Tolerance of young infants to a single, large dose of vitamin A: a randomized community trial in Nepal.

PubMed

West, K P; Khatry, S K; LeClerq, S C; Adhikari, R; See, L; Katz, J; Shrestha, S R; Pradhan, E K; Pokhrel, R P; Sommer, A

1992-01-01

A randomized, double-masked trial was carried out in rural Nepal to investigate the incidence and severity of acute side-effects among neonates ( < 1 month of age) and infants aged 1-6 months who received a large, oral dose of vitamin A (15,000 retinol equivalents (RE) (50,000 IU) and 30,000 RE (100,000 IU), respectively) or placebo (75 RE (250 IU) and 150 RE (500 IU), respectively) in oil. Infants (vitamin A group, n = 1461; controls, n = 1379) were assessed for vomiting, loose stools, fever, and irritability during the 24 hours before and after dosing. Fontanelles were palpated 24 hours after dosing. Neonates exhibited no excess risk of adverse side-effects after receiving 15,000 RE. Compared with controls the older infants who ingested 30,000 RE had a 1.6% excess rate of vomiting (95% confidence interval (CI): 0.2-3.0%) and a 0.5% excess rate (95% CI: -0.1 to 1.1%) in the occurrence of bulging fontanelles. There were no other significant differences in the older infants. The controlled, periodic distribution of a single 15,000 RE dose of vitamin A therefore confers no apparent acute risk to young infants; a 30,000 RE dose is associated with a minimum risk of transient, acute side-effects.

Local Hypothermia as a Radioprotector of the Rectal Wall During Prostate Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hrycushko, Brian A., E-mail: Brian.Hrycushko@utsouthwestern.edu; Chopra, Rajiv; Sayre, James W.

Purpose: To compare the single-fraction dose-related incidence of rectal obstruction and/or bleeding in normothermic and hypothermic rectums of a rat model. Methods and Materials: A 1.9-cm length of rectum was irradiated with a single fraction in 57 Sprague-Dawley rats using a dedicated image-guided small animal irradiator and Monte Carlo–based treatment planning system. All rats had a rectal temperature control apparatus placed during irradiation and were stratified to achieve either a normothermic (37°C) or hypothermic (15°C) rectal wall temperature. Radiation was delivered to a 1-cm-diameter cylindrical volume about the cooling device and rectal wall. The radiation dose was escalated from 16 Gy upmore » to 37 Gy to assess the dose response in each arm. The primary endpoint of this study was rectal obstruction and/or bleeding during a follow-up of 180 to 186 days. Histologic scoring was performed on all study rats. Results: Probit analysis showed a dose associated with a 50% incidence of rectal obstruction of 24.6 Gy and 40.8 Gy for normothermic and hypothermic arms, respectively. The occurrence of obstruction and/or bleeding correlated with the posttreatment histologic score for normothermic rats; however, there was no difference in histologic score between normothermic and hypothermic rats at the highest dose levels evaluated. Conclusions: A significant radioprotective effect was observed using local hypothermia during a single large dose of radiation for the functional endpoint of rectal obstruction and/or bleeding. A confirmatory study in a large animal model with anatomic and physiologic similarities to humans is suggested.« less

Gastrophysa polygoni herbivory on Rumex confertus: Single leaf VOC induction and dose dependent herbivore attraction/repellence to individual compounds

USDA-ARS?s Scientific Manuscript database

We report large induction (> 65fold increases) of volatile organic compounds (VOCs) emitted from a single leaf of the invasive weed mossy sorrel, Rumex confertus Willd. (Polygonaceae), by herbivory of the dock leaf beetle, Gastrophysa polygoni L. (Coleoptera: Chrysomelidae). The R. confertus VOC ble...

SU-F-T-02: Estimation of Radiobiological Doses (BED and EQD2) of Single Fraction Electronic Brachytherapy That Equivalent to I-125 Eye Plaque: By Using Linear-Quadratic and Universal Survival Curve Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Y; Waldron, T; Pennington, E

Purpose: To test the radiobiological impact of hypofractionated choroidal melanoma brachytherapy, we calculated single fraction equivalent doses (SFED) of the tumor that equivalent to 85 Gy of I125-BT for 20 patients. Corresponding organs-at-risks (OARs) doses were estimated. Methods: Twenty patients treated with I125-BT were retrospectively examined. The tumor SFED values were calculated from tumor BED using a conventional linear-quadratic (L-Q) model and an universal survival curve (USC). The opposite retina (α/β = 2.58), macula (2.58), optic disc (1.75), and lens (1.2) were examined. The % doses of OARs over tumor doses were assumed to be the same as for amore » single fraction delivery. The OAR SFED values were converted into BED and equivalent dose in 2 Gy fraction (EQD2) by using both L-Q and USC models, then compared to I125-BT. Results: The USC-based BED and EQD2 doses of the macula, optic disc, and the lens were on average 118 ± 46% (p < 0.0527), 126 ± 43% (p < 0.0354), and 112 ± 32% (p < 0.0265) higher than those of I125-BT, respectively. The BED and EQD2 doses of the opposite retina were 52 ± 9% lower than I125-BT. The tumor SFED values were 25.2 ± 3.3 Gy and 29.1 ± 2.5 Gy when using USC and LQ models which can be delivered within 1 hour. All BED and EQD2 values using L-Q model were significantly larger when compared to the USC model (p < 0.0274) due to its large single fraction size (> 14 Gy). Conclusion: The estimated single fraction doses were feasible to be delivered within 1 hour using a high dose rate source such as electronic brachytherapy (eBT). However, the estimated OAR doses using eBT were 112 ∼ 118% higher than when using the I125-BT technique. Continued exploration of alternative dose rate or fractionation schedules should be followed.« less

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

NASA Astrophysics Data System (ADS)

Şahiner, Eren; Meriç, Niyazi; Polymeris, George S.

2017-02-01

Equivalent dose estimation (De) 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 De 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 De 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 De 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 interesting that most of De values yielded using different luminescence signals agree with each other and ESR Ge center has very large D0 values. The results presented above highly support the argument that the stability and the initial ESR signal of the Ge center is highly sample-dependent, without any instability problems for the cases of quartz resulting from fault gouge.

21 CFR 520.2044 - Pyrantel pamoate paste.

Code of Federal Regulations, 2010 CFR

2010-04-01

... control of infections from the following mature parasites: large strongyles (Strongylus vulgaris, S...). (ii) 6 mg/lb body weight as single oral dose for the removal and control of mature infections of...

21 CFR 520.2044 - Pyrantel pamoate paste.

Code of Federal Regulations, 2012 CFR

2012-04-01

... control of infections from the following mature parasites: large strongyles (Strongylus vulgaris, S...). (ii) 6 mg/lb body weight as single oral dose for the removal and control of mature infections of...

21 CFR 520.2044 - Pyrantel pamoate paste.

Code of Federal Regulations, 2014 CFR

2014-04-01

... control of infections from the following mature parasites: large strongyles (Strongylus vulgaris, S...). (ii) 6 mg/lb body weight as single oral dose for the removal and control of mature infections of...

21 CFR 520.2044 - Pyrantel pamoate paste.

Code of Federal Regulations, 2011 CFR

2011-04-01

... control of infections from the following mature parasites: large strongyles (Strongylus vulgaris, S...). (ii) 6 mg/lb body weight as single oral dose for the removal and control of mature infections of...

21 CFR 520.2044 - Pyrantel pamoate paste.

Code of Federal Regulations, 2013 CFR

2013-04-01

... control of infections from the following mature parasites: large strongyles (Strongylus vulgaris, S...). (ii) 6 mg/lb body weight as single oral dose for the removal and control of mature infections of...

Effect of Temporal Pattern of Radiation in Intensity Modulated Radiotherapy on Cell Cycle Progression and Apoptosis of ACHN Renal Cell Carcinoma Cell Line.

PubMed

Khorramizadeh, Maryam; Saberi, Alihossein; Tahmasebi-Birgani, Mohammadjavad; Shokrani, Parvaneh; Amouhedari, Alireza

The existence of a hypersensitive radiation response to doses below 1 Gy is well established for many normal and tumor cell lines. The aim of this study was to ascertain the impact of temporal pattern modeling IMRT on survival, cell cycle and apoptosis of human RCC cell line ACHN, so as to provide radiobiological basis for optimizing IMRT plans for this disease. The ACHN renal cell carcinoma cell line was used in this study. Impact of the triangle, V, small-large or large-small temporal patterns in the presence and absence of threshold dose of hyper-radiosensitivity at the beginning of patterns were studied using soft agarclonogenic assays. Cell cycle and apoptosis analysis were performed after irradiation with the temporal patterns. For triangle and small-large dose sequences, survival fraction was significantly reduced after irradiation with or without threshold dose of hyper-radiosensitivity at the beginning of the patterns. In all of the dose patterns, cell cycle distributions and the percentage of apoptotic cells at 24 h after irradiation with or without priming dose of hyper-radiosensitivity showed no significant difference. However, apoptotic cells were increased when beams with the smallest dose applied at the beginning of dose pattern like triangle and small-large dose sequence. These data show that the biologic effects of single fraction may differ in clinical settings depending on the size and sequence of the partial fractions. Doses at the beginning but not at the end of sequences may change cytotoxicity effects of radiation.

Ovarian Cancer

MedlinePlus

... term use and in large doses. Age when menstruation started and ended. Beginning menstruation at an early age or starting menopause at ... Advertising and sponsorship opportunities Reprint Permissions A single copy of these materials may be reprinted for noncommercial ...

Inhibition of nocturnal acidity is important but not essential for duodenal ulcer healing.

PubMed Central

Bianchi Porro, G; Parente, F; Sangaletti, O

1990-01-01

We have determined the relative importance of day and night time gastric acid inhibition for duodenal ulcer healing by comparing the anti-ulcer efficacy of a single morning with that of a single bedtime dose of ranitidine. One hundred and thirty patients with active duodenal ulcer were randomly assigned to a double-blind therapy with ranitidine 300 mg at 8 am or the same dose at 10 pm for up to eight weeks. The antisecretory effects of these regimens were also assessed by 24 h intragastric pH monitoring in 18 of these patients. At four weeks ulcers had healed in 41/61 (67%) of patients taking the morning dose and in 47/63 (75%) of those receiving the nocturnal dose (95% CI for the difference -0.09 +0.25; p ns). At eight weeks, the corresponding healing rates were 82% and 85.5%, respectively (95% CI for the difference -0.11 +0.17; p ns). Both treatments were significantly superior to placebo in raising 24 h intragastric pH, although the effects of the morning dose were of shorter duration than those of the nocturnal dose. These findings suggest that suppression of nocturnal acidity is important but not essential to promote healing of duodenal ulcers; a prolonged period of acid inhibition during the day (as obtained with a single large morning dose of H2-blockers) may be equally effective. PMID:2186980

The evolution of anti-ulcer therapy with cimetidine. Is a single large nocturnal dose of cimetidine the right therapy for duodenal ulcer?

PubMed

Barbara, L; Corinaldesi, B; Stanghellini, V; Paternicò, A; Fabbri, L; Sacco, T

1986-01-01

Peptic ulcer results from the prevalence of agents causing endoluminal lesions over the defence mechanisms of the mucosa of the upper GI tract. Particularly, in the case of duodenal ulcer, the pathogenetic relevance of non-buffered acid secretion of the early nighttime period has been emphasized. This is indeed confirmed by the fact that a single night dose of 800 mg cimetidine has apparently been proved able--in numerous controlled clinical trials--to provide results that are similar to those obtained with the classic dose of 1 g daily or 400 mg twice daily. Our centre carried out a crossover double-blind controlled trial aimed at evaluating titrable acidity and pH during the 24-h period in seven patients with active duodenal ulcer. The single nighttime dose of cimetidine resulted in a significant and long-lasting inhibition of acid secretion during the entire night. During the day, secretory values returned to levels similar to those obtained with placebo, hence allowing normal digestive functions.

SU-E-T-393: Evaluation of Large Field IMRT Versus RapidArc Planning for Carcinoma Cervix with Para-Aotic Node Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raman, S Kothanda; Girigesh, Y; MISHRA, M

Purpose: The objective of this work is to evaluate and compare Large field IMRT and RapidArc planning for Carcinoma Cervix and Para-aotic node irradiation. Methods: In this study, ten patients of Cervix with para-aotic node have been selected with PTV length 35+2cm. All plans were generated in Eclipse TPS V10.0 with Dynamic IMRT and RapidArc technique using 6MV photon energy. In IMRT planning, 7 fields were chosen to get optimal plan and in RapidArc, double Full arc clockwise and counter clockwise were used for planning. All the plans were generated with single isocenter and calculated using AAA dose algorithm. Formore » all the cases the prescribed dose to PTV was same and the plan acceptance criteria is; 95% of the PTV volume should receive 100% prescribed dose. The tolerance doses for the OAR’s is also taken in to account. The evaluation criteria used for analysis are; 1) Homogeneity Index, 2) Conformity Index, 3) Mean Dose to OAR’s, 4)Total monitor units delivered. Results: DVH analysis were performed for both IMRT and RapidArc planning. In both the plans, 95% of PTV volume receives prescribed dose and maximum dose are less than 107%. The conformity index are same in both the techniques. The mean Homogeneity index are 1.036 and 1.053 for IMRT and RapidArc plan. The mean (mean + SD) dose of bladder and rectum in IMRT is 44.2+1.55, 42.05+2.52 and RapidArc is 46.66+1.6, 44.2+2.75 respectively. There is no significant difference found in Right Femoral head, Left Femoral head and Kidney doses. It is found that total MU’s are more in IMRT compared with RapidArc planning. Conclusion: In the case of cervix with Para-arotic node single isocenter irradiation, IMRT planning in large-field is better compared to RapidArc planning in terms of Homogeneity Index and mean dose of Bladder and Rectum.« less

Anterior segment sparing to reduce charged particle radiotherapy complications in uveal melanoma

NASA Technical Reports Server (NTRS)

Daftari, I. K.; Char, D. H.; Verhey, L. J.; Castro, J. R.; Petti, P. L.; Meecham, W. J.; Kroll, S.; Blakely, E. A.; Chatterjee, A. (Principal Investigator)

1997-01-01

PURPOSE: The purpose of this investigation is to delineate the risk factors in the development of neovascular glaucoma (NVG) after helium-ion irradiation of uveal melanoma patients and to propose treatment technique that may reduce this risk. METHODS AND MATERIALS: 347 uveal melanoma patients were treated with helium-ions using a single-port treatment technique. Using univariate and multivariate statistics, the NVG complication rate was analyzed according to the percent of anterior chamber in the radiation field, tumor size, tumor location, sex, age, dose, and other risk factors. Several University of California San Francisco-Lawrence Berkeley National Laboratory (LBNL) patients in each size category (medium, large, and extralarge) were retrospectively replanned using two ports instead of a single port. By using appropriate polar and azimuthal gaze angles or by treating patients with two ports, the maximum dose to the anterior segment of the eye can often be reduced. Although a larger volume of anterior chamber may receive a lower dose by using two ports than a single port treatment. We hypothesize that this could reduce the level of complications that result from the irradiation of the anterior chamber of the eye. Dose-volume histograms were calculated for the lens, and compared for the single and two-port techniques. RESULTS: NVG developed in 121 (35%) patients. The risk of NVG peaked between 1 and 2.5 years posttreatment. By univariate and multivariate analysis, the percent of lens in the field was strongly correlated with the development of NVG. Other contributing factors were tumor height, history of diabetes, and vitreous hemorrhage. Dose-volume histogram analysis of single-port vs. two-port techniques demonstrate that for some patients in the medium and large category tumor groups, a significant decrease in dose to the structures in the anterior segment of the eye could have been achieved with the use of two ports. CONCLUSION: The development of NVG after helium-ion irradiation is correlated to the amount of lens, anterior chamber in the treatment field, tumor height, proximity to the fovea, history of diabetes, and the development of vitreous hemorrhage. Although the influence of the higher LET deposition of helium-ions is unclear, this study suggests that by reducing the dose to the anterior segment of the eye may reduce the NVG complications. Based on this retrospective analysis of LBNL patients, we have implemented techniques to reduce the amount of the anterior segment receiving a high dose in our new series of patients treated with protons using the cyclotron at the UC Davis Crocker Nuclear Laboratory (CNL).

A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-04-01

To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, when administered to healthy male subjects. Twelve subjects took part in this fed-fasted cross-over study and received a single dose of THC/CBD spray (4 sprays = 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time-points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC). Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80-14.91 ng/ml) and lower in 5 subjects (2.81-3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97-9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0-t), AUC(0-inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2-2.5 h. Only mild adverse events were reported. The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.

Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups.

PubMed

Limdi, Nita A; Wadelius, Mia; Cavallari, Larisa; Eriksson, Niclas; Crawford, Dana C; Lee, Ming-Ta M; Chen, Chien-Hsiun; Motsinger-Reif, Alison; Sagreiya, Hersh; Liu, Nianjun; Wu, Alan H B; Gage, Brian F; Jorgensen, Andrea; Pirmohamed, Munir; Shin, Jae-Gook; Suarez-Kurtz, Guilherme; Kimmel, Stephen E; Johnson, Julie A; Klein, Teri E; Wagner, Michael J

2010-05-06

Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 -1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 -1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 -1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the -1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Besemer, A; Marsh, I; Bednarz, B

Purpose: The calculation of 3D internal dose calculations in targeted radionuclide therapy requires the acquisition and temporal coregistration of a serial PET/CT or SPECT/CT images. This work investigates the dosimetric impact of different temporal coregistration methods commonly used for 3D internal dosimetry. Methods: PET/CT images of four mice were acquired at 1, 24, 48, 72, 96, 144 hrs post-injection of {sup 124}I-CLR1404. The therapeutic {sup 131}I-CLR1404 absorbed dose rate (ADR) was calculated at each time point using a Geant4-based MC dosimetry platform using three temporal image coregistration Methods: (1) no coregistration (NC), whole body sequential CT-CT affine coregistration (WBAC), andmore » individual sequential ROI-ROI affine coregistration (IRAC). For NC, only the ROI mean ADR was integrated to obtain ROI mean doses. For WBAC, the CT at each time point was coregistered to a single reference CT. The CT transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the whole CT volume. For IRAC, each individual ROI was isolated and sequentially coregistered to a single reference ROI. The ROI transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the ROI volumes. Results: The percent differences in the ROI mean doses were as large as 109%, 88%, and 32%, comparing the WBAC vs. IRAC, NC vs. IRAC, and NC vs. WBAC methods, respectively. The CoV in the mean dose between the all three methods ranged from 2–36%. The pronounced curvature of the spinal cord was not adequately coregistered using WBAC which resulted in large difference between the WBAC and IRAC. Conclusion: The method used for temporal image coregistration can result in large differences in 3D internal dosimetry calculations. Care must be taken to choose the most appropriate method depending on the imaging conditions, clinical site, and specific application. This work is partially funded by NIH Grant R21 CA198392-01.« less

Evaluation of Timing and Dosing of Caffeine Citrate in Preterm Neonates for the Prevention of Bronchopulmonary Dysplasia.

