only for those with elevated Gleason scores (p < 0.03, HR 0.25–0.48). When treated with ADT and dose-escalated EBRT, patients with Gleason scores 8 to 10, without other high-risk features, had 8-year freedom from BF of 74%, freedom from distant metastases of 93%, and cause-specific survival of 92%, with salvage ADT used in 16% of patients. Conclusion: Adjuvant ADT results in a significant improvement in clinical progression and PCSM across multiple definitions of high-risk disease even with dose-escalated EBRT. There is a subset of patients, characterized by multiple high-risk features or the presence of Gleason Pattern 5, who remain at significant risk for metastasis and PCSM despite current treatment.

  14. Treatment of aggressive multiple myeloma by high-dose chemotherapy and total body irradiation followed by blood stem cells autologous graft

    Fermand, J.P.; Levy, Y.; Gerota, J.; Benbunan, M.; Cosset, J.M.; Castaigne, S.; Seligmann, M.; Brouet, J.C.

    1989-01-01

    Eight patients with stage III aggressive multiple myeloma, refractory to current chemotherapy in six cases, were treated by high-dose chemotherapy (nitrosourea, etoposide, and melphalan) (HDC) and total body irradiation (TBI), followed by autografting with blood stem cells. These cells were previously collected by leukapheresis performed during hematologic recovery following cytotoxic drug-induced bone marrow aplasia. Seven patients were alive 9 to 17 months after HDC-TBI and graft. One died at day 40 from cerebral bleeding. All living patients achieved a 90% or greater reduction in tumor mass. In two cases, a complete remission (CR) has persisted at a follow-up of 15 and 16 months. Three patients have been well and off therapy with stable minimal residual disease (RD) since 10, 11, and 17 months, respectively. A patient in apparent CR and another with RD have relapsed 9 to 12 months posttreatment. Autologous blood-derived hematopoietic stem cells induced successful and sustained engraftment in all living patients. These results, although still preliminary, indicate that HDC and TBI, followed by blood stem cells autograft, which has both practical and theoretical interest over allogeneic or autologous bone marrow transplantation, deserve consideration in selected patients with multiple myeloma

  15. Prophylactic single-dose administration of 600 mg clindamycin versus 4-time administration of 600 mg clindamycin in orthognathic surgery: A prospective randomized study in bilateral mandibular sagittal ramus osteotomies

    Lindeboom, Jerôme A. H.; Baas, Eric M.; Kroon, Frans H. M.

    2003-01-01

    Objective. The purpose of this study was to compare a single 600-mg dose of preoperative intravenously administered clindamycin with a 24-hour 600-mg regimen of clindamycin as prophylaxis for postoperative infections in bilateral sagittal ramus osteotomies. Study design. Seventy patients were

  16. Age and Chronicity of Administration Dramatically Influenced the Impact of Low Dose Paraquat Exposure on Behavior and Hypothalamic-Pituitary-Adrenal Activity

    Chris A. Rudyk

    2017-07-01

    Full Text Available Little is known of the age-dependent and long-term consequences of low exposure levels of the herbicide and dopaminergic toxicant, paraquat. Thus, we assessed the dose-dependent effects of paraquat using a typical short-term (3 week exposure procedure, followed by an assessment of the effects of chronic (16 weeks exposure to a very low dose (1/10th of what previously induced dopaminergic neuronal damage. Short term paraquat treatment dose-dependently induced deficits in locomotion, sucrose preference and Y-maze performance. Chronic low dose paraquat treatment had a very different pattern of effects that were also dependent upon the age of the animal: in direct contrast to the short-term effects, chronic low dose paraquat increased sucrose consumption and reduced forced swim test (FST immobility. Yet these effects were age-dependent, only emerging in mice older than 13 months. Likewise, Y-maze spontaneous alternations and home cage activity were dramatically altered as a function of age and paraquat chronicity. In both the short and long-term exposure studies, increased corticosterone and altered hippocampal glucocorticoid receptor (GR levels were induced by paraquat, but surprisingly these effects were blunted in the older mice. Thus, paraquat clearly acts as a systemic stressor in terms of corticoid signaling and behavioral outcomes, but that paradoxical effects may occur with: (a repeated exposure at; (b very low doses; and (c older age. Collectively, these data raise the possibility that repeated “hits” with low doses of paraquat in combination with aging processes might have promoted compensatory outcomes.