PubMed

Shenk, Eleni E; Bondi, Deborah S; Pellerite, Matthew M; Sriram, Sudhir

2018-01-01

The aim of this study was to evaluate the timing and dosing of caffeine therapy in relation to the development of bronchopulmonary dysplasia (BPD). This was a single-center, retrospective cohort study comparing early (days of life 0-2) to late (day of life 3 or greater) caffeine initiation in extremely low birth weight neonates, with a secondary analysis of large (10 mg/kg/day) to small dose (5 mg/kg/day) caffeine. There were 138 patients in the primary timing analysis. The early caffeine group had a lower incidence and reduced odds of the composite outcome of BPD or all-cause mortality, compared with the late caffeine group (64% vs. 88%, respectively; adjusted p < 0.05; adjusted OR 0.36 [95% CI 0.13-0.98]). No statistically significant difference was found between dosing groups (p = 0.29) in the primary outcome; however, there was a lower rate of patent ductus arteriosus requiring treatment (p = 0.05) and decreased likelihood of discharging home on oxygen (p = 0.02) in the large-dose group compared with the small-dose group. Early caffeine initiation significantly decreased the incidence of BPD or all-cause mortality in extremely low birth weight neonates. Patients receiving large-dose caffeine had improved secondary outcomes, although no difference in BPD was noted. Further studies are needed to determine the optimal dosing of caffeine.

Multiple anatomy optimization of accumulated dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watkins, W. Tyler, E-mail: watkinswt@virginia.edu; Siebers, Jeffrey V.; Moore, Joseph A.

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 dosemore » 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.« less

Radiation Tests of Single Photon Avalanche Diode for Space Applications

NASA Technical Reports Server (NTRS)

Moscatelli, Francesco; Marisaldi, Martino; MacCagnani, Piera; Labanti, Claudio; Fuschino, Fabio; Prest, Michela; Berra, Alessandro; Bolognini, Davide; Ghioni, Massimo; Rech, Ivan;

Diverse spectrum of tumors in male Sprague-Dawley rats following single high doses of N-ethyl-N-nitrosourea (ENU).

PubMed Central

Stoica, G.; Koestner, A.

1984-01-01

In this study, 30-day-old male Sprague-Dawley rats, were inoculated intraperitoneally with a single dose of 45, 90, and 180 mg/kg of N-ethyl-N-Nitrosourea (ENU). A wide spectrum of neoplasms occurred. The most common tumors were those of the mammary gland and of the nervous system. Although the incidence of mammary tumors was highest in the two high-dose groups (90 and 180 mg/kg ENU), the incidence of neurogenic tumors was highest in the 45 mg/kg dose group. Mammary tumor development led to early death and precluded development of tumors of the nervous system, which require a longer latency period. A variety of neoplasms of other organs have been associated particularly with high doses of ENU, including ameloblastic tumors, carcinomas of the thyroid, prostate, kidney, pancreas, intestine, and lung, hemilymphatic tumors, and sarcomas. It is concluded that large doses of ENU are capable of expanding the tumor spectrum in young male rats beyond the target organs generally affected with lower doses, as described in earlier reports. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:6465287

Spatiotemporal Fractionation Schemes for Irradiating Large Cerebral Arteriovenous Malformations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Unkelbach, Jan, E-mail: junkelbach@mgh.harvard.edu; Bussière, Marc R.; Chapman, Paul H.

2016-07-01

Purpose: To optimally exploit fractionation effects in the context of radiosurgery treatments of large cerebral arteriovenous malformations (AVMs). In current practice, fractionated treatments divide the dose evenly into several fractions, which generally leads to low obliteration rates. In this work, we investigate the potential benefit of delivering distinct dose distributions in different fractions. Methods and Materials: Five patients with large cerebral AVMs were reviewed and replanned for intensity modulated arc therapy delivered with conventional photon beams. Treatment plans allowing for different dose distributions in all fractions were obtained by performing treatment plan optimization based on the cumulative biologically effective dosemore » delivered at the end of treatment. Results: We show that distinct treatment plans can be designed for different fractions, such that high single-fraction doses are delivered to complementary parts of the AVM. All plans create a similar dose bath in the surrounding normal brain and thereby exploit the fractionation effect. This partial hypofractionation in the AVM along with fractionation in normal brain achieves a net improvement of the therapeutic ratio. We show that a biological dose reduction of approximately 10% in the healthy brain can be achieved compared with reference treatment schedules that deliver the same dose distribution in all fractions. Conclusions: Boosting complementary parts of the target volume in different fractions may provide a therapeutic advantage in fractionated radiosurgery treatments of large cerebral AVMs. The strategy allows for a mean dose reduction in normal brain that may be valuable for a patient population with an otherwise normal life expectancy.« less

Single-Dose Versus Fractionated Stereotactic Radiotherapy for Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Yeon-Joo; Cho, Kwan Ho, E-mail: kwancho@ncc.re.kr; Kim, Joo-Young

2011-10-01

Purpose: To evaluate the efficacy of stereotactic radiotherapy in patients with brain metastases by comparing two different treatment regimens, single-dose radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT). Methods and Materials: Between November 2003 and December 2008, 98 patients with brain metastases were included. Fifty-eight patients were treated with SRS, and forty were treated with FSRT. Fractionated stereotactic radiotherapy was used for large lesions or lesions located near critical structures. The median doses were 20 Gy for the SRS group and 36 Gy in 6 fractions for the FSRT group. Results: With a median follow-up period of 7 months, the medianmore » survival was 7 months for all patients, with a median of 6 months for the SRS group and 8 months for the FSRT group (p = 0.89). Local progression-free survival (LPFS) rates at 6 months and 1 year were 81% and 71%, respectively, for the SRS group and 97% and 69%, respectively, for the FSRT group (p = 0.31). Despite the fact that FSRT was used for large lesions and lesions in adverse locations, LPFS was not inferior to SRS. Toxicity was more frequently observed in the SRS group than in the FSRT group (17% vs. 5%, p = 0.05). Conclusions: Because patients treated with FSRT exhibited similar survival times and LPFS rates with a lower risk of toxicity in comparison to those treated with SRS, despite the fact that FSRT was used for large lesions and lesions in adverse locations, we find that FSRT can particularly be beneficial for patients with large lesions or lesions located near critical structures. Further investigation is warranted to determine the optimal dose/fractionation.« less

Is patient size important in dose determination and optimization in cardiology?

NASA Astrophysics Data System (ADS)

Reay, J.; Chapple, C. L.; Kotre, C. J.

2003-12-01

Patient dose determination and optimization have become more topical in recent years with the implementation of the Medical Exposures Directive into national legislation, the Ionising Radiation (Medical Exposure) Regulations. This legislation incorporates a requirement for new equipment to provide a means of displaying a measure of patient exposure and introduces the concept of diagnostic reference levels. It is normally assumed that patient dose is governed largely by patient size; however, in cardiology, where procedures are often very complex, the significance of patient size is less well understood. This study considers over 9000 cardiology procedures, undertaken throughout the north of England, and investigates the relationship between patient size and dose. It uses simple linear regression to calculate both correlation coefficients and significance levels for data sorted by both room and individual clinician for the four most common examinations, left ventrical and/or coronary angiography, single vessel stent insertion and single vessel angioplasty. This paper concludes that the correlation between patient size and dose is weak for the procedures considered. It also illustrates the use of an existing method for removing the effect of patient size from dose survey data. This allows typical doses and, therefore, reference levels to be defined for the purposes of dose optimization.

The intracellular responses of frog eggs to novel orientations to gravity

NASA Technical Reports Server (NTRS)

Radice, G. P.; Neff, A. W.; Malacinski, G. M.

1982-01-01

It is found that multiple short doses of ultraviolet light are as effective as a single large dose in producing neural defects. In addition, 180 deg rotation (inversion) of irradiated eggs reduces the ultraviolet effect. Since yolk platelets may be the gravity sensing mechanism, their size, density, and distribution in normal and inverted eggs are investigated. Large platelets are denser and for the most part are in a distinct zone in the vegetal hemisphere, whereas small platelets are less dense and occur in the animal hemisphere. When inverted, the large platelets flow into the animal hemisphere as a coherent mass and partially displace the small platelets. Inversion is thought to rearrange cytoplasmic components necessary for later neural development into an appropriate configuration.

Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers.

PubMed

Chien, S C; Wong, F A; Fowler, C L; Callery-D'Amico, S V; Williams, R R; Nayak, R; Chow, A T

1998-04-01

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0-24) following a single 750-mg dose were 7.1 microg/ml and 71.3 microg x h/ml, respectively, compared to 8.6 microg/ml and 90.7 microg x h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0-24 values were 8.9 microg/ml and 95.4 microg x h/ml, respectively; corresponding values at steady state were 11.8 microg/ml and 118 microg x h/ml. These Cmax and AUC0-24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CL[R]) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CL(R) following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.

Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers

PubMed Central

Chien, Shu-Chean; Wong, Frank A.; Fowler, Cynthia L.; Callery-D’Amico, Susan V.; Williams, R. Rex; Nayak, Ramchandra; Chow, Andrew T.

1998-01-01

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These Cmax and AUC0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CLR) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CLR following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache. PMID:9559801

Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration of a single dose to American kestrels (Falco sparverius)

USGS Publications Warehouse

Guzman, David Sanchez-Migallon; KuKanich, Butch; Drazenovich, Tracy L.; Olsen, Glenn H.; Paul-Murphy, Joanne R.

2014-01-01

Results indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies regarding the effects of other doses, other administration routes, constantrate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels may be indicated.

Poster - Thur Eve - 52: Clinical use of nanoDots: In-vivo dosimetry and treatment validation for stereotactic targets with VMAT techniques.

PubMed

Wierzbicki, W; Nicol, S; Furstoss, C; Brunet-Benkhoucha, M; Leduc, V

2012-07-01

A newly acquired nanoDot In-Light system was compared with TLD-100 dosimeters to confirm the treatment dose in the multiple cases: an electron eye treatment, H&N IMRT and VMAT validation for small targets. Eye tumour treatment with 9 MeV electrons A dose of 1.8 Gy per fraction was prescribed to the 85% isodose. The average dose measured by three TLDs and three Dots was 1.90 and 1.97 Gy. Both detectors overestimated dose, by 2.9% and 6.7% respectively. H&N IMRT treatment of skin cancer with 6 MV photons Dose per fraction is 2.5 Gy. The average doses measured by two TLDs and two Dots were 2.48 and 2.56 Gy, which represent errors of -0.8% and 2.2%, respectively. VMAT validation for small targets using an Agarose phantom, dose 15 Gy A single-tumour brain treatment was delivered using two coplanar arcs to an Agarise phantom containing a large plastic insert holding 3 nanoDots and 4 TLDs. The difference between the average Pinnacle dose and the average dose of the corresponding detectors was -0.6% for Dots and -1.7% for TLDs. A two-tumour brain treatment was delivered using three non-coplanar arcs. Small and large plastic inserts separated by 5 cm were used to validate the dose. The difference between the average Pinnacle dose and the average dose of the corresponding detectors was the following; small phantom 0.7% for Dots and 0.3% for TLDs, large phantom-1.9% for Dots and -0.6% for TLDs. In conclusion, nanoDot detectors are suitable for in-vivo dosimetry with photon and electron beams. © 2012 American Association of Physicists in Medicine.

Randomized trial of single-dose versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim report.

PubMed

Stevens, R Brian; Mercer, David F; Grant, Wendy J; Freifeld, Alison G; Lane, James T; Groggel, Gerald C; Rigley, Theodore H; Nielsen, Kathleen J; Henning, Megan E; Skorupa, Jill Y; Skorupa, Anna J; Christensen, Kecia A; Sandoz, John P; Kellogg, Anna M; Langnas, Alan N; Wrenshall, Lucile E

2008-05-27

The optimal dosing protocol for rabbit anti-thymocyte globulin (rATG) induction in renal transplantation has not been determined, but evidence exists that rATG infusion before renal allograft reperfusion improves early graft function. Infusing a large rATG dose over a short interval has not previously been evaluated for its effect on renal function and allograft nephropathy in a prospective, randomized comparison against conventional rATG induction. Between April 20, 2004 and December 26, 2007 we enrolled renal transplant patients into a prospective, randomized, nonblinded trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment=160) followed after 6 months by calcineurin-inhibitor withdrawal. Primary endpoints are renal function by calculated glomerular filtration rate (GFR) and chronic allograft nephropathy at protocol biopsy. We now present the early GFR data of all 160 patients and safety and efficacy data of the first 142 patients with 6 months follow up and before calcineurin inhibitor withdrawal (average follow up=23.3+/-11.6 months). There were no differences between groups in rATG-related adverse events, patient and graft survival, acute rejection, or chronic allograft nephropathy rate at 6 months. Calculated DeltaGFR (POD 1-4) was significantly better in the single-dose group (P=0.02), with a trend toward improved renal function from months 2 to 6 in recipients of deceased donor kidneys (P=0.08). This study demonstrates that administering 6 mg/kg of rATG over 24 hr is safe and is associated with improved early renal function compared with administering rATG in alternate-day doses.

Shot sequencing based on biological equivalent dose considerations for multiple isocenter Gamma Knife radiosurgery.

PubMed

Ma, Lijun; Lee, Letitia; Barani, Igor; Hwang, Andrew; Fogh, Shannon; Nakamura, Jean; McDermott, Michael; Sneed, Penny; Larson, David A; Sahgal, Arjun

2011-11-21

Rapid delivery of multiple shots or isocenters is one of the hallmarks of Gamma Knife radiosurgery. In this study, we investigated whether the temporal order of shots delivered with Gamma Knife Perfexion would significantly influence the biological equivalent dose for complex multi-isocenter treatments. Twenty single-target cases were selected for analysis. For each case, 3D dose matrices of individual shots were extracted and single-fraction equivalent uniform dose (sEUD) values were determined for all possible shot delivery sequences, corresponding to different patterns of temporal dose delivery within the target. We found significant variations in the sEUD values among these sequences exceeding 15% for certain cases. However, the sequences for the actual treatment delivery were found to agree (<3%) and to correlate (R² = 0.98) excellently with the sequences yielding the maximum sEUD values for all studied cases. This result is applicable for both fast and slow growing tumors with α/β values of 2 to 20 according to the linear-quadratic model. In conclusion, despite large potential variations in different shot sequences for multi-isocenter Gamma Knife treatments, current clinical delivery sequences exhibited consistent biological target dosing that approached that maximally achievable for all studied cases.

Process Performance of Optima XEx Single Wafer High Energy Implanter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, J. H.; Yoon, Jongyoon; Kondratenko, S.

2011-01-07

To meet the process requirements for well formation in future CMOS memory production, high energy implanters require more robust angle, dose, and energy control while maintaining high productivity. The Optima XEx high energy implanter meets these requirements by integrating a traditional LINAC beamline with a robust single wafer handling system. To achieve beam angle control, Optima XEx can control both the horizontal and vertical beam angles to within 0.1 degrees using advanced beam angle measurement and correction. Accurate energy calibration and energy trim functions accelerate process matching by eliminating energy calibration errors. The large volume process chamber and UDC (upstreammore » dose control) using faraday cups outside of the process chamber precisely control implant dose regardless of any chamber pressure increase due to PR (photoresist) outgassing. An optimized RF LINAC accelerator improves reliability and enables singly charged phosphorus and boron energies up to 1200 keV and 1500 keV respectively with higher beam currents. A new single wafer endstation combined with increased beam performance leads to overall increased productivity. We report on the advanced performance of Optima XEx observed during tool installation and volume production at an advanced memory fab.« less

Single dose pharmacokinetics of fenspiride hydrochloride: phase I clinical trial.

PubMed

Montes, B; Catalan, M; Roces, A; Jeanniot, J P; Honorato, J M

1993-01-01

The absolute bioavailability of fenspiride has been studied in twelve healthy volunteers. It was administered IV and orally in single doses of 80 mg fenspiride hydrochloride according to a randomised crossover pattern. Following IV administration, the plasma clearance of fenspiride was about 184 ml.min-1, and its apparent volume of distribution was moderately large (215 l). When given orally as a tablet, fenspiride exhibited fairly slow ab- sorption; the maximum plasma concentration (206 ng.ml-1) was achieved 6 h after administration. The absolute bioavailability was almost complete (90%). The tablet had slow release characteristics. The elimination half-life obtained from the plasma data was 14 to 16 h independent of the route of administration.

Single atom visibility in STEM optical depth sectioning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ishikawa, Ryo; Pennycook, Stephen J.; Lupini, Andrew R.

The continuing development of aberration correctors for the scanning transmission electron microscope (STEM) offers the possibility of locating single atoms in crystals in 3D via optical depth sectioning. The main factors that determine the feasibility of such an approach are visibility and dose requirements. In this paper, we show how Poisson's statistics can be quantitatively incorporated into STEM image simulations and demonstrate that the 3D location of single cerium atoms in wurtzite-type aluminum nitride is indeed feasible under large-angle illumination conditions with a relatively low dose. We also show that chromatic aberration does not presently represent a limitation provided amore » cold field emission source is used. Finally, these results suggest efforts into improved aberration corrector designs for larger illumination angles that offer significant potential for 3D structure determination of materials.« less

Single atom visibility in STEM optical depth sectioning

DOE PAGES

Ishikawa, Ryo; Pennycook, Stephen J.; Lupini, Andrew R.; ...

2016-10-19

The continuing development of aberration correctors for the scanning transmission electron microscope (STEM) offers the possibility of locating single atoms in crystals in 3D via optical depth sectioning. The main factors that determine the feasibility of such an approach are visibility and dose requirements. In this paper, we show how Poisson's statistics can be quantitatively incorporated into STEM image simulations and demonstrate that the 3D location of single cerium atoms in wurtzite-type aluminum nitride is indeed feasible under large-angle illumination conditions with a relatively low dose. We also show that chromatic aberration does not presently represent a limitation provided amore » cold field emission source is used. Finally, these results suggest efforts into improved aberration corrector designs for larger illumination angles that offer significant potential for 3D structure determination of materials.« less

Mumps-containing vaccine effectiveness during outbreaks in two schools in Guangdong, China, 2012.

PubMed

Man, Wang; Jin-Kou, Zhao; Tao, Wang; Li-Xin, Hao; Chao, Ma; Qi-Ru, Su; Hui-Ming, Luo

2012-10-01

Mumps-containing vaccine was licensed in the 1990s in China with a single dose administered routinely to children aged 18-24 months since 2008. However, an increase in reported mumps cases during the period 2009 to 2012 casts doubt on the effectiveness of a single-dose mumps vaccination. In March 2012, large numbers of mumps cases in a day-care centre and primary school in Guangdong Province were investigated to estimate the effectiveness of mumps-containing vaccine. A mumps case was defined as a case with acute onset of unilateral or bilateral swelling of the parotid gland or other salivary glands. Clinical data were collected among students and staff members in the two schools from 6 February to 3 June 2012. Vaccination history was obtained from immunization certificates. Vaccine effectiveness (VE) was calculated among children in classes that had more than two mumps cases. The cohort included 369 children from seven classes, four from the day-care centre and three from the primary school. Vaccination certificates available for 347 children showed immunization coverage of 82% (285/347). The overall attack rate was 14.6% (54/369); the VE for a single dose of mumps vaccine was 65% (95% confidence interval [CI]: 19%-85%) when given within three years and 15% (95% CI: -2%-52%) when given three to six years before the outbreak. For two doses of vaccine the VE was 53% (95% CI: -15-80%). A single dose of mumps-containing vaccine was not effective to prevent these outbreaks among preschool and schoolchildren. A second dose of mumps-containing vaccine to four to five-year-old children should be considered in China.

On the use of Lineal Energy Measurements to Estimate Linear Energy Transfer Spectra

NASA Technical Reports Server (NTRS)

Adams, David A.; Howell, Leonard W., Jr.; Adam, James H., Jr.

2007-01-01

This paper examines the error resulting from using a lineal energy spectrum to represent a linear energy transfer spectrum for applications in the space radiation environment. Lineal energy and linear energy transfer spectra are compared in three diverse but typical space radiation environments. Different detector geometries are also studied to determine how they affect the error. LET spectra are typically used to compute dose equivalent for radiation hazard estimation and single event effect rates to estimate radiation effects on electronics. The errors in the estimations of dose equivalent and single event rates that result from substituting lineal energy spectra for linear energy spectra are examined. It is found that this substitution has little effect on dose equivalent estimates in interplanetary quiet-time environment regardless of detector shape. The substitution has more of an effect when the environment is dominated by solar energetic particles or trapped radiation, but even then the errors are minor especially if a spherical detector is used. For single event estimation, the effect of the substitution can be large if the threshold for the single event effect is near where the linear energy spectrum drops suddenly. It is judged that single event rate estimates made from lineal energy spectra are unreliable and the use of lineal energy spectra for single event rate estimation should be avoided.

Impact of the vaginal applicator and dummy pellets on the dosimetry parameters of Cs-137 brachytherapy source.

PubMed

Sina, Sedigheh; Faghihi, Reza; Meigooni, Ali S; Mehdizadeh, Simin; Mosleh Shirazi, M Amin; Zehtabian, Mehdi

2011-05-19

In this study, dose rate distribution around a spherical 137Cs pellet source, from a low-dose-rate (LDR) Selectron remote afterloading system used in gynecological brachytherapy, has been determined using experimental and Monte Carlo simulation techniques. Monte Carlo simulations were performed using MCNP4C code, for a single pellet source in water medium and Plexiglas, and measurements were performed in Plexiglas phantom material using LiF TLD chips. Absolute dose rate distribution and the dosimetric parameters, such as dose rate constant, radial dose functions, and anisotropy functions, were obtained for a single pellet source. In order to investigate the effect of the applicator and surrounding pellets on dosimetric parameters of the source, the simulations were repeated for six different arrangements with a single active source and five non-active pellets inside central metallic tubing of a vaginal cylindrical applicator. In commercial treatment planning systems (TPS), the attenuation effects of the applicator and inactive spacers on total dose are neglected. The results indicate that this effect could lead to overestimation of the calculated F(r,θ), by up to 7% along the longitudinal axis of the applicator, especially beyond the applicator tip. According to the results obtained in this study, in a real situation in treatment of patients using cylindrical vaginal applicator and using several active pellets, there will be a large discrepancy between the result of superposition and Monte Carlo simulations.

Salicylate-induced enzymuria: comparison with other anti-inflammatory agents.

PubMed

Proctor, R A; Kunin, C M

1978-12-01

N-acetyl-beta glucosaminidase (NAG) enzymuria was used as a marker of renal injury in patients with rheumatic disease. An elevated NAG level was particularly common in patients receiving gold or aspirin therapy. The multiplicity of drugs received and the unknown role of underlying disease in these patients led to a study in healthy volunteers. Customary therapeutic doses of aspirin, choline salicylate, ibuprofen, indomethacin and acetaminophen did not produce enzymuria. Large single doses of salicylates equivalent to 6 tablets of aspirin consistently did produce enzymuria. The size of the individual dose in relation to body weight was more important than the total daily dose. NAG enzymuria appears to be a sensitive tool for identifying potentially nephrotoxic drugs.

The risk of solar proton events to space missions

NASA Technical Reports Server (NTRS)

Burrell, M. O.

1972-01-01

The total dose in rads-tissue from solar protons was tabulated for weekly time intervals, and the number of weeks which gave a dose above 25 rads behind 10 g/sq cm of aluminum for the active 6 years of the 19th cycle were called dangerous or large event weeks. The number of such event weeks was found to be only 3 weeks for the past 20 years. Even though the chance for smaller events is examined, it was found that for any reasonable, high confidence level (95%), the smaller events could be ignored. Consequently, the total particle flux for the 19th cycle was divided by a factor of 3 and determined a single large event week. Using this spectrum, the tissue dose in rads is calculated at the center of an aluminum spherical shell.

Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration of a single dose to American kestrels (Falco sparverius)

USGS Publications Warehouse

Sanchez-Migallon Guzman, David; KuKanich, Butch; Drazenovich, Tracy L.; Olsen, Glenn H.; Paul-Murphy, Joanne R.

2014-01-01

Conclusion and Clinical Relevance—Results indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies regarding the effects of other doses, other administration routes, constantrate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels may be indicated.

Pharmacokinetics of valerenic acid after single and multiple doses of valerian in older women.

PubMed

Anderson, Gail D; Elmer, Gary W; Taibi, Diana M; Vitiello, Michael V; Kantor, Eric; Kalhorn, Thomas F; Howald, William N; Barsness, Suzanne; Landis, Carol A

2010-10-01

Insomnia is a commonly reported clinical problem with as many as 50% of older adults reporting difficulty in falling and/or remaining asleep. Valerian (Valeriana officinalis) is a commonly used herb that has been advocated for promoting sleep. Valerenic acid is used as a marker for quantitative analysis of valerian products with evidence of pharmacological activity relevant to the hypnotic effects of valerian. The objective of this study was to determine the pharmacokinetics of valerenic acid in a group of elderly women after receiving a single nightly valerian dose and after 2 weeks of valerian dosing. There was not a statistically significant difference in the average peak concentration (C(max)), time to maximum concentration (T(max)) area under the time curve (AUC), elimination half-life (T(1/2)) and oral clearance after a single dose compared with multiple dosing. There was considerable inter- and intra-subject variability in the pharmacokinetic parameters. C(max) and AUC deceased and T(1/2) increased with increased body weight. The variability between the capsules was extremely low: 2.2%, 1.4% and 1.4%, for hydroxyvalerenic acid, acetoxyvalerenic acid and valerenic acid, respectively. In conclusion, large variability in the pharmacokinetics of valerenic acid may contribute to the inconsistencies in the effect of valerian as a sleep aid. Copyright © 2010 John Wiley & Sons, Ltd.

A Measurement and Analysis of Buildup Region Dose for Open Field Photon Beams (Cobalt-60 through 24 MV)

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCullough, Edwin C.

2015-01-15

The central axis depth dose in the build-up region (surface to d{sub max}) of single open field photon beams (cobalt-60 through 24 MV) has been measured utilizing parallel plate and extrapolation chamber methodology. These data were used to derive, for a prescription dose of 100 cGy, values of surface dose, the maximum value of dose along the central axis (D{sub max}) and the depth (nearest the surface) at which 90% of the prescription dose occurs (d{sub 90}). For both single and parallel opposed pair (POP) open field configurations, data are presented at field sizes of 5 × 5, 15 ×more » 15 and 25 × 25 cm{sup 2} for prescription depths of 10, 15 and 20 cm (midplane for POP). For the treatment machines, field sizes, and prescription depths studied, it is possible to conclude that: for single open field irradiation, surface dose values (as a percentage of the prescription dose) can be either low (<10%) or comparable to the prescription dose itself; for POP open fields, surface dose values are relatively independent of photon energy and midplane depth, and range between 30% and 70% of prescription dose, being principally dependent on field size; the depth of the initial 90 cGy point for a prescription dose of 100 cGy, d{sub 90}, was larger for POP fields. For either single or POP open field treatments, d{sub 90} was always less than 22 mm, while for 6 MV or less, values of d{sub 90} were less than 4 mm; D{sub max} values can be very large (e.g., above 300 cGy) for certain treatment situations and are reduced significantly for POP treatments; for open field POP treatments, the percent reduction in D{sub max} with each increment in beam energy above 10 MV is reduced over that seen at 10 MV or less and, possibly, this further reduction may be clinically insignificant; for open field POP treatments, changes in surface dose, d{sub 90} and D{sub max} with beam energy above 10 MV do not suggest, with regard to these specific build-up curve parameters, any obvious advantage for treatment with beam energies greater than 10 MV for the specific machines and situations studied.« less

SU-F-T-185: Study of the Robustness of a Proton Arc Technique Based On PBS Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Z; Zheng, Y

Purpose: One potential technique to realize proton arc is through using PBS beams from many directions to form overlaid Bragg peak (OBP) spots and placing these OBP spots throughout the target volume to achieve desired dose distribution. In this study, we analyzed the robustness of this proton arc technique. Methods: We used a cylindrical water phantom of 20 cm in radius in our robustness analysis. To study the range uncertainty effect, we changed the density of the phantom by ±3%. To study the setup uncertainty effect, we shifted the phantom by 3 & 5 mm. We also combined the rangemore » and setup uncertainties (3mm/±3%). For each test plan, we performed dose calculation for the nominal and 6 disturbed scenarios. Two test plans were used, one with single OBP spot and the other consisting of 121 OBP spots covering a 10×10cm{sup 2} area. We compared the dose profiles between the nominal and disturbed scenarios to estimate the impact of the uncertainties. Dose calculation was performed with Gate/GEANT based Monte Carlo software in cloud computing environment. Results: For each of the 7 scenarios, we simulated 100k & 10M events for plans consisting of single OBP spot and 121 OBP spots respectively. For single OBP spot, the setup uncertainty had minimum impact on the spot’s dose profile while range uncertainty had significant impact on the dose profile. For plan consisting of 121 OBP spots, similar effect was observed but the extent of disturbance was much less compared to single OBP spot. Conclusion: For PBS arc technique, range uncertainty has significantly more impact than setup uncertainty. Although single OBP spot can be severely disturbed by the range uncertainty, the overall effect is much less when a large number of OBP spots are used. Robustness optimization for PBS arc technique should consider range uncertainty with priority.« less

Peptidase inhibitors reduce opiate narcotic withdrawal signs, including seizure activity, in the rat.

PubMed

Pinsky, C; Dua, A K; LaBella, F S

1982-07-15

Narcotic withdrawal was precipitated by administration of naloxone in a low dose at 2 h after the final dose of morphine in a 9-day dependency-inducing schedule. Withdrawal was characterized by leaps, increased nocifensor activity and by cerebral cortical epileptiform activity, the latter not generally reported to be prominent in narcotic withdrawal. Single large doses of morphine did not provoke epileptiform activity at 2 h postinjection but did induce an acute opioid dependency wherein a moderately high dose of naloxone, ineffective in non-dependent rats, provoked upward leaping and electrocortical epileptiform activity. Pretreatment of the 9-day dependent rats with peptidase inhibitors, administered intracerebroventricularly, significantly reduced withdrawal severity including the epileptiform activity. We propose that peptidase inhibitors protect certain species of endogenous opioids and/or other neuropeptides that tend to suppress expression of the narcotic withdrawal syndrome. Furthermore, our findings suggest that epileptiform activity is a nascent form of cerebral activity hitherto largely unnoticed in narcotic withdrawal and that neuropeptides may be involved in certain epileptic states.

Motion-robust intensity-modulated proton therapy for distal esophageal cancer.

PubMed

Yu, Jen; Zhang, Xiaodong; Liao, Li; Li, Heng; Zhu, Ronald; Park, Peter C; Sahoo, Narayan; Gillin, Michael; Li, Yupeng; Chang, Joe Y; Komaki, Ritsuko; Lin, Steven H

2016-03-01

To develop methods for evaluation and mitigation of dosimetric impact due to respiratory and diaphragmatic motion during free breathing in treatment of distal esophageal cancers using intensity-modulated proton therapy (IMPT). This was a retrospective study on 11 patients with distal esophageal cancer. For each patient, four-dimensional computed tomography (4D CT) data were acquired, and a nominal dose was calculated on the average phase of the 4D CT. The changes of water equivalent thickness (ΔWET) to cover the treatment volume from the peak of inspiration to the valley of expiration were calculated for a full range of beam angle rotation. Two IMPT plans were calculated: one at beam angles corresponding to small ΔWET and one at beam angles corresponding to large ΔWET. Four patients were selected for the calculation of 4D-robustness-optimized IMPT plans due to large motion-induced dose errors generated in conventional IMPT. To quantitatively evaluate motion-induced dose deviation, the authors calculated the lowest dose received by 95% (D95) of the internal clinical target volume for the nominal dose, the D95 calculated on the maximum inhale and exhale phases of 4D CT DCT0 andDCT50 , the 4D composite dose, and the 4D dynamic dose for a single fraction. The dose deviation increased with the average ΔWET of the implemented beams, ΔWETave. When ΔWETave was less than 5 mm, the dose error was less than 1 cobalt gray equivalent based on DCT0 and DCT50 . The dose deviation determined on the basis of DCT0 and DCT50 was proportionally larger than that determined on the basis of the 4D composite dose. The 4D-robustness-optimized IMPT plans notably reduced the overall dose deviation of multiple fractions and the dose deviation caused by the interplay effect in a single fraction. In IMPT for distal esophageal cancer, ΔWET analysis can be used to select the beam angles that are least affected by respiratory and diaphragmatic motion. To further reduce dose deviation, the 4D-robustness optimization can be implemented for IMPT planning. Calculation of DCT0 and DCT50 is a conservative method to estimate the motion-induced dose errors.

21 CFR 520.2473b - Tioxidazole paste.

Code of Federal Regulations, 2012 CFR

2012-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

21 CFR 520.2473a - Tioxidazole granules.

Code of Federal Regulations, 2010 CFR

2010-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

21 CFR 520.2473a - Tioxidazole granules.

Code of Federal Regulations, 2011 CFR

2011-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

21 CFR 520.2473a - Tioxidazole granules.

Code of Federal Regulations, 2014 CFR

2014-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

21 CFR 520.2473b - Tioxidazole paste.

Code of Federal Regulations, 2013 CFR

2013-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

21 CFR 520.2473a - Tioxidazole granules.

Code of Federal Regulations, 2013 CFR

2013-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

21 CFR 520.2473b - Tioxidazole paste.

Code of Federal Regulations, 2014 CFR

2014-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

21 CFR 520.2473b - Tioxidazole paste.

Code of Federal Regulations, 2010 CFR

2010-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

21 CFR 520.2473b - Tioxidazole paste.

Code of Federal Regulations, 2011 CFR

2011-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

21 CFR 520.2473a - Tioxidazole granules.

Code of Federal Regulations, 2012 CFR

2012-04-01

... pound of body weight as a single dose. (ii) Indications for use. Removal of mature large strongyles (Strongylus edentatus, S. equinus, and S. vulgaris), mature ascarids (Parascaris equorum), mature and immature (4th larval stage) pinworms (Oxyuris equi), and mature small strongyles (Triodontophorus spp.). (iii...

Determination of the uncertainties in radiation doses from ingestion of strontium-90

NASA Astrophysics Data System (ADS)

Apostoaei, Andrei Iulian

Quantification of the uncertainties in the internal dosimetry is important because it can impact the outcome of dose reconstruction, risk assessment or epidemiological studies. This research focused on determination of the uncertainties in the dose factors from a single ingestion of 90Sr by adults, and analyzed the changes with age and the effect of gender. The uncertainties in the estimated dose factors are a factor of 6 for the bone surface, 5 for the red bone marrow, 2.5 for bladder and stomach, 2.2 for the small intestine, 2.1 for the upper large intestine and 2.7 for the lower large intestine. For the rest of the organs the uncertainty is a factor of 3. Only four parameters of the biokinetic model showed an age-dependency within the adult age group: the fractional transfers of strontium from plasma to cortical and trabecular bone, and the removal rates from the cortical and trabecular bone, respectively. When age-dependent biokinetic parameters were used, the estimated dose-factors are very close to the dose factors obtained using age-independent kinetics (within 40%). Thus, the dose factors based on age-independent parameters should suffice for most practical purposes. The dose factors and the associated uncertainties were also calculated as a function of age-at-exposure and attained age. These age dependent curves can be used for estimating doses from continuous intakes, or doses delivered over a limited portion of time. In addition to the committed dose, an expected dose is also estimated in this work. The expected dose is calculated using the dose rate weighted by the probability of surviving up to the age when the dose-rate is delivered. For exposure at young ages the expected dose and the committed dose are similar, but the committed dose decreases to zero when exposure occurs close to age 70, while the expected dose has elevated values pass age 70. No gender differences were found for bone surface, for red bone marrow, and the large intestine. The doses to the soft tissues for females are larger by 20% than the doses for males, because of the differences in the whole-body mass between males and females.

Tumor Control Outcomes After Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases From Renal Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zelefsky, Michael J., E-mail: zelefskm@mskcc.org; Greco, Carlo; Motzer, Robert

2012-04-01

Purpose: To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Patients and Methods: Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18-24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20-30 Gy. The median follow-up was 12 months (range, 1-48). Results: The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a highmore » single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). Conclusion: High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking.« less

Discrepancies between patterns of potentially lethal damage repair in the RIF-1 tumor system in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rasey, J.S.; Nelson, N.J.

1983-01-01

Repair of potentially lethal damage (PLD) was studied in the RIF-1 tumor system in several different growth states in vivo. Exponentially growing, fed plateau, and unfed plateau cells in cell culture as well as small and large subcutaneous or intramuscular tumors were investigated. Large single doses of radiation followed by variable repair times as well as graded doses of radiation to generate survival curves immediately after irradiation or after full repair were investigated. All repair-promoting conditions studied in vitro (delayed subculture, exposure of cells to depleted growth medium after irradiation) increased surviving fraction after a single dose. The D/sub 0/more » of the cell survival curve was also increased by these procedures. No PLD repair was observed for any tumors irradiated in vivo and maintained in the animal for varying times prior to assay in vitro. The nearly 100% cell yield obtained when this tumor is prepared as a single-cell suspension for colony formation, the representative cell sample obtained, and the constant cell yield per gram as a function of time postirradiation suggest that this discrepancy is not an artifact of the assay system. The most logical explanation of these data and information on radiocurability of this neoplasm is that PLD repair, which is so frequently demonstrated in vitro, may not be a major factor in the radioresponse of this tumor when left in situ.« less

Discrepancies between patterns of potentially lethal damage repair in the RIF-1 tumor system in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rasey, J.S.; Nelson, N.J.

1983-01-01

Repair of potentially lethal damage (PLD) was studied in the RIF-1 tumor system in several different growth states in vivo and in vitro. Exponentially growing, fed plateau, and unfed plateau cells in cell culture as well as small and large subcutaneous or intramuscular tumors were investigated. Large single doses of radiation followed by variable repair times as well as graded doses of radiation to generate survival curves immediately after irradiation or after full repair were investigated. All repair-promoting conditions studied in vitro (delayed subculture, exposure of cells to depleted growth medium after irradiation) increased surviving fraction after a single dose.more » The D0 of the cell survival curve was also increased by these procedures. No PLD repair was observed for any tumors irradiated in vivo and maintained in the animal for varying times prior to assay in vitro. The nearly 100% cell yield obtained when this tumor is prepared as a single-cell suspension for colony formation, the representative cell sample obtained, and the constant cell yield per gram as a function of time postirradiation suggest that this discrepancy is not an artifact of the assay system. The most logical explanation of these data and information on radiocurability of this neoplasm is that PLD repair, which is so frequently demonstrated in vitro, may not be a major factor in the radioresponse of this tumor when left in situ.« less

Dose fractionation theorem in 3-D reconstruction (tomography)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glaeser, R.M.