  17. Intestinal morphological effect of brachytherapy of low rate of dose, administrated in therapeutic form and its clinical manifestations in uterine cervix tumors

    Mendoza, Carmen; Contreras, Manuel

    2005-01-01

    Brachytherapy is effective to eradicate cancer in the cervix, in order to obtain the control of disease we use high dose with vesical and rectum toxicity. The objective is to investigate if brachytherapy by itself is the cause of intestinal damage, to know in addition if the intensity of the clinic manifestations is in direct relation to the given radiation dose and this gets worse when it is received in several applications. Hypothesis: The intensity of the radiation with brachytherapy of low rate of dose is proportional to the degree of clinical manifestations and morphologic damage of the intestine. A prospective analysis was made inpatients with cancer of cervix from september 2000 to june 2004. Each patient who enters to the department of brachytherapy of the hospital must be done laboratory examination that includes plaque and coagulation test before being accepted. We use the clinical card and a table in order to register data concerning teletherapy, implants of brachytherapy of low rate of dose, symptoms of intestinal toxicity and details of colonoscopia. Subsequent to the hospitable discharge the patient is sent to gastroenterology for clinical evaluation and to realize colonoscopia. From september 2000 to june 2004, 540 patients entered, 80 patients (15%) displayed intestinal manifestations, all received teletherapy and brachytherapy, nobody else received brachytherapy in exclusive form and only one patient (0.1%) received the total of the dose in 2 applications. The equipment of teletherapy Primus with energy of 6 and 18 Mv and implants of brachytherapy Manchester were used (70/55 patients). 79 (98%) patients received dose between 85-75 Gy in one single application, 58 (72%) received the total of the dose to the tumor, 21 (26%) in vaginal mucosa. Discussion: Brachytherapy is the cause of the damages in the intestinal mucosa. (The author)

  18. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

    Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

    2009-06-01

    The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P open field test.

  19. Intravenous administration of high-dose Paclitaxel reduces gut-associated lymphoid tissue cell number and respiratory immunoglobulin A concentrations in mice.

    Moriya, Tomoyuki; Fukatsu, Kazuhiko; Noguchi, Midori; Okamoto, Koichi; Murakoshi, Satoshi; Saitoh, Daizoh; Miyazaki, Masaru; Hase, Kazuo; Yamamoto, Junji

    2014-02-01

    Chemotherapy remains a mainstay of treatment for cancer patients. However, anti-cancer drugs frequently cause a wide range of side effects, including leukopenia and gastrointestinal toxicity. These adverse effects can lead to treatment delays or necessitate temporary dose reductions. Although chemotherapy-related changes in gut morphology have been demonstrated, the influences of chemotherapeutic regimens on gut immunity are understood poorly. This study aimed to examine whether the anti-cancer drug paclitaxel (PTX) impairs gut immunity in mice. Male ICR mice were randomized into three groups: Control, low-dose PTX (low PTX; 2 mg/kg), or high-dose PTX (high PTX; 4 mg/kg). A single intravenous dose was given. On day seven after the injection, lymphocytes from Peyer patches (PP), intraepithelial (IE) spaces, and the lamina propria (LP) were counted and analyzed by flow cytometry (CD4(+), CD8(+), αβTCR(+), γδTCR(+), B220(+)). Immunoglobulin A (IgA) concentrations were measured in small intestinal and respiratory tract washings. Total, CD4(+) and γδTCR(+) lymphocyte numbers in PPs were significantly lower in the high PTX than in the control group. The CD4(+) lymphocyte numbers in the IE spaces were significantly lower in both PTX groups than in the control group. Respiratory tract IgA concentrations were lower in the high PTX than in the control group. The present data suggest high-dose PTX impairs mucosal immunity, possibly rendering patients more vulnerable to infection. Careful dose selection and new therapies may be important for maintaining mucosal immunity during PTX chemotherapy.