It is commonly assumed that the large number of projections for single-axis tomography precludes its application to most beam-labile specimens. However, Hegerl and Hoppe have pointed out that the total dose required to achieve statistical significance for each voxel of a computed 3-D reconstruction is the same as that required to obtain a single 2-D image of that isolated voxel, at the same level of statistical significance. Thus a statistically significant 3-D image can be computed from statistically insignificant projections, as along as the total dosage that is distributed among these projections is high enough that it would have resultedmore » in a statistically significant projection, if applied to only one image. We have tested this critical theorem by simulating the tomographic reconstruction of a realistic 3-D model created from an electron micrograph. The simulations verify the basic conclusions of high absorption, signal-dependent noise, varying specimen contrast and missing angular range. Furthermore, the simulations demonstrate that individual projections in the series of fractionated-dose images can be aligned by cross-correlation because they contain significant information derived from the summation of features from different depths in the structure. This latter information is generally not useful for structural interpretation prior to 3-D reconstruction, owing to the complexity of most specimens investigated by single-axis tomography. These results, in combination with dose estimates for imaging single voxels and measurements of radiation damage in the electron microscope, demonstrate that it is feasible to use single-axis tomography with soft X-ray microscopy of frozen-hydrated specimens.« less

The Effects of Low Dose-Rate Ionizing Radiation on the Shapes of Transients in the LM124 Operational Amplifier

NASA Technical Reports Server (NTRS)

Buchner, Stephen; McMorrow, Dale; Roche, Nicholas; Dusseau, Laurent; Pease, Ron L.

2008-01-01

Shapes of single event transients (SETs) in a linear bipolar circuit (LM124) change with exposure to total ionizing dose (TID) radiation. SETs shape changes are a direct consequence of TID-induced degradation of bipolar transistor gain. A reduction in transistor gain causes a reduction in the drive current of the current sources in the circuit, and it is the lower drive current that most affects the shapes of large amplitude SETs.

ON THE PROBLEM OF THE OPTIMAL DOSE IN THE RADIOTHERAPY OF NONMALIGNANT DISEASES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pape, R.

1961-01-01

Dosage for the treatment of benign conditions is considered from the viewpoint of 15 yr experience with 2514 patients. It was judged that doses of 1 to 20 r are optimal for treatment of inflammatory and degenerative joint diseases, although many authors call for 30- to 50-r single doses for these conditions. Equally good subjective results were obtained in arthritis and spondylitis cases with the lower doses, but suggestion plays a large role in improvement following radiotherapy. For juvenile mastitis, surface doses of 10 to 12 r, giving depth doses of approximates 1 r at 5 cm, are recommended. Somemore » estimates were made of gonadal doses encountered in various types of nonabdominal radiotherapy. For example, 10-r doses of 90-kv x rays given in the axillary region result in ovarian doses of 0.2 mr. The effect of radiation on the brain and other neural structures is discussed. (H.H.D.)« less

Fractionation Spares Mice From Radiation-Induced Reductions in Weight Gain But Does Not Prevent Late Oligodendrocyte Lineage Side Effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Begolly, Sage; Shrager, Peter G.; Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York

Purpose: To determine the late effects of fractionated versus single-dose cranial radiation on murine white matter. Methods and Materials: Mice were exposed to 0 Gy, 6 × 6 Gy, or 1 × 20 Gy cranial irradiation at 10 to 12 weeks of age. Endpoints were assessed through 18 months from exposure using immunohistochemistry, electron microscopy, and electrophysiology. Results: Weight gain was temporarily reduced after irradiation; greater loss was seen after single versus fractionated doses. Oligodendrocyte progenitor cells were reduced early and late after both single and fractionated irradiation. Both protocols also increased myelin g-ratio, reduced the number of nodes of Ranvier, and promoted a shift in the proportion of small, unmyelinatedmore » versus large, myelinated axon fibers. Conclusions: Fractionation does not adequately spare normal white matter from late radiation side effects.« less

Estimating the effective radiation dose imparted to patients by intraoperative cone-beam computed tomography in thoracolumbar spinal surgery.

PubMed

Lange, Jeffrey; Karellas, Andrew; Street, John; Eck, Jason C; Lapinsky, Anthony; Connolly, Patrick J; Dipaola, Christian P

2013-03-01

Observational. To estimate the radiation dose imparted to patients during typical thoracolumbar spinal surgical scenarios. Minimally invasive techniques continue to become more common in spine surgery. Computer-assisted navigation systems coupled with intraoperative cone-beam computed tomography (CT) represent one such method used to aid in instrumented spinal procedures. Some studies indicate that cone-beam CT technology delivers a relatively low dose of radiation to patients compared with other x-ray-based imaging modalities. The goal of this study was to estimate the radiation exposure to the patient imparted during typical posterior thoracolumbar instrumented spinal procedures, using intraoperative cone-beam CT and to place these values in the context of standard CT doses. Cone-beam CT scans were obtained using Medtronic O-arm (Medtronic, Minneapolis, MN). Thermoluminescence dosimeters were placed in a linear array on a foam-plastic thoracolumbar spine model centered above the radiation source for O-arm presets of lumbar scans for small or large patients. In-air dosimeter measurements were converted to skin surface measurements, using published conversion factors. Dose-length product was calculated from these values. Effective dose was estimated using published effective dose to dose-length product conversion factors. Calculated dosages for many full-length procedures using the small-patient setting fell within the range of published effective doses of abdominal CT scans (1-31 mSv). Calculated dosages for many full-length procedures using the large-patient setting fell within the range of published effective doses of abdominal CT scans when the number of scans did not exceed 3. We have demonstrated that single cone-beam CT scans and most full-length posterior instrumented spinal procedures using O-arm in standard mode would likely impart a radiation dose within the range of those imparted by a single standard CT scan of the abdomen. Radiation dose increases with patient size, and the radiation dose received by larger patients as a result of more than 3 O-arm scans in standard mode may exceed the dose received during standard CT of the abdomen. Understanding radiation imparted to patients by cone-beam CT is important for assessing risks and benefits of this technology, especially when spinal surgical procedures require multiple intraoperative scans.

Adverse events associated with single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews.

PubMed

Moore, R Andrew; Derry, Sheena; Aldington, Dominic; Wiffen, Philip J

2015-10-13

This is an update of a Cochrane overview published in Issue 9, 2011; that overview considered both efficacy and adverse events. This overview considers adverse events, with efficacy dealt with in a separate overview.Thirty-nine Cochrane reviews of randomised trials have examined the adverse events associated with individual drug interventions in acute postoperative pain. This overview brings together the results of those individual reviews. To provide an overview of adverse event rates associated with single-dose oral analgesics, compared with placebo, for acute postoperative pain in adults. We identified systematic reviews in The Cochrane Database of Systematic Reviews on The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group. We extracted information related to participants experiencing any adverse event, and reports of serious adverse events, and deaths from the individual reviews. Information was available from 39 Cochrane reviews for 41 different analgesics or analgesic combinations (51 drug/dose/formulations) tested in single oral doses in participants with moderate or severe postoperative pain. This involved around 350 unique studies involving about 35,000 participants. Most studies involved younger participants with pain following removal of molar teeth.For most nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and combinations not containing opioids, there were few examples where participants experienced significantly more or fewer adverse events than with placebo. For aspirin 1000 mg and diflunisal 1000 mg, opioids, or fixed-dose combination drugs containing opioids, participants typically experienced significantly more adverse events than with placebo. Studies of combinations of ibuprofen and paracetamol reported significantly fewer adverse events.Serious adverse events were rare, occurring a rate of about 1 in 3200 participants.Most reviews did not report specific adverse events. Despite ongoing problems with the measurement, recording, and reporting of adverse events in clinical trials and in systematic reviews, the large amount of information available for single oral doses of analgesics provides evidence that adverse events rates are generally similar with active drug and placebo in these circumstances, except at higher doses of some drugs, and in combinations including opioids.

Shot sequencing based on biological equivalent dose considerations for multiple isocenter Gamma Knife radiosurgery

NASA Astrophysics Data System (ADS)

Ma, Lijun; Lee, Letitia; Barani, Igor; Hwang, Andrew; Fogh, Shannon; Nakamura, Jean; McDermott, Michael; Sneed, Penny; Larson, David A.; Sahgal, Arjun

2011-11-01

Rapid delivery of multiple shots or isocenters is one of the hallmarks of Gamma Knife radiosurgery. In this study, we investigated whether the temporal order of shots delivered with Gamma Knife Perfexion would significantly influence the biological equivalent dose for complex multi-isocenter treatments. Twenty single-target cases were selected for analysis. For each case, 3D dose matrices of individual shots were extracted and single-fraction equivalent uniform dose (sEUD) values were determined for all possible shot delivery sequences, corresponding to different patterns of temporal dose delivery within the target. We found significant variations in the sEUD values among these sequences exceeding 15% for certain cases. However, the sequences for the actual treatment delivery were found to agree (<3%) and to correlate (R2 = 0.98) excellently with the sequences yielding the maximum sEUD values for all studied cases. This result is applicable for both fast and slow growing tumors with α/β values of 2 to 20 according to the linear-quadratic model. In conclusion, despite large potential variations in different shot sequences for multi-isocenter Gamma Knife treatments, current clinical delivery sequences exhibited consistent biological target dosing that approached that maximally achievable for all studied cases.

In vivo verification of particle therapy: how Compton camera configurations affect 3D image quality

NASA Astrophysics Data System (ADS)

Mackin, D.; Draeger, E.; Peterson, S.; Polf, J.; Beddar, S.

2017-05-01

The steep dose gradients enabled by the Bragg peaks of particle therapy beams are a double edged sword. They enable highly conformal dose distributions, but even small deviations from the planned beam range can cause overdosing of healthy tissue or under-dosing of the tumour. To reduce this risk, particle therapy treatment plans include margins large enough to account for all the sources of range uncertainty, which include patient setup errors, patient anatomy changes, and CT number to stopping power ratios. Any system that could verify the beam range in vivo, would allow reduced margins and more conformal dose distributions. Toward our goal developing such a system based on Compton camera (CC) imaging, we studied how three configurations (single camera, parallel opposed, and orthogonal) affect the quality of the 3D images. We found that single CC and parallel opposed configurations produced superior images in 2D. The increase in parallax produced by an orthogonal CC configuration was shown to be beneficial in producing artefact free 3D images.

Tumor Control Outcomes Following Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases from Renal Cell Carcinoma

PubMed Central

Zelefsky, Michael J; Greco, Carlo; Motzer, Robert; Magsanoc, Juan Martin; Pei, Xin; Lovelock, Michael; Mechalakos, Jim; Zatcky, Joan; Fuks, Zvi; Yamada, Yoshiya

2014-01-01

Purpose To report tumor local progression-free outcomes following treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Methods and Materials Between 2004 and 2010, a total of 105 lesions from renal cell carcinomas were treated with either SD-IGRT to prescription doses of 18–24 Gy (median, 24 Gy) or hypofractionation (3 or 5 fractions) with prescription doses ranging between 20 and 30 Gy. The median follow-up was 12 months (range, 1–48 months). Results The overall 3-year actuarial local progression-free survival (LPFS) for all lesions was 44%. The 3-year LPFS for those who received high single-dose (24 Gy; n = 45), low single-dose (< 24 Gy; n = 14), and hypofractionation regimens (n = 46) were 88%, 21%, and 17%, respectively (high single dose versus low single dose, p = 0.001; high single dose versus hypofractionation, p < 0.001). Multivariate analysis revealed the following variables as significant predictors of improved LPFS: dose of 24 Gy compared with lower dose (p = 0.009), and single dose versus hypofractionation (p = 0.008). Conclusion High-dose SD-IGRT is a non-invasive procedure resulting in high probability of local tumor control for metastatic renal cell cancers, generally considered radioresistant according to classical radiobiological ranking. PMID:21596489

Measured Neutron Spectra and Dose Equivalents From a Mevion Single-Room, Passively Scattered Proton System Used for Craniospinal Irradiation.

PubMed

Howell, Rebecca M; Burgett, Eric A; Isaacs, Daniel; Price Hedrick, Samantha G; Reilly, Michael P; Rankine, Leith J; Grantham, Kevin K; Perkins, Stephanie; Klein, Eric E

2016-05-01

To measure, in the setting of typical passively scattered proton craniospinal irradiation (CSI) treatment, the secondary neutron spectra, and use these spectra to calculate dose equivalents for both internal and external neutrons delivered via a Mevion single-room compact proton system. Secondary neutron spectra were measured using extended-range Bonner spheres for whole brain, upper spine, and lower spine proton fields. The detector used can discriminate neutrons over the entire range of the energy spectrum encountered in proton therapy. To separately assess internally and externally generated neutrons, each of the fields was delivered with and without a phantom. Average neutron energy, total neutron fluence, and ambient dose equivalent [H* (10)] were calculated for each spectrum. Neutron dose equivalents as a function of depth were estimated by applying published neutron depth-dose data to in-air H* (10) values. For CSI fields, neutron spectra were similar, with a high-energy direct neutron peak, an evaporation peak, a thermal peak, and an intermediate continuum between the evaporation and thermal peaks. Neutrons in the evaporation peak made the largest contribution to dose equivalent. Internal neutrons had a very low to negligible contribution to dose equivalent compared with external neutrons, largely attributed to the measurement location being far outside the primary proton beam. Average energies ranged from 8.6 to 14.5 MeV, whereas fluences ranged from 6.91 × 10(6) to 1.04 × 10(7) n/cm(2)/Gy, and H* (10) ranged from 2.27 to 3.92 mSv/Gy. For CSI treatments delivered with a Mevion single-gantry proton therapy system, we found measured neutron dose was consistent with dose equivalents reported for CSI with other proton beamlines. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buckley, L; Lambert, C; Nyiri, B

Purpose: To standardize the tube calibration for Elekta XVI cone beam CT (CBCT) systems in order to provide a meaningful estimate of the daily imaging dose and reduce the variation between units in a large centre with multiple treatment units. Methods: Initial measurements of the output from the CBCT systems were made using a Farmer chamber and standard CTDI phantom. The correlation between the measured CTDI and the tube current was confirmed using an Unfors Xi detector which was then used to perform a tube current calibration on each unit. Results: Initial measurements showed measured tube current variations of upmore » to 25% between units for scans with the same image settings. In order to reasonably estimate the imaging dose, a systematic approach to x-ray generator calibration was adopted to ensure that the imaging dose was consistent across all units at the centre and was adopted as part of the routine quality assurance program. Subsequent measurements show that the variation in measured dose across nine units is on the order of 5%. Conclusion: Increasingly, patients receiving radiation therapy have extended life expectancies and therefore the cumulative dose from daily imaging should not be ignored. In theory, an estimate of imaging dose can be made from the imaging parameters. However, measurements have shown that there are large differences in the x-ray generator calibration as installed at the clinic. Current protocols recommend routine checks of dose to ensure constancy. The present study suggests that in addition to constancy checks on a single machine, a tube current calibration should be performed on every unit to ensure agreement across multiple machines. This is crucial at a large centre with multiple units in order to provide physicians with a meaningful estimate of the daily imaging dose.« less

SU-F-T-151: Measurement Evaluation of Skin Dose in Scanning Proton Beam Therapy for Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, J; Nichols, E; Strauss, D

Purpose: To measure the skin dose and compare it with the calculated dose from a treatment planning system (TPS) for breast cancer treatment using scanning proton beam therapy (SPBT). Methods: A single en-face-beam SPBT plan was generated by a commercial TPS for two breast cancer patients. The treatment volumes were the entire breasts (218 cc and 1500 cc) prescribed to 50.4 Gy (RBE) in 28 fractions. A range shifter of 5 cm water equivalent thickness was used. The organ at risk (skin) was defined to be 5 mm thick from the surface. The skin doses were measured in water withmore » an ADCL calibrated parallel plate (PP) chamber. The measured data were compared with the values calculated in the TPS. Skin dose calculations can be subject to uncertainties created by the definition of the external contour and the limitations of the correction based algorithms, such as proton convolution superposition. Hence, the external contours were expanded by 0, 3 mm and 1 cm to include additional pixels for dose calculation. In addition, to examine the effects of the cloth gown on the skin dose, the skin dose measurements were conducted with and without gown. Results: On average the measured skin dose was 4% higher than the calculated values. At deeper depths, the measured and calculated doses were in better agreement (< 2%). Large discrepancy occur for the dose calculated without external expansion due to volume averaging. The addition of the gown only increased the measured skin dose by 0.4%. Conclusion: The implemented TPS underestimated the skin dose for breast treatments. Superficial dose calculation without external expansion would result in large errors for SPBT for breast cancer.« less

Beta-adrenoreceptor blockade abolishes atomoxetine-induced risk taking.

PubMed

Yang, Fan Nils; Pan, Jing Samantha; Li, Xinwang

2016-01-01

Clinical studies have shown that patients with exaggerated risk-taking tendencies have high baseline levels of norepinephrine. In this work, we systemically manipulated norepinephrine levels in rats and studied their behavioral changes in a probabilistic discounting task, which is a paradigm for gauging risk taking. This study aims to explore the effects of the selective norepinephrine reuptake inhibitor (atomoxetine at doses of 0.6, 1.0 and 1.8 mg/kg), and receptor selective antagonists (propranolol at a single dose of 1.0/kg, and prazosin at a single dose of 0.1 mg/kg), on risk taking using a probabilistic discounting task. In this task, there were two levers available to rats: pressing the 'small/certain' lever guaranteed a single food pellet, and pressing the 'large/risky' lever yielded either four pellets or none. The probability of receiving four food pellets decreased across the four experimental blocks from 100% to 12.5%. Atomoxetine increased the tendency to choose the large/risky lever. It significantly reduced the lose-shift effect (i.e. pressing a different lever after losing a trial), but did not affect the win-stay effect (i.e. pressing the same lever after winning a trial). Furthermore, co-administration of beta-adrenoreceptor antagonist, propranolol, eliminated the effects of atomoxetine on risk taking and the lose-shift effect; but co-administration of alpha1-adrenoreceptor antagonist, prazosin, did not. Atomoxetine boosted NE levels and increased risk taking. This was because atomoxetine decreased rats' sensitivity to losses. These effects were likely mediated by beta-adrenoreceptor. Copyright © 2015 Elsevier Inc. All rights reserved.

High dose bystander effects in spatially fractionated radiation therapy

PubMed Central

Asur, Rajalakshmi; Butterworth, Karl T.; Penagaricano, Jose A.; Prise, Kevin M.; Griffin, Robert J.

2014-01-01

Traditional radiotherapy of bulky tumors has certain limitations. Spatially fractionated radiation therapy (GRID) and intensity modulated radiotherapy (IMRT) are examples of advanced modulated beam therapies that help in significant reductions in normal tissue damage. GRID refers to the delivery of a single high dose of radiation to a large treatment area that is divided into several smaller fields, while IMRT allows improved dose conformity to the tumor target compared to conventional three-dimensional conformal radiotherapy. In this review, we consider spatially fractionated radiotherapy approaches focusing on GRID and IMRT, and present complementary evidence from different studies which support the role of radiation induced signaling effects in the overall radiobiological rationale for these treatments. PMID:24246848

Parsimonious Development of a Physiologically-Based Pharmacokinetic Model for PFOA

EPA Science Inventory

We examine pharmacokinetic (PK) models of varying complexity with respect to a large data set for female CD1 mice (Lau et al.) exposed to a range of single and repeated oral doses of PFOA. These data can be broadly grouped into 1) plasma concentrations 2) liver and kidney concen...

Testing for Additivity in Chemical Mixtures Using a Fixed-Ratio Ray Design and Statistical Equivalence Testing Methods

EPA Science Inventory

Fixed-ratio ray designs have been used for detecting and characterizing interactions of large numbers of chemicals in combination. Single chemical dose-response data are used to predict an “additivity curve” along an environmentally relevant ray. A “mixture curve” is estimated fr...

Pathological effects of in utero methylmercury exposure on the cerebellum of the golden hamster: early effects upon the neonatal cerebellar cortex-Part I

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reuhl, K.R.; Chang, L.W.; Townsend, J.W.