  20. Body fluids, circadian blood pressure and plasma renin during growth hormone administration: a placebo-controlled study with two growth hormone doses in healthy adults

    Møller, Jens; Jørgensen, Jens Otto Lunde; Frandsen, Erik

    1995-01-01

    Abstract Side effects that can be related to fluid retention are common during the initial phases of growth hormone (GH) administration. The aim of this study was to examine the changes in body fluid compartments, diurnal blood pressure and plasma renin concentration during GH administration......-2, 20.65 +/- 0.94; pbody water (l) increased significantly during GH administration (placebo, 50.8 +/- 2.6; 3 IU m-2, 52.6 +/- 2.3; 6 IU m-2, 53.9 +/- 1.8, p... of treatment a significant increase in renin (p = 0.03) was observed. Mean diurnal blood pressure levels remained unchanged, whereas mean diurnal heart rate (min-1) increased significantly (placebo, 75 +/- 3.6; 3 IU m-2, 79 +/- 3.2; 6 IU m-2, 79 +/- 3.7; p

  1. Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir Following Intravenous and Oral Administrations in Rats: A Study Involving In vivo Corneal Uptake of Acyclovir Following Oral Dosing

    Ravi S.Talluri

    2009-10-01

    Full Text Available Objective: To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV in rats. Methods: Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV, L-valine- D-valine-acyclovir (LDACV and D-valine-L-valine acyclovir (DLACV prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results: Following i.v. administration, the area under the curve (AUC in µM*min of generated ACV was in the order of LACV › LDACV › DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 µM*min, respectively. DLACV exhibited poor oral absorption. Cmax (µM and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions: LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV. Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration.

  2. Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir Following Intravenous and Oral Administrations in Rats: A Study Involving In vivo Corneal Uptake of Acyclovir Following Oral Dosing

    Talluri, Ravi S.; Gaudana, Ripal; Hariharan, Sudharshan; Mitra, Ashim K.

    2009-01-01

    Objective To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV) in rats. Methods Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV), L-valine-D-valine-acyclovir (LDACV) and D-valine-L-valine acyclovir (DLACV) prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results Following i.v. administration, the area under the curve (AUC) in μM*min of generated ACV was in the order of LACV > LDACV > DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 μM*min, respectively. DLACV exhibited poor oral absorption. Cmax (μM) and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV. Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration. PMID:23861607

  3. Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir following Intravenous and Oral Administrations in Rats: A study Involving in vivo corneal Uptake of Acyclovir following Oral Dosing

    Ravi S. Talluri

    2009-01-01

    Full Text Available Objective To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV in rats. Methods Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV, L-valine-D-valine-acyclovir (LDACV and D-valine-L-valine acyclovir (DLACV prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results Following i.v. administration, the area under the curve (AUC in μM*min of generated ACV was in the order of LACV > LDACV > DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 μM*min, respectively. DLACV exhibited poor oral absorption. C max (μM and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration.

  4. Pharmacokinetics and dose estimates following intrathecal administration of 131I-monoclonal antibodies for the treatment of central nervous system malignancies

    Papanastassiou, Varnavus; Pizer, Barry L.; Chandler, Christopher L.; Zananiri, Tony F.; Kemshead, John T.; Hopkins, Kirsten I.

    1995-01-01

    Purpose: Treatment of malignant disease in the central nervous system (CNS) with systemic radiolabeled monoclonal antibodies (MoAbs) is compromised by poor penetration into the cerebrospinal fluid (CSF), limited diffusion into solid tumors, and the generation of anti-mouse antibodies. To attempt to avoid these problems we have treated patients with diffuse neoplastic meningitis with radioimmunoconjugates injected directly into the intrathecal space. Methods and Materials: Tumor-specific MoAbs were conjugated to Iodine-131 ( 131 I) (629-3331 MBq) by the Iodogen technique, and administered via an intraventricular reservoir. A clinical response rate of approximately 33% was achieved, with better results in more radiosensitive tumors. Here, we present detailed pharmacodynamic data on patients receiving this intracompartmental targeted therapy. Results: Elimination from the ventricular CSF appeared biphasic, with more rapid clearance occurring in the first 24 h. Radioimmunoconjugate entered the subarachnoid space and subsequently the vascular compartment. From this information, the areas under the effective activity curves for ventricular CSF, blood, and subarachnoid CSF were calculated to permit dosimetry. Critical organ doses were calculated using conventional medical internal radiation dose (MIRD) formalism. Where available, S-values were taken from standard tables. To calculate the doses to CSF, brain, and spinal cord, S-values were evaluated using the models described in the text. Conclusion: A marked advantage could be demonstrated for the dose delivered to tumor cells within the CSF as compared to other neural elements