1981-12-01

Pregnant golden hamsters (Mesocricetus auratus) were given either a single dose of 10 mg methylmercury/kg on gestational day 10 or daily doses of 2 mg/kg on gestational days 10-15. Cerebella of experimental and control offspring were examined by light and electron microscopy during the first month of postnatal life. Degenerative changes, characterized by accumulations of lysosomes and areas of floccular cytoplasmic degradation, were frequently observed in neuroblasts of the external granular layer (EGL) as well as in more differentiated neural elements in the molecular and internal granular layers. Pyknotic nuclei were seen singly and in groups throughout the EGL ofmore » treated animals. Developing dendrites appeared particularly sensitive to methylmercury. Affected dendrites were swollen and packed with degenerating cytoplasmic material. Astrocytes and perivascular macrophages also contained large aggregates of irregular electron-opague debris, lysosomes, and large lipid droplets. Pathological alterations in the cerebellum were most pronounced during the first 15 days of postpartum life.« less

Reduction of spontaneous somatic mutation frequency by a low-dose X irradiation of Drosophila larvae and possible involvement of DNA single-strand damage repair.

PubMed

Koana, Takao; Takahashi, Takashi; Tsujimura, Hidenobu

2012-03-01

The third instar larvae of Drosophila were irradiated with X rays, and the somatic mutation frequency in their wings was measured after their eclosion. In the flies with normal DNA repair and apoptosis functions, 0.2 Gy irradiation at 0.05 Gy/min reduced the frequency of the so-called small spot (mutant cell clone with reduced reproductive activity) compared with that in the sham-irradiated flies. When apoptosis was suppressed using the baculovirus p35 gene, the small spot frequency increased four times in the sham-irradiated control group, but the reduction by the 0.2-Gy irradiation was still evident. In a non-homologous end joining-deficient mutant, the small spot frequency was also reduced by 0.2 Gy radiation. In a mutant deficient in single-strand break repair, no reduction in the small spot frequency by 0.2 Gy radiation was observed, and the small spot frequency increased with the radiation dose. Large spot (mutant cell clone with normal reproductive activity) frequency was not affected by suppression of apoptosis and increased monotonically with radiation dose in wild-type larvae and in mutants for single- or double-strand break repair. It is hypothesized that some of the small spots resulted from single-strand damage and, in wild-type larvae, 0.2 Gy radiation activated the normal single-strand break repair gene, which reduced the background somatic mutation frequency.

Reference dosimetry of proton pencil beams based on dose-area product: a proof of concept.

PubMed

Gomà, Carles; Safai, Sairos; Vörös, Sándor

2017-06-21

This paper describes a novel approach to the reference dosimetry of proton pencil beams based on dose-area product ([Formula: see text]). It depicts the calibration of a large-diameter plane-parallel ionization chamber in terms of dose-area product in a 60 Co beam, the Monte Carlo calculation of beam quality correction factors-in terms of dose-area product-in proton beams, the Monte Carlo calculation of nuclear halo correction factors, and the experimental determination of [Formula: see text] of a single proton pencil beam. This new approach to reference dosimetry proves to be feasible, as it yields [Formula: see text] values in agreement with the standard and well-established approach of determining the absorbed dose to water at the centre of a broad homogeneous field generated by the superposition of regularly-spaced proton pencil beams.

Frame average optimization of cine-mode EPID images used for routine clinical in vivo patient dose verification of VMAT deliveries

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCowan, P. M., E-mail: pmccowan@cancercare.mb.ca; McCurdy, B. M. C.; Medical Physics Department, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9

Purpose: The in vivo 3D dose delivered to a patient during volumetric modulated arc therapy (VMAT) delivery can be calculated using electronic portal imaging device (EPID) images. These images must be acquired in cine-mode (i.e., “movie” mode) in order to capture the time-dependent delivery information. The angle subtended by each cine-mode EPID image during an arc can be changed via the frame averaging number selected within the image acquisition software. A large frame average number will decrease the EPID’s angular resolution and will result in a decrease in the accuracy of the dose information contained within each image. Alternatively, lessmore » EPID images acquired per delivery will decrease the overall 3D patient dose calculation time, which is appealing for large-scale clinical implementation. Therefore, the purpose of this study was to determine the optimal frame average value per EPID image, defined as the highest frame averaging that can be used without an appreciable loss in 3D dose reconstruction accuracy for VMAT treatments. Methods: Six different VMAT plans and six different SBRT-VMAT plans were delivered to an anthropomorphic phantom. Delivery was carried out on a Varian 2300ix model linear accelerator (Linac) equipped with an aS1000 EPID running at a frame acquisition rate of 7.5 Hz. An additional PC was set up at the Linac console area, equipped with specialized frame-grabber hardware and software packages allowing continuous acquisition of all EPID frames during delivery. Frames were averaged into “frame-averaged” EPID images using MATLAB. Each frame-averaged data set was used to calculate the in vivo dose to the patient and then compared to the single EPID frame in vivo dose calculation (the single frame calculation represents the highest possible angular resolution per EPID image). A mean percentage dose difference of low dose (<20% prescription dose) and high dose regions (>80% prescription dose) was calculated for each frame averaged scenario for each plan. The authors defined their unacceptable loss of accuracy as no more than a ±1% mean dose difference in the high dose region. Optimal frame average numbers were then determined as a function of the Linac’s average gantry speed and the dose per fraction. Results: The authors found that 9 and 11 frame averages were suitable for all VMAT and SBRT-VMAT treatments, respectively. This resulted in no more than a 1% loss to any of the dose region’s mean percentage difference when compared to the single frame reconstruction. The optimized number was dependent on the treatment’s dose per fraction and was determined to be as high as 14 for 12 Gy/fraction (fx), 15 for 8 Gy/fx, 11 for 6 Gy/fx, and 9 for 2 Gy/fx. Conclusions: The authors have determined an optimal EPID frame averaging number for multiple VMAT-type treatments. These are given as a function of the dose per fraction and average gantry speed. These optimized values are now used in the authors’ clinical, 3D, in vivo patient dosimetry program. This provides a reduction in calculation time while maintaining the authors’ required level of accuracy in the dose reconstruction.« less

Single dose irradiation response of pig skin: a comparison of brachytherapy using a single, high dose rate iridium-192 stepping source with 200 kV X-rays.

PubMed

Hamm, P C; Bakker, E J; van den Berg, A P; van den Aardweg, G J; Visser, A G; Levendag, P C

2000-07-01

An experimental brachytherapy model has been developed to study acute and late normal tissue reactions as a tool to examine the effects of clinically relevant multifractionation schedules. Pig skin was used as a model since its morphology, structure, cell kinetics and radiation-induced responses are similar to human skin. Brachytherapy was performed using a microSelectron high dose rate (HDR) afterloading machine with a single stepping source and a custom-made template. In this study the acute epidermal reactions of erythema and moist desquamation and the late dermal reactions of dusky mauve erythema and necrosis were evaluated after single doses of irradiation over a follow-up period of 16 weeks. The major aims of this work were: (a) to compare the effects of iridium-192 (192Ir) irradiation with effects after X-irradiation; (b) to compare the skin reactions in Yorkshire and Large White pigs; and (c) to standardize the methodology. For 192Ir irradiation with 100% isodose at the skin surface, the 95% isodose was estimated at the basal membrane, while the 80% isodose covered the dermal fat layers. After HDR 192Ir irradiation of Yorkshire pig skin the ED50 values (95% isodose) for moderate/severe erythema and moist desquamation were 24.8 Gy and 31.9 Gy, respectively. The associated mean latent period (+/- SD) was 39 +/- 7 days for both skin reactions. Late skin responses of dusky mauve erythema and dermal necrosis were characterized by ED50 values (80% isodose) of 16.3 Gy and 19.5 Gy, with latent periods of 58 +/- 7 days and 76 +/- 12 days, respectively. After X-irradiation, the incidence of the various skin reactions and their latent periods were similar. Acute and late reactions were well separated in time. The occurrence of skin reactions and the incidence of effects were comparable in Yorkshire and Large White pigs for both X-irradiation and HDR 192Ir brachytherapy. This pig skin model is feasible for future studies on clinically relevant multifractionation schedules in a brachytherapy setting.

Effect of Study Design on Sample Size in Studies Intended to Evaluate Bioequivalence of Inhaled Short‐Acting β‐Agonist Formulations

PubMed Central

Zeng, Yaohui; Singh, Sachinkumar; Wang, Kai

2017-01-01

Abstract Pharmacodynamic studies that use methacholine challenge to assess bioequivalence of generic and innovator albuterol formulations are generally designed per published Food and Drug Administration guidance, with 3 reference doses and 1 test dose (3‐by‐1 design). These studies are challenging and expensive to conduct, typically requiring large sample sizes. We proposed 14 modified study designs as alternatives to the Food and Drug Administration–recommended 3‐by‐1 design, hypothesizing that adding reference and/or test doses would reduce sample size and cost. We used Monte Carlo simulation to estimate sample size. Simulation inputs were selected based on published studies and our own experience with this type of trial. We also estimated effects of these modified study designs on study cost. Most of these altered designs reduced sample size and cost relative to the 3‐by‐1 design, some decreasing cost by more than 40%. The most effective single study dose to add was 180 μg of test formulation, which resulted in an estimated 30% relative cost reduction. Adding a single test dose of 90 μg was less effective, producing only a 13% cost reduction. Adding a lone reference dose of either 180, 270, or 360 μg yielded little benefit (less than 10% cost reduction), whereas adding 720 μg resulted in a 19% cost reduction. Of the 14 study design modifications we evaluated, the most effective was addition of both a 90‐μg test dose and a 720‐μg reference dose (42% cost reduction). Combining a 180‐μg test dose and a 720‐μg reference dose produced an estimated 36% cost reduction. PMID:29281130

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

PubMed

Palanca-Wessels, Maria Corinna A; Czuczman, Myron; Salles, Gilles; Assouline, Sarit; Sehn, Laurie H; Flinn, Ian; Patel, Manish R; Sangha, Randeep; Hagenbeek, Anton; Advani, Ranjana; Tilly, Herve; Casasnovas, Olivier; Press, Oliver W; Yalamanchili, Sreeni; Kahn, Robert; Dere, Randall C; Lu, Dan; Jones, Surai; Jones, Cheryl; Chu, Yu-Waye; Morschhauser, Franck

2015-06-01

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Genentech. Copyright © 2015 Elsevier Ltd. All rights reserved.

A swinging seesaw as a novel model mechanism for time-dependent hormesis under dose-dependent stimulatory and inhibitory effects: A case study on the toxicity of antibacterial chemicals to Aliivibrio fischeri.

PubMed

Sun, Haoyu; Calabrese, Edward J; Zheng, Min; Wang, Dali; Pan, Yongzheng; Lin, Zhifen; Liu, Ying

2018-08-01

Hormesis occurs frequently in broadly ranging biological areas (e.g. plant biology, microbiology, biogerontology), toxicology, pharmacology and medicine. While numerous mechanisms (e.g. receptor and pathway mediated pathway responses) account for stimulatory and inhibitory features of hormetic dose responses, the vast majority emphasizes the inclusion of many doses but only one timepoint or use of a single optimized dose that is assessed over a broad range of timepoints. In this paper, a toxicity study was designed using a large number of properly spaced doses with responses determined over a large number of timepoints, which could help us reveal the underlying mechanism of hormesis. We present the results of a dose-time-response study on hormesis using five antibacterial chemicals on the bioluminescence of Aliivibrio fischeri, measuring expression of protein mRNA based on quorum sensing, simulating bioluminescent reaction and analyzing toxic actions of test chemicals. The findings show dose-time-dependent responses conforming to the hormetic dose-response model, while revealing unique response dynamics between agent induced stimulatory and inhibitory effects within bacterial growth phase dynamics. These dynamic dose-time features reveal a type of biological seesaw model that integrates stimulatory and inhibitory responses within unique growth phase, dose and time features, which has faultlessly explained the time-dependent hormetic phenomenon induced by five antibacterial chemicals (characterized by low-dose stimulation and high-dose inhibition). This study offers advances in understanding cellular dynamics, the biological integration of diverse and opposing responses and their role in evolutionary adaptive strategies to chemicals, which can provide new insight into the mechanistic investigation of hormesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effectiveness of one dose of oral cholera vaccine in response to an outbreak: a case-cohort study.

PubMed

Azman, Andrew S; Parker, Lucy A; Rumunu, John; Tadesse, Fisseha; Grandesso, Francesco; Deng, Lul L; Lino, Richard Laku; Bior, Bior K; Lasuba, Michael; Page, Anne-Laure; Ontweka, Lameck; Llosa, Augusto E; Cohuet, Sandra; Pezzoli, Lorenzo; Sodjinou, Dossou Vincent; Abubakar, Abdinasir; Debes, Amanda K; Mpairwe, Allan M; Wamala, Joseph F; Jamet, Christine; Lessler, Justin; Sack, David A; Quilici, Marie-Laure; Ciglenecki, Iza; Luquero, Francisco J

2016-11-01

Oral cholera vaccines represent a new effective tool to fight cholera and are licensed as two-dose regimens with 2-4 weeks between doses. Evidence from previous studies suggests that a single dose of oral cholera vaccine might provide substantial direct protection against cholera. During a cholera outbreak in May, 2015, in Juba, South Sudan, the Ministry of Health, Médecins Sans Frontières, and partners engaged in the first field deployment of a single dose of oral cholera vaccine to enhance the outbreak response. We did a vaccine effectiveness study in conjunction with this large public health intervention. We did a case-cohort study, combining information on the vaccination status and disease outcomes from a random cohort recruited from throughout the city of Juba with that from all the cases detected. Eligible cases were those aged 1 year or older on the first day of the vaccination campaign who sought care for diarrhoea at all three cholera treatment centres and seven rehydration posts throughout Juba. Confirmed cases were suspected cases who tested positive to PCR for Vibrio cholerae O1. We estimated the short-term protection (direct and indirect) conferred by one dose of cholera vaccine (Shanchol, Shantha Biotechnics, Hyderabad, India). Between Aug 9, 2015, and Sept 29, 2015, we enrolled 87 individuals with suspected cholera, and an 898-person cohort from throughout Juba. Of the 87 individuals with suspected cholera, 34 were classified as cholera positive, 52 as cholera negative, and one had indeterminate results. Of the 858 cohort members who completed a follow-up visit, none developed clinical cholera during follow-up. The unadjusted single-dose vaccine effectiveness was 80·2% (95% CI 61·5-100·0) and after adjusting for potential confounders was 87·3% (70·2-100·0). One dose of Shanchol was effective in preventing medically attended cholera in this study. These results support the use of a single-dose strategy in outbreaks in similar epidemiological settings. Médecins Sans Frontières. Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.

Large-scale production of foot-and-mouth disease virus (serotype Asia1) VLP vaccine in Escherichia coli and protection potency evaluation in cattle.

PubMed

Xiao, Yan; Chen, Hong-Ying; Wang, Yuzhou; Yin, Bo; Lv, Chaochao; Mo, Xiaobing; Yan, He; Xuan, Yajie; Huang, Yuxin; Pang, Wenqiang; Li, Xiangdong; Yuan, Y Adam; Tian, Kegong

2016-07-02

Foot-and-mouth disease (FMD) is an acute, highly contagious disease that infects cloven-hoofed animals. Vaccination is an effective means of preventing and controlling FMD. Compared to conventional inactivated FMDV vaccines, the format of FMDV virus-like particles (VLPs) as a non-replicating particulate vaccine candidate is a promising alternative. In this study, we have developed a co-expression system in E. coli, which drove the expression of FMDV capsid proteins (VP0, VP1, and VP3) in tandem by a single plasmid. The co-expressed FMDV capsid proteins (VP0, VP1, and VP3) were produced in large scale by fermentation at 10 L scale and the chromatographic purified capsid proteins were auto-assembled as VLPs in vitro. Cattle vaccinated with a single dose of the subunit vaccine, comprising in vitro assembled FMDV VLP and adjuvant, developed FMDV-specific antibody response (ELISA antibodies and neutralizing antibodies) with the persistent period of 6 months. Moreover, cattle vaccinated with the subunit vaccine showed the high protection potency with the 50 % bovine protective dose (PD50) reaching 11.75 PD50 per dose. Our data strongly suggest that in vitro assembled recombinant FMDV VLPs produced from E. coli could function as a potent FMDV vaccine candidate against FMDV Asia1 infection. Furthermore, the robust protein expression and purification approaches described here could lead to the development of industrial level large-scale production of E. coli-based VLPs against FMDV infections with different serotypes.

4D planning over the full course of fractionation: assessment of the benefit of tumor trailing

NASA Astrophysics Data System (ADS)

McQuaid, D.; Bortfeld, T.

2011-11-01

Tumor trailing techniques have been proposed as a method of reducing the problem of intrafraction motion in radiotherapy. However the dosimetric assessment of trailing strategies is complicated by the requirement to study dose deposition over a full fraction delivery. Common 4D planning strategies allowing assessment of dosimetric motion effects study a single cycle acquired with 4DCT. In this paper, a methodology to assess dose deposited over an entire treatment course is advanced and used to assess the potential benefit of tumor trailing strategies for lung cancer patients. Two digital phantoms mimicking patient anatomy were each programmed to follow the tumor respiratory trajectory observed from 33 lung cancer patients. The two phantoms were designed to represent the cases of a small (volume = 13.6 cm3) and large (volume = 181.7 cm3) lung lesion. Motion margins required to obtain CTV coverage by 95% of the prescription dose to 90% of the available cases were computed for a standard treatment strategy and a trailing treatment strategy. The trailing strategy facilitated a margin reduction of over 30% relative to the conventional delivery. When the dose was computed across the entire delivery for the 33 cases, the trailing strategy was found to significantly reduce the underdosage to the outlier cases and the reduced trailing margin facilitated a 15% (small lesion) and 4% (large lesion) reduction for the mean lung dose and 7% (small lesion) and 10% (large lesion) for the mean esophagus dose. Finally, for comparison an ideal continuous tracking strategy was assessed and found to further reduce the mean lung and esophagus dose. However, this improvement comes at the price of increased delivery complexity and increased reliance on tumor localization accuracy.

Addition of Lubiprostone to polyethylene glycol(PEG) enhances the quality & efficacy of colonoscopy preparation: a randomized, double-blind, placebo controlled trial.

PubMed

Banerjee, Rupa; Chaudhari, Hrushikesh; Shah, Nirish; Saravanan, Arjunan; Tandan, Manu; Reddy, D Nageshwar

2016-10-13

Adequate bowel preparation is an essential prerequisite for complete mucosal visualization during colonoscopy. Polyethylene glycol (PEG) solutions are commonly used. However the large volume of the solution is often poorly tolerated. Addition of Lubiprostone (LB) could improve the adequacy of standard PEG preparation & reduce requirement. The aims to assess adequacy of PEG preparation with addition of single dose LB (24mcg) vs placebo and efficacy of reduced dose PEG + LB compared with full dose PEG + LB. Single center prospective double blind randomized controlled trial. Part I: 442 patients for colonoscopy randomized to receive placebo (GrA) or single dose of LB (GrB) prior to PEG preparation. Quality of bowel preparation graded 0-9 according to Boston Bowel Preparation Scale (BBPS). BBPS-9: excellent and BBPS 0-4: repeat procedure. Part II: 146 patients randomized to receive LB + 1.5 L PEG (GrC; 75) or LB + 1 L PEG (GrD; 71). BBPS score compared with GrB (2 L PEG). Part I: 442 patients (221 GrA & 221 Gr B). LB resulted in significant improvement in total BBPS (7.44 + 0.14 vs. 6.36 + 0.16, p < 0.0001). 66.5 % Gr B vs 38 % Gr A had excellent prep; 42.5 % GrB vs 24 % GrA had adequate prep. Repeat procedure needed 9.5 % Gr B vs 16.7 % Gr A (P < 0.01). Part II: No difference in BBPS scores with lower doses (Gr C&D) compared to standard (GrB) (Mean BBPS 7.44 + 0.14 GrA,7.30 + 0.25 GrC;7.25 + 0.26 GrD;p >0.05). Single dose LB prior to PEG significantly enhanced bowel preparation compared to PEG alone. There was no significant difference in quality of preparation with lower doses of PEG when combined with LB. The study protocol was approved by institutional review board and the trial was registered on March 22, 2011 with clinicaltrials.gov ( NCT01324284 ).

Defining unnecessary disinfection procedures for single-dose and multiple-dose vials.

PubMed

Buckley, T; Dudley, S M; Donowitz, L G

1994-11-01

Recommendations in the literature conflict on the necessity of disinfecting single-use vials prior to aspiration of fluid. Interventions to disinfect the stopper surface on multiple-dose vials vary considerably. To determine the necessity of alcohol disinfection of the stopper on single-dose vials and to compare povidone-iodine and alcohol versus alcohol-only disinfection of the stopper prior to each needle penetration on multiple-dose vials. The rubber stopper surfaces of 100 single-dose vials were cultured for the presence of bacteria. To determine the efficacy of two procedures for disinfection of multiple-dose vials, 87 stopper surfaces routinely disinfected with both povidone-iodine and alcohol were cultured for bacteria. After a change in practice, 100 multiple-dose vials routinely disinfected with alcohol only were cultured for the presence of bacteria. Of the cultures done on single-dose vial stoppers, 99% were sterile. A comparison of the two disinfection techniques for multiple-dose vials revealed that 83 (95%) of the 87 vials prepped with both povidone-iodine and alcohol were sterile, compared with all stoppers disinfected with alcohol only. This study shows the lack of necessity of any disinfection procedure on the rubber stopper of single-dose vials and the efficacy of alcohol only for disinfecting the stopper of multiple-dose vials.

Beyond Gaussians: a study of single spot modeling for scanning proton dose calculation

PubMed Central

Li, Yupeng; Zhu, Ronald X.; Sahoo, Narayan; Anand, Aman; Zhang, Xiaodong

2013-01-01

Active spot scanning proton therapy is becoming increasingly adopted by proton therapy centers worldwide. Unlike passive-scattering proton therapy, active spot scanning proton therapy, especially intensity-modulated proton therapy, requires proper modeling of each scanning spot to ensure accurate computation of the total dose distribution contributed from a large number of spots. During commissioning of the spot scanning gantry at the Proton Therapy Center in Houston, it was observed that the long-range scattering protons in a medium may have been inadequately modeled for high-energy beams by a commercial treatment planning system, which could lead to incorrect prediction of field-size effects on dose output. In the present study, we developed a pencil-beam algorithm for scanning-proton dose calculation by focusing on properly modeling individual scanning spots. All modeling parameters required by the pencil-beam algorithm can be generated based solely on a few sets of measured data. We demonstrated that low-dose halos in single-spot profiles in the medium could be adequately modeled with the addition of a modified Cauchy-Lorentz distribution function to a double-Gaussian function. The field-size effects were accurately computed at all depths and field sizes for all energies, and good dose accuracy was also achieved for patient dose verification. The implementation of the proposed pencil beam algorithm also enabled us to study the importance of different modeling components and parameters at various beam energies. The results of this study may be helpful in improving dose calculation accuracy and simplifying beam commissioning and treatment planning processes for spot scanning proton therapy. PMID:22297324

Combination of High-Dose Methylprednisolone and Defibrotide for Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplant Recipients.

PubMed

Gloude, Nicholas J; Jodele, Sonata; Teusink-Cross, Ashley; Grimley, Michael; Davies, Stella M; Lane, Adam; Myers, Kasiani C

2018-01-01

Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplant (HSCT), with high mortality in severe cases and until recently very limited therapeutic options consisting largely of supportive care. Defibrotide was recently approved in the United States for the treatment of severe VOD in patients with renal or pulmonary dysfunction after HSCT. Our group previously published on the use of high-dose methylprednisolone (500 mg/m 2 per dose every 12 hours for 6 doses) in patients with VOD, showing good success. A small subset of these individuals were also treated with defibrotide, but additional studies using the combination of high-dose methylprednisolone and defibrotide for the treatment of VOD are lacking. We present a single-institution retrospective chart review of 15 HSCT patients with VOD treated with the combination of high-dose methylprednisolone and defibrotide. VOD developed at a median of 17 days post-HSCT, and combination therapy was initiated within 1 day of VOD diagnosis. Twelve of 15 patients (80%) had multiorgan failure. Our single-center experience using both high-dose methylprednisolone and defibrotide showed a day +100 survival rate of 73% and an overall VOD complete resolution rate of 66.7%, higher than the rates reported in the recent literature using defibrotide alone (40% to 50% day +100 overall survival). These data suggest that the combination of high-dose steroids and defibrotide may be superior to defibrotide alone and warrant further investigation. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

TH-E-BRF-01: Exploiting Tumor Shrinkage in Split-Course Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Unkelbach, J; Craft, D; Hong, T

2014-06-15

Purpose: In split-course radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated by radiobiological considerations. However, using modern image-guidance, it also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. In this work, we consider the optimal design of split-course treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. Methods: We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cellmore » repopulation. The design of splitcourse radiotherapy is formulated as a mathematical optimization problem in which the total dose to the liver is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. Results: We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one third of the dose should be delivered in the first stage. The projected benefit of split-course treatments in terms of liver sparing depends on model assumptions. However, the model predicts large liver dose reductions by more than a factor of two for plausible model parameters. Conclusion: The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at split-course radiotherapy for selected disease sites where substantial tumor regression translates into reduced target volumes.« less

PROBABILISTIC SAFETY ASSESSMENT OF OPERATIONAL ACCIDENTS AT THE WASTE ISOLATION PILOT PLANT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rucker, D.F.

2000-09-01

This report presents a probabilistic safety assessment of radioactive doses as consequences from accident scenarios to complement the deterministic assessment presented in the Waste Isolation Pilot Plant (WIPP) Safety Analysis Report (SAR). The International Council of Radiation Protection (ICRP) recommends both assessments be conducted to ensure that ''an adequate level of safety has been achieved and that no major contributors to risk are overlooked'' (ICRP 1993). To that end, the probabilistic assessment for the WIPP accident scenarios addresses the wide range of assumptions, e.g. the range of values representing the radioactive source of an accident, that could possibly have beenmore » overlooked by the SAR. Routine releases of radionuclides from the WIPP repository to the environment during the waste emplacement operations are expected to be essentially zero. In contrast, potential accidental releases from postulated accident scenarios during waste handling and emplacement could be substantial, which necessitates the need for radiological air monitoring and confinement barriers (DOE 1999). The WIPP Safety Analysis Report (SAR) calculated doses from accidental releases to the on-site (at 100 m from the source) and off-site (at the Exclusive Use Boundary and Site Boundary) public by a deterministic approach. This approach, as demonstrated in the SAR, uses single-point values of key parameters to assess the 50-year, whole-body committed effective dose equivalent (CEDE). The basic assumptions used in the SAR to formulate the CEDE are retained for this report's probabilistic assessment. However, for the probabilistic assessment, single-point parameter values were replaced with probability density functions (PDF) and were sampled over an expected range. Monte Carlo simulations were run, in which 10,000 iterations were performed by randomly selecting one value for each parameter and calculating the dose. Statistical information was then derived from the 10,000 iteration batch, which included 5%, 50%, and 95% dose likelihood, and the sensitivity of each assumption to the calculated doses. As one would intuitively expect, the doses from the probabilistic assessment for most scenarios were found to be much less than the deterministic assessment. The lower dose of the probabilistic assessment can be attributed to a ''smearing'' of values from the high and low end of the PDF spectrum of the various input parameters. The analysis also found a potential weakness in the deterministic analysis used in the SAR, a detail on drum loading was not taken into consideration. Waste emplacement operations thus far have handled drums from each shipment as a single unit, i.e. drums from each shipment are kept together. Shipments typically come from a single waste stream, and therefore the curie loading of each drum can be considered nearly identical to that of its neighbor. Calculations show that if there are large numbers of drums used in the accident scenario assessment, e.g. 28 drums in the waste hoist failure scenario (CH5), then the probabilistic dose assessment calculations will diverge from the deterministically determined doses. As it is currently calculated, the deterministic dose assessment assumes one drum loaded to the maximum allowable (80 PE-Ci), and the remaining are 10% of the maximum. The effective average of drum curie content is therefore less in the deterministic assessment than the probabilistic assessment for a large number of drums. EEG recommends that the WIPP SAR calculations be revisited and updated to include a probabilistic safety assessment.« less

Impact of inadequate doses of rituximab in the treatment of diffuse large B cell lymphoma in Malaysian patients.

PubMed

Gan, Gin Gin; Subramaniam, Rajaletchumy; Bee, Ping Chong; Chin, Edmund Fui Min; Abdul-Halim, Habibah; Tai, Mei Chee

2014-01-01

The current standard treatment for patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) is rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). A significant number of patients were not treated with recommended dose of rituximab due to limited financial resources in Malaysia. This study evaluates the efficacy of R-CHOP like chemotherapy in Malaysian patients with DLBCL. The study comprised a retrospective analysis of patients with DLBCL treated at a single centre. The outcome was compared with patients who were treated with R-CHOP like and CHOP like chemotherapy. Patients who were treated with lower dose of rituximab was subanalysed for outcome. A total of 86 patients who had CHOP-like chemotherapy were included. Only 39 (45%) patients had rituximab and only 12 (29%) patients had the recommended dose. The overall response (OR) and complete response (CR) rates were 88% and 81% respectively. There was no significant difference in OR and CR in patients who had rituximab and those without rituxmab. Those with International Prognostic Index (IPI) score of ≤ 2 had significant higher CR rate, progression free survival (PFS) and overall survival (p<0.001). The lack of significant improvement in CR and DFS in our patients may be due to an inadequate dose of rituximab.

[Effect of clinical doses of Realgar-Indigo Naturalis formula and large-dose of realgar on CYP450s of rat liver].

PubMed

Xu, Huan-Hua; Wang, Mei-Xi; Tan, Hong-Ling; Wang, Yu-Guang; Tang, Xiang-Lin; Xiao, Cheng-Rong; Li, Hua; Gao, Yue; Ma, Zeng-Chun

2017-02-01

To investigate the effect of clinical dose of Realgar-Indigo Naturais formula (RIF) and large-dose of Realgar on main drug-metabolizing enzymes CYP450s of rat liver, as well as its regulatory effect on mRNA expression. Wistar rats were administrated orally with tested drugs for 14 days. A Cocktail method combined with HPLC-MS/MS was used in the determination of 4 cytochrome P450 isozymes (CYP1A2, CYP2B, CYP3A and CYP2C) in liver of the rats, and the mRNA expression levels of the above subtypes were detected by real-time fluorescent quantitative PCR. The results showed that RIF can significantly induce CYP1A2 and CYP2B enzyme activity, and inhibit CYP3A enzyme activity. This result was consistent with the mRNA expression. However, its single compound showed weaker or even contrary phenomenon. Different doses of Realgar also showed significant inconsistencies on CYP450 enzymes activity and mRNA expression. These phenomena may be relevant with RIF compatibility synergies or toxicity reduction. The results can also prompt drug interactions when RIF is combined with other medicines in application. Copyright© by the Chinese Pharmaceutical Association.

Immune Responses to an Oral Cholera Vaccine in Internally Displaced Persons in South Sudan.

PubMed

Iyer, Anita S; Bouhenia, Malika; Rumunu, John; Abubakar, Abdinasir; Gruninger, Randon J; Pita, Jane; Lino, Richard Lako; Deng, Lul L; Wamala, Joseph F; Ryan, Edward T; Martin, Stephen; Legros, Dominique; Lessler, Justin; Sack, David A; Luquero, Francisco J; Leung, Daniel T; Azman, Andrew S

2016-10-24

Despite recent large-scale cholera outbreaks, little is known about the immunogenicity of oral cholera vaccines (OCV) in African populations, particularly among those at highest cholera risk. During a 2015 preemptive OCV campaign among internally displaced persons in South Sudan, a year after a large cholera outbreak, we enrolled 37 young children (1-5 years old), 67 older children (6-17 years old) and 101 adults (≥18 years old), who received two doses of OCV (Shanchol) spaced approximately 3 weeks apart. Cholera-specific antibody responses were determined at days 0, 21 and 35 post-immunization. High baseline vibriocidal titers (>80) were observed in 21% of the participants, suggesting recent cholera exposure or vaccination. Among those with titers ≤80, 90% young children, 73% older children and 72% adults seroconverted (≥4 fold titer rise) after the 1 st OCV dose; with no additional seroconversion after the 2 nd dose. Post-vaccination immunological endpoints did not differ across age groups. Our results indicate Shanchol was immunogenic in this vulnerable population and that a single dose alone may be sufficient to achieve similar short-term immunological responses to the currently licensed two-dose regimen. While we found no evidence of differential response by age, further immunologic and epidemiologic studies are needed.

WE-AB-207B-10: On Spinal Nerve Toxicity from Single-Session SAbR in Pigs and the Translation of Small Animal NTCP Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hrycushko, B; Medin, P

Purpose: The incidence of peripheral neuropathy has risen with increased utilization of SAbR. There is no consensus regarding the dose-tolerance of the peripheral nervous system. In 2015, we commenced an investigation to test the hypotheses that single-session irradiation to the pig spinal nerves exhibit a similar dose-tolerance as that of the spinal cord and that a dose-length effect exists. This work evaluates the direct application of small animal NTCP models to both large animal spinal cord and preliminary peripheral nerve data. Methods: To date, 16 of 25 Yucatan minipigs have received single-session SAbR to a 1.5cm length and 4 ofmore » 25 have received irradiation to a 0.5cm length of left-sided C6-C8 spinal nerves. Toxicity related gait change has been observed in 13 animals (9 from the long length group and 4 from the short). This preliminary data is overlaid on several dose-response models which have been fit to rodent spinal cord tolerance experiments. Model parameters define a toxicity profile between a completely serial or parallel behaving organ. Adequacy of model application, including how length effects are handled, to published minipig spinal cord dose-response data and to preliminary peripheral nerve response data was evaluated through residual analysis. Results: No rodent-derived dose-response models were directly applicable to all pig data for the different lengths irradiated. Several models fit the long-length irradiated spinal cord data well, with the more serial-like models fitting best. Preliminary data on the short-length irradiation suggests no length effect exists, disproving our hypothesis. Conclusion: Direct application of small-animal NTCP models to pig data suggests dose-length effect predictions from small animal data may not translate clinically. However, the small animal models used have not considered dose heterogeneity and it is expected that including the low-to-mid dose levels in the penumbral region will improve this match. This work was funded by the Cancer Prevention Research Institute of Texas (CPRIT).« less

The effect of single large dose hydrocortisone treatment on IgM and IgG antibody production, morphological distribution of antibody producing cells and immunological memory

PubMed Central

Petrányi, Gy.; Benczúr, M.; Alföldy, P.

1971-01-01

The effect of a single subcutaneous dose of hydrocortisone (730 mg/kg ∼ 21-day LD50) on the haemolysin response of mice to sheep erythrocyte antigen was examined. Hydrocortisone was administered once at times varying from 5 days before immunization with sheep erythrocytes to 9 days after antigen. Total suppression of the 7S haemolysin titre was brought about by treatment with single dose of 750 mg/kg in the period 5 days prior to antigen until 2 days after antigen; at the same time, the titre of 19S haemolysin exceeded the control 19S titre. Microplaque assay on the 5th day failed to confirm total suppression of 7S antibody synthesis, as 4 per cent of the splenic plaque-forming cells produced 7S. The same assay failed to verify the augmentation of 19S production on a cellular level, as the number of 19S plaque-forming was significantly decreased. Hydrocortisone could be shown to influence the morphology of the 19S antibody producing cells by increasing the percentage of mature cell types. A selective depressing activity by hydrocortisone on 7S memory was found. The theoretical implications of these findings are discussed. PMID:4934137

Impact of dose size in single fraction spatially fractionated (grid) radiotherapy for melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Hualin, E-mail: hualin.zhang@northwestern.edu, E-mail: hualinzhang@yahoo.com; Zhong, Hualiang; Barth, Rolf F.

2014-02-15

Purpose: To evaluate the impact of dose size in single fraction, spatially fractionated (grid) radiotherapy for selectively killing infiltrated melanoma cancer cells of different tumor sizes, using different radiobiological models. Methods: A Monte Carlo technique was employed to calculate the 3D dose distribution of a commercially available megavoltage grid collimator in a 6 MV beam. The linear-quadratic (LQ) and modified linear quadratic (MLQ) models were used separately to evaluate the therapeutic outcome of a series of single fraction regimens that employed grid therapy to treat both acute and late responding melanomas of varying sizes. The dose prescription point was atmore » the center of the tumor volume. Dose sizes ranging from 1 to 30 Gy at 100% dose line were modeled. Tumors were either touching the skin surface or having their centers at a depth of 3 cm. The equivalent uniform dose (EUD) to the melanoma cells and the therapeutic ratio (TR) were defined by comparing grid therapy with the traditional open debulking field. The clinical outcomes from recent reports were used to verify the authors’ model. Results: Dose profiles at different depths and 3D dose distributions in a series of 3D melanomas treated with grid therapy were obtained. The EUDs and TRs for all sizes of 3D tumors involved at different doses were derived through the LQ and MLQ models, and a practical equation was derived. The EUD was only one fifth of the prescribed dose. The TR was dependent on the prescribed dose and on the LQ parameters of both the interspersed cancer and normal tissue cells. The results from the LQ model were consistent with those of the MLQ model. At 20 Gy, the EUD and TR by the LQ model were 2.8% higher and 1% lower than by the MLQ, while at 10 Gy, the EUD and TR as defined by the LQ model were only 1.4% higher and 0.8% lower, respectively. The dose volume histograms of grid therapy for a 10 cm tumor showed different dosimetric characteristics from those of conventional radiotherapy. A significant portion of the tumor volume received a very large dose in grid therapy, which ensures significant tumor cell killing in these regions. Conversely, some areas received a relatively small dose, thereby sparing interspersed normal cells and increasing radiation tolerance. The radiobiology modeling results indicated that grid therapy could be useful for treating acutely responding melanomas infiltrating radiosensitive normal tissues. The theoretical model predictions were supported by the clinical outcomes. Conclusions: Grid therapy functions by selectively killing infiltrating tumor cells and concomitantly sparing interspersed normal cells. The TR depends on the radiosensitivity of the cell population, dose, tumor size, and location. Because the volumes of very high dose regions are small, the LQ model can be used safely to predict the clinical outcomes of grid therapy. When treating melanomas with a dose of 15 Gy or higher, single fraction grid therapy is clearly advantageous for sparing interspersed normal cells. The existence of a threshold fraction dose, which was found in the authors’ theoretical simulations, was confirmed by clinical observations.« less

Uracil-ftorafur: an oral fluoropyrimidine active in colorectal cancer.