  5. The relationship between rate of administration of an intubating dose of rocuronium and time to 50% and 90% block at the adductor pollicis muscle

    De Haes, A; Eleveld, DJ; Wierda, JMKH

    2000-01-01

    Objective. To determine the relationship between the rate of rocuronium injection and the onset time of neuromuscular block. Methods.After intravenous induction, 60 female patients (ASA I-II) were assigned randomly into 3 groups for rocuronium administration within 1-15, 15-30 or 30-60 seconds.

  6. Computed tomography in multiple trauma patients. Technical aspects, work flow, and dose reduction; Polytrauma-Computertomographie. Technische Grundlagen, Workflow und Dosisreduktion

    Fellner, F.A. [AKH Linz - Kepler Universitaetsklinikum/JKU, Zentrales Radiologie Institut, Linz (Austria); Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen (Germany); Krieger, J.; Floery, D. [AKH Linz - Kepler Universitaetsklinikum/JKU, Zentrales Radiologie Institut, Linz (Austria); Lechner, N. [AKH Linz - Kepler Universitaetsklinikum/JKU, Abteilung fuer Medizintechnik, Linz (Austria)

    2014-09-15

    Patients with severe, life-threatening trauma require a fast and accurate clinical and imaging diagnostic workup during the first phase of trauma management. Early whole-body computed tomography has clearly been proven to be the current standard of care of these patients. A similar imaging quality can be achieved in the multiple trauma setting compared with routine imaging especially using rapid, latest generation computed tomography (CT) scanners. This article encompasses a detailed view on the use of CT in patients with life-threatening trauma. A special focus is placed on radiological procedures in trauma units and on the methods for CT workup in routine cases and in challenging situations. Another focus discusses the potential of dose reduction of CT scans in multiple trauma as well as the examination of children with severe trauma. Various studies have demonstrated that early whole-body CT positively correlates with low morbidity and mortality and is clearly superior to the use of other imaging modalities. Optimal trauma unit management means a close cooperation between trauma surgeons, anesthesiologists and radiologists, whereby the radiologist is responsible for a rapid and accurate radiological workup and the rapid communication of imaging findings. However, even in the trauma setting, aspects of patient radiation doses should be kept in mind. (orig.) [German] Polytraumatisierte Patienten beduerfen im Rahmen der initialen Schockraumversorgung einer schnellen und exakten klinischen und bildgebenden Diagnostik. Fuer ein optimales Schockraummanagement ist heute die essenzielle Bedeutung einer zeitnah durchgefuehrten Ganzkoerper-CT unbestritten. Insbesondere durch schnelle CT-Scanner der letzten Generationen kann im Rahmen der Schockraum-CT eine aehnlich gute Bildqualitaet wie in der Routinediagnostik erzielt werden. Dieser Artikel beleuchtet den Einsatz der CT im Schockraum bei polytraumatisierten Patienten, wobei das Hauptaugenmerk auf Methoden des

  7. A phase 1, open-label, randomized study to compare the immunogenicity and safety of different administration routes and doses of virosomal influenza vaccine in elderly.

    Levin, Yotam; Kochba, Efrat; Shukarev, Georgi; Rusch, Sarah; Herrera-Taracena, Guillermo; van Damme, Pierre

    2016-10-17

    Influenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity. A total of 370 healthy participants (⩾65years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60-63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45μg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months. Intradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45μg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%). Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45μg) virosomal vaccine did not demonstrate any benefit on vaccine's immunogenicity over 15μg commercial presentation. All treatments were generally safe and well-tolerated. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Planning magnetic resonance imaging for prostate cancer intensity-modulated radiation therapy: Impact on target volumes, radiotherapy dose and androgen deprivation administration.