PubMed

Sulkes, A; Benner, S E; Canetta, R M

1998-10-01

This review describes the early clinical development of uracil-ftorafur (UFT), an oral fluoropyrimidine, designed in 1978 by adding uracil to ftorafur. The review focuses on the treatment of colorectal cancer and summarizes the Japanese experience and the phase I and II trials performed in the United States and Europe. Clinical trials of UFT published in the Western world have included 581 patients with colorectal cancer. UFT has been administered in these trials as a single agent or biomodulated by leucovorin (LV). UFT was administered daily in split doses for periods that ranged from 14 to 28 days. The activity of oral UFT in large-bowel cancer when administered with oral LV (approximately 50 mg/dose) has resulted in objective response rates of approximately 40%. Response rates of approximately 25% (range, 17% to 39%) were reported when UFT was administered as a single agent or with lower doses of LV. The highest dose-intensities of UFT are achieved with 28-day schedules of administration. The maximum-tolerated dose (MTD) of UFT with this schedule, when administered concomitantly with oral LV 150 mg daily, is 300 mg/m2 daily. The dose-limiting toxicity (DLT) of UFT has generally been diarrhea. Other commonly described toxicities include nausea and vomiting, fatigue, and stomatitis. Myelosuppression occurs infrequently. Typically, hand-foot syndrome and neurologic toxicity are lacking. UFT is a fluoropyrimidine active in colorectal cancer. The oral route of administration and improved safety profile represent important advantages over both conventional and infusional fluorouracil (5-FU) regimens.

Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes.

PubMed

Hatorp, V; Huang, W C; Strange, P

1999-04-01

Pharmacokinetic profiles of single- and multiple-dose regimens of repaglinide were evaluated in 12 elderly subjects with type 2 diabetes. On day 1, following a 10-hour fast, subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, each subject received a 2-mg dose of repaglinide 15 minutes before each of the three main meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve (AUC), log(AUC), maximal concentration (Cmax), log(Cmax), time to maximal concentration (Tmax), and half-life (T(1/2)), were determined at completion of the single- and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7. The mean log(AUC) values after multiple dosing were significantly higher than the values obtained after a single dose. The mean values for log(Cmax), and Tmax were comparable after each dosing regimen. The T(1/2) of repaglinide after multiple dosing was 1.7 hours. The trough values for repaglinide were low. No hypoglycemic events were reported. The pharmacokinetic profiles of repaglinide after single- and multiple-dose regimens were similar, and repaglinide was well tolerated by elderly subjects with type 2 diabetes.

Effects of cosmic rays on single event upsets

NASA Technical Reports Server (NTRS)

Venable, D. D.; Zajic, V.; Lowe, C. W.; Olidapupo, A.; Fogarty, T. N.

1989-01-01

Assistance was provided to the Brookhaven Single Event Upset (SEU) Test Facility. Computer codes were developed for fragmentation and secondary radiation affecting Very Large Scale Integration (VLSI) in space. A computer controlled CV (HP4192) test was developed for Terman analysis. Also developed were high speed parametric tests which are independent of operator judgment and a charge pumping technique for measurement of D(sub it) (E). The X-ray secondary effects, and parametric degradation as a function of dose rate were simulated. The SPICE simulation of static RAMs with various resistor filters was tested.

Radiation-induced impairment of osseous healing: Quantitative studies usine a standard drilling defect in rat femur

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arnold, M.; Kummermehr, J.; Trott, K.R.

1995-07-01

The femora of adult Wistar rats were locally irradiated with single doses of X rays and 1 day later were wounded by a standardized drilling defect that extended through the diaphyseal cortex into the marrow cavity. Healing of the lesion was followed over 30 weeks to assess the time course of osseous closure. In unirradiated bones healing was complete by week 7. Irradiation with doses up to 15 Gy imparted a dose-dependent delay in the formation of primary callus and its subsequent replacement by more mature bone, while after higher doses healing doses healing remained permanently comprised or even suppressed.more » Using histomorphometry, osseous closure was also measured quantitatively for healing periods of 7, 10, 16 and 30 weeks and the data were expressed as the percentage of responders with {ge}40% fractional closure. the resulting dose-response curves were steep, displaying a large threshold dose and ED{sub 50} values between 16.8 to 17.5 Gy (7 to 16 weeks) and 19.4 Gy (30 weeks), respectively. 35 refs., 4 figs., 2 tabs.« less

Absorbed radiation dose in adults from iodine-131 and iodine-123 orthoiodohippurate and technetium-99m DTPA renography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carlsen, O.

1988-03-01

A mathematic model for evaluation of absorbed dose in radionuclide renography has been developed and programmed for automatic calculation in the computer. Input data to the model are readily available from the results of the renography and, hence, the method described is suitable for individual dose determinations in adults. Apart from the situation with very considerable outflow obstructions (/sup 131/I)OIH single probe renography involves a 15-20 times smaller dose to radiation sensitive organs than (/sup 123/I)OIH gamma camera renography. Further, the latter examination results in a 2-10 times smaller dose than (/sup 99m/Tc)DTPA gamma camera renography under normal outflow conditions.more » Absorbed renal dose is large, approximately 70 mGy, in the three renographies in the borderline case with total outflow obstructions. For comparison, i.v. pyelography, which is the x-ray examination often used instead of radionuclide renography, involves an absorbed dose to ovaries 10-1000 times larger than in radionuclide renography« less

The effects of peritoneal dialysis on the single dose and steady state pharmacokinetics of valproic acid in a uremic epileptic child.

PubMed

Orr, J M; Farrell, K; Abbott, F S; Ferguson, S; Godolphin, W J

1983-01-01

The pharmacokinetics of valproic acid (VPA) have been studied during peritoneal dialysis in a uremic male epileptic child following a single 500 mg dose and after multiple doses over 5 months (700 mg daily) of valproic acid as the syrup. Serum level decline was biphasic in both instances with a terminal half-life of 27.2 after the single dose and 10.2 h at steady-state. Total serum clearance was 0.0236 l/h/kg after the single dose and increased to 0.0408 l/h/kg after 5 months. Free (intrinsic) serum clearances were 0.1489 and 0.1518 l/h/kg and serum free fractions were 0.224 and 0.272 respectively for the single dose and steady-state studies. Peritoneal dialysis for periods of 12 or 24 h removed an average of 4.5% of the VPA dose.

Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity in Relapsed and Refractory Non-Hodgkin’s Lymphoma

PubMed Central

Jones, Jeffrey A.; Rupert, Amy S.; Poi, Ming; Phelps, Mitch A.; Andritsos, Leslie; Baiocchi, Robert; Benson, Don M.; Blum, Kristie A.; Christian, Beth; Flynn, Joseph; Penza, Sam; Porcu, Pierluigi; Grever, Michael R.; Byrd, John C.

2014-01-01

Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkin’s lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (cohort 1), mantle cell (cohort 2), intermediate grade B-cell including transformed lymphoma (cohort 3), and T-/NK-cell excluding primary cutaneous disease (cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common non-hematologic toxicties included diarrhea and fatigue. Biochemical tumor lysis was observed in only 2 patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m2 bolus + 50 mg/m2 continuous infusion weekly for 4 consecutive weeks of a 6 week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (2 mantle cell, 3 indolent B-cell, and 1 diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. PMID:23959599

Influence of Al³⁺ addition on the flocculation and sedimentation of activated sludge: comparison of single and multiple dosing patterns.

PubMed

Wen, Yue; Zheng, Wanlin; Yang, Yundi; Cao, Asheng; Zhou, Qi

2015-05-15

In this study, the flocculation and sedimentation performance of activated sludge (AS) with single and multiple dosing of trivalent aluminum (Al(3+)) were studied. The AS samples were cultivated in sequencing batch reactors at 22 °C. The dosages of Al(3+) were 0.00, 0.125, 0.5, 1.0, and 1.5 meq/L for single dosing, and 0.1 meq/L for multiple dosing. Under single dosing conditions, as Al(3+) dosage increased, the zeta potential, total interaction energy, and effluent turbidity decreased, whereas the sludge volume index (SVI) increased, indicating that single Al(3+) dosing could enhance sludge flocculation, but deteriorate sedimentation. By comparison, adding an equal amount of Al(3+) through multiple dosing achieved a similar reduction in turbidity, but the zeta potential was higher, while the loosely bound extracellular polymeric substances (LB-EPS) content and SVI remarkably declined. Although the difference in the flocculation performances between the two dosing patterns was not significant, the underlying mechanisms were quite distinct: the interaction energy played a more important role under single dosing conditions, whereas multiple dosing was more effective in reducing the EPS content. Multiple dosing, which allows sufficient time for sludge restructuring and floc aggregation, could simultaneously optimize sludge flocculation and sedimentation. Copyright © 2015 Elsevier Ltd. All rights reserved.

An international dosimetry exchange for boron neutron capture therapy. Part I: Absorbed dose measurements.

PubMed

Binns, P J; Riley, K J; Harling, O K; Kiger, W S; Munck af Rosenschöld, P M; Giusti, V; Capala, J; Sköld, K; Auterinen, I; Serén, T; Kotiluoto, P; Uusi-Simola, J; Marek, M; Viererbl, L; Spurny, F

2005-12-01

An international collaboration was organized to undertake a dosimetry exchange to enable the future combination of clinical data from different centers conducting neutron capture therapy trials. As a first step (Part I) the dosimetry group from the Americas, represented by MIT, visited the clinical centers at Studsvik (Sweden), VTT Espoo (Finland), and the Nuclear Research Institute (NRI) at Rez (Czech Republic). A combined VTT/NRI group reciprocated with a visit to MIT. Each participant performed a series of dosimetry measurements under equivalent irradiation conditions using methods appropriate to their clinical protocols. This entailed in-air measurements and dose versus depth measurements in a large water phantom. Thermal neutron flux as well as fast neutron and photon absorbed dose rates were measured. Satisfactory agreement in determining absorbed dose within the experimental uncertainties was obtained between the different groups although the measurement uncertainties are large, ranging between 3% and 30% depending upon the dose component and the depth of measurement. To improve the precision in the specification of absorbed dose amongst the participants, the individually measured dose components were normalized to the results from a single method. Assuming a boron concentration of 15 microg g(-1) that is typical of concentrations realized clinically with the boron delivery compound boronophenylalanine-fructose, systematic discrepancies in the specification of the total biologically weighted dose of up to 10% were apparent between the different groups. The results from these measurements will be used in future to normalize treatment plan calculations between the different clinical dosimetry protocols as Part II of this study.

Single-Dose Pharmacokinetics and Safety of Ziprasidone in Children and Adolescents

ERIC Educational Resources Information Center

Sallee, Floyd R.; Miceli, Jeffrey J.; Tensfeldt, Thomas; Robarge, Lisa; Wilner, Keith; Patel, Nick C.

2006-01-01

Objective: The purpose of this study was to provide single-dose pharmacokinetic, safety, and tolerability data for ziprasidone in youths with tic disorder, for comparison to adult studies to discern whether ziprasidone pediatric dosing could be modeled from adult data. Method: A single-dose, open-label study of ziprasidone was conducted in youths…

WE-EF-BRA-02: A Monte Carlo Study of Macroscopic and Microscopic Dose Descriptors for Kilovoltage Cellular Dosimetry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oliver, P; Thomson, R

2015-06-15

Purpose: To investigate how doses to cellular (microscopic) targets depend on cell morphology, and how cellular doses relate to doses to bulk tissues and water for 20 to 370 keV photon sources using Monte Carlo (MC) simulations. Methods: Simulation geometries involve cell clusters, single cells, and single nuclear cavities embedded in various healthy and cancerous bulk tissue phantoms. A variety of nucleus and cytoplasm elemental compositions are investigated. Cell and nucleus radii range from 5 to 10 microns and 2 to 9 microns, respectively. Doses to water and bulk tissue cavities are compared to nucleus and cytoplasm doses. Results: Variationsmore » in cell dose with simulation geometry are most pronounced for lower energy sources. Nuclear doses are sensitive to the surrounding geometry: the nuclear dose in a multicell model differs from the dose to a cavity of nuclear medium in an otherwise homogeneous bulk tissue phantom by more than 7% at 20 keV. Nuclear doses vary with cell size by up to 20% at 20 keV, with 10% differences persisting up to 90 keV. Bulk tissue and water cavity doses differ from cellular doses by up to 16%. MC results are compared to cavity theory predictions; large and small cavity theories qualitatively predict nuclear doses for energies below and above 50 keV, respectively. Burlin’s (1969) intermediate cavity theory best predicts MC results with an average discrepancy of 4%. Conclusion: Cellular doses vary as a function of source energy, subcellular compartment size, elemental composition, and tissue morphology. Neither water nor bulk tissue is an appropriate surrogate for subcellular targets in radiation dosimetry. The influence of microscopic inhomogeneities in the surrounding environment on the nuclear dose and the importance of the nucleus as a target for radiation-induced cell death emphasizes the potential importance of cellular dosimetry for understanding radiation effects. Funded by the Natural Sciences and Engineering Research Council of Canada (NSERC), the Canada Research Chairs Program (CRC), and the Ontario Ministry of Training, Colleges and Universities.« less

Continuous spinal anaesthesia versus single dosing. A comparative study.

PubMed

De Andrés, J A; Febré, E; Bellver, J; Bolinches, R

1995-03-01

Continuous and single dose spinal anaesthesia were compared in a prospective randomized fashion in 108 patients undergoing orthopaedic surgery. Continuous spinal anaesthesia was via a 20 gauge polyamide multiperforated catheter introduced through an 18 gauge Tuohy needle. Single-dose spinal anaesthesia was performed with a 24 guage x 103 mm Sprotte spinal needle. The mean local anaesthetic dose for the continuous technique was 38.4 (SD 16.5) mg as hyperbaric lignocaine 5%, and for the single-dose spinal anaesthesia 10.8 (SD 2.2) mg as hyperbaric bupivacaine 0.5%. Segmental levels reached with the initial dose did not differ significantly between the two groups. Mean time required to perform continuous spinal anaesthesia was 6.7 (SD 3.9) min, which was longer than for single dose 4.9 (SD 2.8) min (P < 0.05). The onset time and efficacy of anaesthesia, and the duration of the operation were similar in the two groups. Analgesia was inadequate in six patients who received continuous spinal anaesthesia (11%) and one patient who received single dose (2%) (P = 0.18). Hypotension was more frequent in those receiving single doses (P < 0.05). Caudal rotation of the outlet needle orifice to advance the catheter correlated with inadequate analgesia (P < 0.01, r = 0.38). There were no significant differences in the incidence of post-operative complications.

Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers.

PubMed Central

Siemann, D. W.

1982-01-01

The effect of combinations of the conventional chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and nitroimidazole radiation sensitizers was evaluated in female C3H mice. Tumour response to single-agent or combination therapy was assessed in a tumour growth-delay assay. In the KHT sarcoma the simultaneous addition of misonidazole (MISO) was found to increase significantly the tumour growth delay resulting from CCNU treatment. The observed enhancement ratios (ER) increased with MISO dose, and ranged from 1.3 to 1.9 for sensitizer doses of 0.25-1.0 mg/g. The combination of CCNU and 1.0 or 0.5 mg/g MISO in the RIF-1 tumour or the MT-1 tumour produced ERs of approximately 2.0 and approximately 1.5 respectively. In the KHT sarcoma a series of other nitroimidazole sensitizers, including Ro-05-9963, SR-2555, SR-2508 and metronidazole (METRO), were also evaluated at equimolar doses (5 mmol/kg) in combination with a 20mg/kg dose of CCNU. Unlike MISO, these compounds in general failed to enhance the CCNU cytotoxicity in this tumour model. However, SR-2508 did enhance the response of the RIF-1 tumour to large single doses of CCNU, though not as much as MISO. Normal-tissue toxicity was determined using peripheral white blood cell (WBC) counts 3 days after treatment. CCNU doses of 10-50 mg/kg given either alone or in simultaneous combination with 0.5 or 1.0 mg/g MISO were studied. WBC toxicity increased with CCNU dose, but the addition of MISO at either dose did not significantly enhance this normal-tissue toxicity. PMID:6460517

Radiation dose reduction using a neck detection algorithm for single spiral brain and cervical spine CT acquisition in the trauma setting.

PubMed

Ardley, Nicholas D; Lau, Ken K; Buchan, Kevin

2013-12-01

Cervical spine injuries occur in 4-8 % of adults with head trauma. Dual acquisition technique has been traditionally used for the CT scanning of brain and cervical spine. The purpose of this study was to determine the efficacy of radiation dose reduction by using a single acquisition technique that incorporated both anatomical regions with a dedicated neck detection algorithm. Thirty trauma patients for brain and cervical spine CT were included and were scanned with the single acquisition technique. The radiation doses from the single CT acquisition technique with the neck detection algorithm, which allowed appropriate independent dose administration relevant to brain and cervical spine regions, were recorded. Comparison was made both to the doses calculated from the simulation of the traditional dual acquisitions with matching parameters, and to the doses of retrospective dual acquisition legacy technique with the same sample size. The mean simulated dose for the traditional dual acquisition technique was 3.99 mSv, comparable to the average dose of 4.2 mSv from 30 previous patients who had CT of brain and cervical spine as dual acquisitions. The mean dose from the single acquisition technique was 3.35 mSv, resulting in a 16 % overall dose reduction. The images from the single acquisition technique were of excellent diagnostic quality. The new single acquisition CT technique incorporating the neck detection algorithm for brain and cervical spine significantly reduces the overall radiation dose by eliminating the unavoidable overlapping range between 2 anatomical regions which occurs with the traditional dual acquisition technique.

Dimensional isotropy of 6H and 3C SiC under neutron irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Snead, Lance L.; Katoh, Yutai; Koyanagi, Takaaki

2016-01-16

This investigation experimentally determines the as-irradiated crystal axes dimensional change of the common polytypes of SiC considered for nuclear application. Single crystal α-SiC (6H), β-SiC (3C), CVD β-SiC, and single crystal Si have been neutron irradiated near 60 °C from 2 × 10 23 to 2 × 10 26 n/m 2 (E > 0.1 MeV), or about 0.02–20 dpa, in order to study the effect of irradiation on bulk swelling and strain along independent crystalline axes. Single crystal, powder diffractometry and density measurement have been carried out. For all neutron doses where the samples remained crystalline all SiC materials demonstratedmore » equivalent swelling behavior. Moreover the 6H–SiC expanded isotropically. The magnitude of the swelling followed a ~0.77 power law against dose consistent with a microstructure evolution driven by single interstitial (carbon) mobility. Extraordinarily large ~7.8% volume expansion in SiC was observed prior to amorphization. Above ~0.9 × 10 25 n/m 2 (E > 0.1 MeV) all SiC materials became amorphous with an identical swelling: a 11.7% volume expansion, lowering the density to 2.84 g/cm 3. As a result, the as-amorphized density was the same at the 2 × 10 25 and 2 × 10 26 n/m 2 (E > 0.1 MeV) dose levels.« less

Duration of treatment for asymptomatic bacteriuria during pregnancy.