    Horsley, Patrick J; Aherne, Noel J; Edwards, Grace V; Benjamin, Linus C; Wilcox, Shea W; McLachlan, Craig S; Assareh, Hassan; Welshman, Richard; McKay, Michael J; Shakespeare, Thomas P

    2015-03-01

    Magnetic resonance imaging (MRI) scans are increasingly utilized for radiotherapy planning to contour the primary tumors of patients undergoing intensity-modulated radiation therapy (IMRT). These scans may also demonstrate cancer extent and may affect the treatment plan. We assessed the impact of planning MRI detection of extracapsular extension, seminal vesicle invasion, or adjacent organ invasion on the staging, target volume delineation, doses, and hormonal therapy of patients with prostate cancer undergoing IMRT. The records of 509 consecutive patients with planning MRI scans being treated with IMRT for prostate cancer between January 2010 and July 2012 were retrospectively reviewed. Tumor staging and treatment plans before and after MRI were compared. Of the 509 patients, 103 (20%) were upstaged and 44 (9%) were migrated to a higher risk category as a result of findings at MRI. In 94 of 509 patients (18%), the MRI findings altered management. Ninety-four of 509 patients (18%) had a change to their clinical target volume (CTV) or treatment technique, and in 41 of 509 patients (8%) the duration of hormone therapy was changed because of MRI findings. The use of radiotherapy planning MRI altered CTV design, dose and/or duration of androgen deprivation in 18% of patients in this large, single institution series of men planned for dose-escalated prostate IMRT. This has substantial implications for radiotherapy target volumes and doses, as well as duration of androgen deprivation. Further research is required to investigate whether newer MRI techniques can simultaneously fulfill staging and radiotherapy contouring roles. © 2014 Wiley Publishing Asia Pty Ltd.

  9. Safety and PK/PD correlation of TV-1106, a recombinant fused human albumin-growth hormone, following repeat dose administration to monkeys.

    Ashkenazi, Nurit; Rosenstock, Moti; Hallak, Hussein; Bassan, Merav; Rasamoelisolo, Michele; Leuschner, Jost; Shinar, Doron

    TV-1106 is a recombinant human albumin genetically fused to growth hormone which is intended to reduce the frequency of injections for GH therapy users. We report the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated subcutaneous injections of TV-1106 in Cynomolgus monkeys. Cynomolgus monkeys received four weekly subcutaneous injections of 0, 5, 10 or 20mg/kg TV-1106 and were monitored for safety signals throughout the study. Serum levels of TV-1106 and insulin-like growth factor 1 (IGF-1) were assayed. Treated animals showed no adverse effects or histopathological changes. TV-1106 serum concentrations showed sustained exposure to the drug. Exposure increased in a dose-dependent manner with peak concentrations at approximately 24h post-dosing and elimination half-lives in the range of 12 to 24h. IGF-1 serum concentrations were elevated throughout the entire study duration, indicative of the pharmacological response. There was a clear correlation between change in IGF-1 levels and dose or exposure to TV-1106. The safety, pharmacokinetic and pharmacodynamic findings support the further development of TV-1106 as a once-weekly administered treatment for patients with GHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Internal dose assessment in nuclear medicine: fetal doses due to radiopharmaceutical administration to the mother; Dosimetria interna en medicina nuclear: dosis absorbida en el feto por la administracion de radiofarmacos a la madre

    Rojo, Ana M; Michelin, Severino C

    2004-07-01

    The objective of this publication is to present a guideline for the dose assessment through a comprehensive introduction of knowledge on ionizing radiation, radiation protection during pregnancy and fetal dosimetry for physician and other professionals involved in nuclear medicine practices. It contains tables with recommended dose estimates at all stages of pregnancy for many radiopharmaceuticals. Compounds for which some information was available regarding placental crossover are shown in shaded rows. It includes the most common diagnostic and therapy practices in nuclear medicine considering the four radioactive isotopes selected: {sup 99m}Tc, {sup 131}I, {sup 201}Tl and {sup 67}Ga. There is a special case included, it is when conception occurs after the iodine has been administered. In almost every case, the diagnostic benefit to the mother outweighs the risk of any irradiation of the fetus. However, there is one situation in which severe fetal injury can be incurred from administering a radiopharmaceutical to the mother, and that is use of iodine-131 therapy for ablation of the thyroid in cases of hyperthyroidism or carcinoma. Radioactive iodine readily crosses the placenta and concentrates in the fetal thyroid, where, because of its small organ mass, high radiation doses are received. (author)

  11. Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults

    Laursen, Torben; Jørgensen, Jens Otto Lunde; Møller, Jens

    1994-01-01

    . CONCLUSIONS: GH administration stimulated peripheral T4 to T3 conversion in a dose-dependent manner. Serum T3 levels were subnormal despite T4 substitution when the patients were off GH but normalized with GH therapy. Energy expenditure increased with GH and correlated with free T3 levels. GH caused......Abstract OBJECTIVE: The impact of exogenous GH on thyroid function remains controversial although most data add support to a stimulation of peripheral T4 to T3 conversion. For further elucidation we evaluated iodothyronine and circadian TSH levels in GH-deficient patients as part of a GH dose...... without GH, whereas GH therapy significantly suppressed the TSH levels and blunted the circadian rhythm (mean TSH levels (mU/l) 0.546 +/- 0.246 (no GH) vs 0.066 +/- 0.031 (2 IU GH) (P

  12. Long term administration of low doses of mycotoxins in poultry. 2. Residues of ochratoxin A and aflatoxins in broilers and laying hens after combined administration of ochratoxin A and aflatoxin B1.

    Micco, C; Miraglia, M; Benelli, L; Onori, R; Ioppolo, A; Mantovani, A

    1988-01-01

    The effects of combined administration of ochratoxin A (OA) and aflatoxin B1 (AFB1) on the occurrence and the levels of residues of mycotoxins in poultry have been investigated. Male broilers and laying hens were fed from 14 days old with standard diets contaminated with 50 micrograms/kg OA and 50 micrograms/kg AFB1. Two groups of broilers and hens were withdrawn from contaminated feed at 37 and 88 days, respectively. At the time of sacrifice no significant lesions were found. Residues were compared with those found after administration of either toxin alone in former trials. Combined treatment resulted in higher content of OA in broiler livers (40 versus 5.0 micrograms/kg) and, to a lesser extent, in kidneys and skin, and of AFB1 in broiler liver and kidney (0.15 versus 0.02 microgram/kg and 0.40 versus 0.05 microgram/kg respectively). Laying hens showed smaller differences (0.20 versus 0.10 microgram/kg in liver and 0.32 versus 0.08 in kidneys). Withdrawal from treatment led to the almost complete disappearance of OA residues in broilers and in hens. These results show a synergistic effect of OA and AFB1, particularly in broilers.

  13. Inter-observer agreement for the evaluation of bone involvement on Whole Body Low Dose Computed Tomography (WBLDCT) in Multiple Myeloma (MM)

    Zacchino, M.; Minetti, V.; Dore, R.; Calliada, F.; Bonaffini, P.A.; Nasatti, A.; Sironi, S.; Corso, A.; Tinelli, C.

    2015-01-01

    We aimed to assess inter-observer agreement in bone involvement evaluation and define accuracy and reproducibility of MDCT images analysis in Multiple Myeloma (MM), by comparing two acquisition protocols at two different institutions. A total of 100 MM patients underwent whole body low-dose computed tomography (WB-LDCT), with two protocols: Group I (50 patients), 80 kV and 200-230 mAs; Group II, 120 kV-40 mAs. Four readers (two experts) retrospectively reviewed 22 anatomical districts, reporting the following for each patient: 1) osteolytic lesions; 2) cortical bone integrity; 3) fractures; 4) risk of vertebral collapse; 5) hyperattenuating bone lesions; and 6) extraosseous extension. Inter-observer agreement (by all readers, expert and young observers and comparison of the two protocols) was then statistically analyzed. According to Cohen's criteria, inter-observer agreement among the four readers and between experts and residents was good for the detection of bone lesions and extra-medullary extension, and for the evaluation of risk of collapse and cortical integrity. There was good agreement when comparing the two protocols. A greater variability was found for the evaluation of hyperattenuating lesions and the presence of fractures. WB-LDCT represents a reproducible and reliable technique that is helpful for defining bone disease in MM patients, with partial influence of readers' experience. (orig.)

  14. Inter-observer agreement for the evaluation of bone involvement on Whole Body Low Dose Computed Tomography (WBLDCT) in Multiple Myeloma (MM)

    Zacchino, M.; Minetti, V.; Dore, R.; Calliada, F. [University of Pavia, Fondazione IRCCS Policlinico San Matteo, Institute of Radiology, Pavia (Italy); Bonaffini, P.A.; Nasatti, A.; Sironi, S. [University of Milano Bicocca, San Gerardo Hospital, Department of Diagnostic Radiology, Monza (Italy); Corso, A. [University of Pavia, Fondazione IRCCS Policlinico San Matteo, Division of Hematology, Pavia (Italy); Tinelli, C. [University of Pavia, Fondazione IRCCS Policlinico San Matteo, Service of Biometry and Statistics, Pavia (Italy)

    2015-11-15

    We aimed to assess inter-observer agreement in bone involvement evaluation and define accuracy and reproducibility of MDCT images analysis in Multiple Myeloma (MM), by comparing two acquisition protocols at two different institutions. A total of 100 MM patients underwent whole body low-dose computed tomography (WB-LDCT), with two protocols: Group I (50 patients), 80 kV and 200-230 mAs; Group II, 120 kV-40 mAs. Four readers (two experts) retrospectively reviewed 22 anatomical districts, reporting the following for each patient: 1) osteolytic lesions; 2) cortical bone integrity; 3) fractures; 4) risk of vertebral collapse; 5) hyperattenuating bone lesions; and 6) extraosseous extension. Inter-observer agreement (by all readers, expert and young observers and comparison of the two protocols) was then statistically analyzed. According to Cohen's criteria, inter-observer agreement among the four readers and between experts and residents was good for the detection of bone lesions and extra-medullary extension, and for the evaluation of risk of collapse and cortical integrity. There was good agreement when comparing the two protocols. A greater variability was found for the evaluation of hyperattenuating lesions and the presence of fractures. WB-LDCT represents a reproducible and reliable technique that is helpful for defining bone disease in MM patients, with partial influence of readers' experience. (orig.)

  15. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.

    Tourbah, Ayman; Lebrun-Frenay, Christine; Edan, Gilles; Clanet, Michel; Papeix, Caroline; Vukusic, Sandra; De Sèze, Jerome; Debouverie, Marc; Gout, Olivier; Clavelou, Pierre; Defer, Gilles; Laplaud, David-Axel; Moreau, Thibault; Labauge, Pierre; Brochet, Bruno; Sedel, Frédéric; Pelletier, Jean

    2016-11-01

    Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated. © The Author(s), 2016.

  16. Pharmacodynamic effects of steady-state fingolimod on antibody response in healthy volunteers: a 4-week, randomized, placebo-controlled, parallel-group, multiple-dose study.

    Boulton, Craig; Meiser, Karin; David, Olivier J; Schmouder, Robert

    2012-12-01

    Fingolimod, a first-in-class oral sphingosine 1-phosphate receptor (S1PR) modulator, is approved in many countries for relapsing-remitting multiple sclerosis, at a once-daily 0.5-mg dose. A reduction in peripheral lymphocyte count is an expected consequence of the fingolimod mechanism of S1PR modulation. The authors investigated if this pharmacodynamic effect impacts humoral and cellular immunogenicity. In this double-blind, parallel-group, 4-week study, 72 healthy volunteers were randomized to steady state, fingolimod 0.5 mg, 1.25 mg, or to placebo. The authors compared T-cell dependent and independent responses to the neoantigens, keyhole limpet hemocyanin (KLH), and pneumococcal polysaccharides vaccine (PPV-23), respectively, and additionally recall antigen response (tetanus toxoid [TT]) and delayed-type hypersensitivity (DTH) to KLH, TT, and Candida albicans. Fingolimod caused mild to moderate decreases in anti-KLH and anti-PPV-23 IgG and IgM levels versus placebo. Responder rates were identical between placebo and 0.5-mg groups for anti-KLH IgG (both > 90%) and comparable for anti-PPV-23 IgG (55% and 41%, respectively). Fingolimod did not affect anti-TT immunogenicity, and DTH response did not differ between placebo and fingolimod 0.5-mg groups. Expectedly, lymphocyte count reduced substantially in the fingolimod groups versus placebo but reversed by study end. Fingolimod was well tolerated, and the observed s