PubMed

Widmer, Mariana; Lopez, Ivana; Gülmezoglu, A Metin; Mignini, Luciano; Roganti, Ariel

2015-11-11

A previous Cochrane systematic review has shown that antibiotic drug treatment of asymptomatic bacteriuria in pregnant women substantially decreases the risk of pyelonephritis and reduces the risk of preterm delivery. However, it is not clear whether single-dose therapy is as effective as longer conventional antibiotic treatment. To assess the effects of different durations of treatment for asymptomatic bacteriuria in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2015) and reference lists of identified articles. Randomized and quasi-randomized trials comparing antimicrobial therapeutic regimens that differed in duration (particularly comparing single dose with longer duration regimens) in pregnant women diagnosed with asymptomatic bacteriuria. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. We included 13 studies, involving 1622 women. All were comparisons of single-dose treatment with short-course (four- to seven-day) treatments. The risk of bias of trials included in this review was largely unclear, and most trials were at high risk of performance bias. The quality of the evidence was assessed using the GRADE approach. When the any antibiotic agent was used, the 'no cure' rate for asymptomatic bacteriuria in pregnant women was slightly lower for the short-course treatment over the single-dose treatment, although there was evidence of statistical heterogeneity (average risk ratio (RR) 1.28, 95% confidence interval (CI) 0.87 to 1.88; women = 1502, studies = 13; I² = 56%; very low quality evidence). Data from only good quality trials also showed better cure rates with short (four- to seven-day) regimens of the same microbial agent (average RR 1.72, 95% CI 1.27 to 2.33; women = 803, studies = two; I² = 0%; high quality evidence). There was no clear difference in the recurrence of asymptomatic bacteriuria rate between treatment and control groups, whether the same or different microbial agents were used (RR 1.13, 95% CI 0.77 to 1.66; 445 women studies = eight; I² = 0%; very low quality evidence). Differences were detected for low birthweight babies, favoring a short course (four- to seven-day treatment) of the same microbial agent, although the data come from a single trial (RR 1.65, 95% CI 1.06 to 2.57; 714 women; high quality evidence), but no differences were observed for preterm delivery (RR 1.17, 95% CI 0.77 to 1.78; women = 804; studies = three; I² = 23%; moderate quality) or pyelonephritis (RR 3.09, 95% CI 0.54 to 17.55; women = 102; studies = two; I² = 0%; very low quality evidence). Finally, single-dose treatment of any microbial agent was associated with a decrease in reports of 'any side effects' (RR 0.70, 95% CI 0.56 to 0.88; 1460 women, studies = 12; I² = 9%; low quality evidence). Evidence was downgraded for risk of bias concerns in trials contributing data and for imprecise effect estimates (wide confidence intervals crossing the line of no effect, and in some cases, small studies with few events). A single-dose regimen of antibiotics may be less effective than a short-course (four- to seven-day) regimen, but more evidence is needed from large trials measuring important outcomes, such as cure rate. Women with asymptomatic bacteriuria in pregnancy should be treated by the standard regimen of antibiotics until more data become available testing seven-day treatment compared with shorter courses of three- or five-day regimens.

Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study).

PubMed

Hegarty, Joanne Elizabeth; Harding, Jane Elizabeth; Gamble, Gregory David; Crowther, Caroline Anne; Edlin, Richard; Alsweiler, Jane Marie

2016-10-01

Neonatal hypoglycaemia is common, affecting up to 15% of newborns, and can cause brain damage. Currently, there are no strategies, beyond early feeding, to prevent neonatal hypoglycaemia. Our aim was to determine a dose of 40% oral dextrose gel that will prevent neonatal hypoglycaemia in newborn babies at risk. We conducted a randomised, double-blind, placebo-controlled dose-finding trial of buccal dextrose gel to prevent neonatal hypoglycaemia at two hospitals in New Zealand. Babies at risk of hypoglycaemia (infant of a mother with diabetes, late preterm delivery, small or large birthweight, or other risk factors) but without indication for admission to a neonatal intensive care unit (NICU) were randomly allocated either to one of four treatment groups: 40% dextrose at one of two doses (0.5 ml/kg = 200 mg/kg, or 1 ml/kg = 400 mg/kg), either once at 1 h of age or followed by three additional doses of dextrose (0.5 ml/kg before feeds in the first 12 h); or to one of four corresponding placebo groups. Treatments were administered by massaging gel into the buccal mucosa. The primary outcome was hypoglycaemia (<2.6 mM) in the first 48 h. Secondary outcomes included admission to a NICU, admission for hypoglycaemia, and breastfeeding at discharge and at 6 wk. Prespecified potential dose limitations were tolerance of gel, time taken to administer, messiness, and acceptability to parents. From August 2013 to November 2014, 416 babies were randomised. Compared to babies randomised to placebo, the risk of hypoglycaemia was lowest in babies randomised to a single dose of 200 mg/kg dextrose gel (relative risk [RR] 0.68; 95% confidence interval [CI] 0.47-0.99, p = 0.04) but was not significantly different between dose groups (p = 0.21). Compared to multiple doses, single doses of gel were better tolerated, quicker to administer, and less messy, but these limitations were not different between dextrose and placebo gel groups. Babies who received any dose of dextrose gel were less likely to develop hypoglycaemia than those who received placebo (RR 0.79; 95% CI 0.64-0.98, p = 0.03; number needed to treat = 10, 95% CI 5-115). Rates of NICU admission were similar (RR 0.64; 95% CI 0.33-1.25, p = 0.19), but admission for hypoglycaemia was less common in babies randomised to dextrose gel (RR 0.46; 95% CI 0.21-1.01, p = 0.05). Rates of breastfeeding were similar in both groups. Adverse effects were uncommon and not different between groups. A limitation of this study was that most of the babies in the trial were infants of mothers with diabetes (73%), which may reduce the applicability of the results to babies from other risk groups. The incidence of neonatal hypoglycaemia can be reduced with a single dose of buccal 40% dextrose gel 200 mg/kg. A large randomised trial (Hypoglycaemia Prevention with Oral Dextrose [hPOD]) is under way to determine the effects on NICU admission and later outcomes. Australian New Zealand Clinical Trials Registry ACTRN12613000322730.

Application of the concept of biologically effective dose (BED) to patients with Vestibular Schwannomas treated by radiosurgery

PubMed Central

Millar, William T.; Lindquist, Christer; Nordström, Håkan; Lidberg, Pär; Gårding, Jonas

2013-01-01

In the application of stereotactic radiosurgery, using the Gamma Knife, there are large variations in the overall treatment time for the same prescription dose, given in a single treatment session, for different patients. This is due to not only changes in the activity of the Cobolt-60 sources, but also to variations in the number of iso-centers used, the collimator size for a particular iso-center, and the time gap between the different iso-centers. Although frequently viewed as a single dose treatment the concept of biologically effective dose (BED), incorporating concurrent fast and a slow components of repair of sublethal damage, would imply potential variations in BED because of the influence of these different variables associated with treatment. This was investigated in 26 patients, treated for Vestibular Schwannomas, using the Series B Gamma-Knife, between 1999 and 2005. The iso-center number varied between 2 and 13, and the overall treatment time from 25.4–129.58 min. The prescription doses varied from 10–14 Gy. To obtain physical dose and dose-rates from each iso-center, in a number of locations in the region of interest, a prototype version of the Leksell GammaPlan® was used. For an individual patient, BED values varied by up to 15% for a given physical iso-dose. This was due to variation in the dose prescription at different locations on that iso-dose. Between patients there was a decline in the range of BED values as the overall treatment time increased. This increased treatment time was partly a function of the slow decline in the activity of the sources with time but predominantly due to changes in the number of iso-centers used. Thus, variations in BED values did not correlate with prescription dose but was modified by the overall treatment time. PMID:29296371

Single Dose Versus 3 Doses of Intramuscular Benzathine Penicillin for Early Syphilis in HIV: A Randomized Clinical Trial.

PubMed

Andrade, Roberto; Rodriguez-Barradas, Maria C; Yasukawa, Kosuke; Villarreal, Erick; Ross, Michael; Serpa, Jose A

2017-03-15

Patients coinfected with syphilis and human immunodeficiency virus (HIV) may have a slower decrease in rapid plasma reagin (RPR) titers. Currently a single dose of 2.4 million units of intramuscular benzathine penicillin G (BPG) is recommended for the treatment of early syphilis. Some observational studies have suggested that this regimen may lead to high failure rates in coinfected patients. We conducted an open-label randomized clinical trial to compare the efficacy of single-dose and 3-dose regimens of BPG for the treatment of early syphilis in HIV-infected individuals. RPR titers were monitored every 3 months. Treatment success was defined as a decrease in RPR titers of ≥2 dilutions (4-fold) during a 12-month follow-up period. Sixty-four patients were included. In the intention-to-treat analysis, treatment success rates were 80% (28 of 35 subjects) and 93% (27 of 29 subjects) in the single-dose and 3-dose regimens, respectively (absolute difference, 13% [95% confidence interval {CI}, -5% to 30%; P = .17). In the per-protocol analysis, success rates were 93% (27 of 29) and 100% in the single-dose and 3-dose regimens, respectively (absolute difference, 7% [95% CI, -7% to 22%]; P = .49). CD4 T-cell count, RPR titer and syphilis stage did not affect treatment results. When compared with a single dose of BPG, a 3-dose regimen did not improve syphilis serological outcomes. Our results support the Centers for Disease Control and Prevention recommendation of a single dose of BPG in HIV-infected patients with early syphilis. NCT02611765. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Juvenile Male Rats Exposed to a Low-Dose Mixture of Twenty-Seven Environmental Chemicals Display Adverse Health Effects

PubMed Central

Svingen, Terje; Mandrup, Karen; Skov, Kasper; Pedersen, Mikael; Frederiksen, Hanne; Frandsen, Henrik Lauritz; Vinggaard, Anne Marie

2016-01-01

Humans are exposed to a large number of environmental chemicals in their daily life, many of which are readily detectable in blood or urine. It remains uncertain if these chemicals can cause adverse health effects when present together at low doses. In this study we have tested whether a mixture of 27 chemicals administered orally to juvenile male rats for three months could leave a pathophysiological footprint. The mixture contained metals, perfluorinated compounds, PCB, dioxins, pesticides, heterocyclic amines, phthalate, PAHs and others, with a combined dose of 0.16 (Low dose), 0.47 (Mid dose) or 1.6 (High dose) mg/kg bw/day. The lowest dose was designed with the aim of obtaining plasma or urine concentrations in rats at levels approaching those observed in humans. Some single congeners were administered at doses representative of combined doses for chemical groups. With this baseline, we found effects on weight, histology and gene expression in the liver, as well as changes to the blood plasma metabolome in all exposure groups, including low-dose. Additional adverse effects were observed in the higher dosed groups, including enlarged kidneys and alterations to the metabolome. No significant effects on reproductive parameters were observed. PMID:27598887

Pharmacokinetic study to compare the absorption and tolerability of two doses of levonorgestrel following single vaginal administration of levonorgestrel in Carraguard gel: a new formulation for "dual protection" contraception.

PubMed

Sitruk-Ware, Regine; Brache, Vivian; Maguire, Robin; Croxatto, Horacio; Kumar, Narender; Kumar, Sushma; Montero, Juan Carlos; Salvatierra, Ana Maria; Phillips, David; Faundes, Anibal

2007-06-01

The study was conducted to assess levonorgestrel (LNG) serum levels achieved after a single administration of two different doses of Carraguard vaginal gel containing LNG (CARRA/LNG), designed for use as microbicide and contraceptive for potential dual protection. This was a randomized double-blind pharmacokinetic study conducted in 12 subjects enrolled at two centers. Each subject received a single vaginal administration of CARRA/LNG containing either 0.75 or 1.5 mg LNG per 4 mL of gel on Days 10-12 of the menstrual cycle. LNG serum levels were measured at 0, 1, 2, 4, 8 and 12 h after administration and for the following 7 days. LH and progesterone (for a preliminary evaluation of effect on the ovarian function) as well as SHBG were measured in the daily samples. Serum LNG maximum concentrations (Cmax) were 14.1+/-2.1 and 11.7+/-2.7 nmol/L and Tmax was 12.0 and 6.0 h for the low and high dose, respectively, with large intersubject variability within the first 48 h. Mean levels at 96 h were 10% of Cmax. Differences in AUC between both doses were not statistically significant. SHBG levels decreased approximately 25% by Day 4 after administration. Luteal activity was observed in 3/6 and 5/6 of the subjects in the low- and high-dose group, respectively. This study demonstrates that the CARRA/LNG gel can sustain elevated serum levels of the contraceptive steroid for up to 96 h after a single application. The serum levels attained with the 0.75-mg formulation are in the range expected to perturb the ovulatory process as observed in some subjects. The lack of correlation between the administered dose and serum concentrations of the steroid may be related to a rate-limiting absorption of LNG from the vaginal mucosa. The results reported here suggest that the CARRA/LNG formulation has good potential to become a dual-protection method, possibly preventing conception and sexually transmitted infections.

Pharmacokinetic study to compare the absorption and tolerability of two doses of levonorgestrel following single vaginal administration of levonorgestrel in Carraguard® gel: a new formulation for “dual protection” contraception

PubMed Central

Sitruk-Ware, R; Brache, V; Maguire, R; Croxatto, H; Kumar, N; Kumar, S; Montero, JC; Salvatierra, AM; Phillips, D; Faundes, A

2007-01-01

Objective: The study was conducted to assess levonorgestrel (LNG) serum levels achieved after a single administration of two different doses of Carraguard vaginal gel containing LNG (CARRA/LNG), designed for use as microbicide and contraceptive for potential dual-protection. Materials and methods: This was a randomized double-blind pharmacokinetic study conducted in 12 subjects enrolled at two centers. Each subject received a single vaginal administration of CARRA/LNG containing either 0.75 or 1.5 mg LNG per 4 mL of gel on day 10-12 of the menstrual cycle. LNG serum levels were measured at 0, 1, 2, 4, 8 and 12 h after administration and for the following seven days. LH and progesterone (for a preliminary evaluation of effect on the ovarian function) as well as SHBG were measured in the daily samples. Results: Serum LNG maximum concentrations (Cmax) were 14.1 ± 5.1 and 11.7 ± 6.5 nmol/L and Tmax was 12.0 and 6.0 h for the low and high dose, respectively, with large intersubject variability within the first 48 h. Mean levels at 96 h were 10% of Cmax. Differences in AUC between both doses were not statistically significant. SHBG levels decreased approximately 25% by day 4 after administration. Luteal activity was observed in 3/6 and 5/6 of the subjects in the low and high dose group, respectively. Conclusion: This study demonstrates that the CARRA/LNG gel can sustain elevated serum levels of the contraceptive steroid for up to 96 h after a single application. The serum levels attained with the 0.75 mg formulation are in the range expected to perturb the ovulatory process as observed in some subjects. The lack of correlation between the administered dose and serum concentrations of the steroid may be related to a rate-limiting absorption of LNG from the vaginal mucosa. The results reported here suggest that the CARRA/LNG formulation has good potential to become a dual-protection method, possibly preventing conception and sexually transmitted infections. PMID:17519152

Post-focus expansion of ion beams for low fluence and large area MeV ion irradiation: Application to human brain tissue and electronics devices

NASA Astrophysics Data System (ADS)

Whitlow, Harry J.; Guibert, Edouard; Jeanneret, Patrick; Homsy, Alexandra; Roth, Joy; Krause, Sven; Roux, Adrien; Eggermann, Emmanuel; Stoppini, Luc

2017-08-01

Irradiation with ∼3 MeV proton fluences of 106-109 protons cm-2 have been applied to study the effects on human brain tissue corresponding to single-cell irradiation doses and doses received by electronic components in low-Earth orbit. The low fluence irradiations were carried out using a proton microbeam with the post-focus expansion of the beam; a method developed by the group of Breese [1]. It was found from electrophysiological measurements that the mean neuronal frequency of human brain tissue decreased to zero as the dose increased to 0-1050 Gy. Enhancement-mode MOSFET transistors exhibited a 10% reduction in threshold voltage for 2.7 MeV proton doses of 10 Gy while a NPN bipolar transistor required ∼800 Gy to reduce the hfe by 10%, which is consistent the expected values.

Field trial on the treatment of fasciolopsiasis with praziquantel.

PubMed

Bunnag, D; Radomyos, P; Harinasuta, T

1983-06-01

Eight-five of 816 (10.7%) students attending a primary school in Central Thailand were examined and found infected with Fasciolopsis buski. All of students ate fresh water lily stems and most ate other fresh water plants including caltrop, water cress and morning glory. The 85 students were given praziquantel in randomized single doses of 15, 25 or 40 mg/kg body weight. Side effects were mild and transient and consisted of headache, dizziness, nausea, sleepiness, abdominal discomfort, anorexia, diarrhea, epigastric pain, vomiting and lassitude. Those receiving the highest dosages had more side effects than students in the other 2 groups. Large blisters were observed on the tegument of F. buski passed in feces and this was believed to be caused by the drug. The authors recommend a single dose of praziquantel in a dosage of 15 mg/kg of body weight for the treatment of parasitosis.

Sensitive X-ray detectors made of methylammonium lead tribromide perovskite single crystals

NASA Astrophysics Data System (ADS)

Wei, Haotong; Fang, Yanjun; Mulligan, Padhraic; Chuirazzi, William; Fang, Hong-Hua; Wang, Congcong; Ecker, Benjamin R.; Gao, Yongli; Loi, Maria Antonietta; Cao, Lei; Huang, Jinsong

2016-05-01

The large mobilities and carrier lifetimes of hybrid perovskite single crystals and the high atomic numbers of Pb, I and Br make them ideal for X-ray and gamma-ray detection. Here, we report a sensitive X-ray detector made of methylammonium lead bromide perovskite single crystals. A record-high mobility-lifetime product of 1.2 × 10-2 cm2 V-1 and an extremely small surface charge recombination velocity of 64 cm s-1 are realized by reducing the bulk defects and passivating surface traps. Single-crystal devices with a thickness of 2-3 mm show 16.4% detection efficiency at near zero bias under irradiation with continuum X-ray energy up to 50 keV. The lowest detectable X-ray dose rate is 0.5 μGyair s-1 with a sensitivity of 80 μC Gy-1air cm-2, which is four times higher than the sensitivity achieved with α-Se X-ray detectors. This allows the radiation dose applied to a human body to be reduced for many medical and security check applications.

A food effect study and dose proportionality study to assess the pharmacokinetics and safety of bardoxolone methyl in healthy volunteers.

PubMed

Teuscher, Nathan S; Kelley, Richard J; Dumas, Emily O; Klein, Cheri Enders; Awni, Walid M; Meyer, Colin J

2014-07-01

This study investigated the effect of food on the plasma pharmacokinetics of bardoxolone methyl, an antioxidant inflammation modulator, at a 20 mg dose, and the dose proportionality of bardoxolone methyl pharmacokinetics from 20 to 80 mg. It was a single-dose study conducted at a single center in 32 healthy volunteers aged 18-45 years using an amorphous spray-dried dispersion formulation of bardoxolone methyl. In Part A, 16 subjects received single 20 mg doses of bardoxolone methyl under fasting and non-fasting conditions. In Part B, 16 subjects received a single 60 or 80 mg dose of bardoxolone methyl and a matching placebo dose under fasting conditions. Blood samples for pharmacokinetic analysis were taken over 120 hours following dose administration. Single dose administration of 20, 60, and 80 mg bardoxolone methyl was safe and well-tolerated in healthy volunteers. Total bardoxolone methyl exposure was unchanged in the presence of food. However, doses of bardoxolone methyl above 20 mg appear to have a saturated dissolution or absorption process and are associated with less than proportional increases in drug exposure. © 2013, The American College of Clinical Pharmacology.

Thermoluminescence kinetics of pyrite (FeS2)

NASA Astrophysics Data System (ADS)

Silverman, A. N.; Levy, P. W.; Kierstead, J. A.

Thermoluminescence of pyrite (FeS2) was investigated to study the kinetics of single peak glow curves. The material used normally exhibits one large and four small peaks. However a glow curve can be obtained with only the large single peak that is suitable for testing thermoluminescence kinetics. Glow curves from aliquots of a single natural pyrite crystal studied in detail contain two low intensity thermoluminescence (TL) peaks at approximately 90 and 250 C, and two chemiluminescence (CL) peaks at approximately 350 and 430 C. The CL peaks are largely removable by initially heating the sample chamber under vacuum, pumping through liquid nitrogen traps, and recording glow curves immediately after helium is introduced, procedures which reduce system contaminants that react with pyrite. The shape, the variation of the temperature of the peak maximum (T(sub max)) with dose, and the retrapping to recombination cross section ratio (sigma) of the large 250 C peak are better described by the general one trap (GOT) kinetic equation, the basic equation from which the 1st and 2nd order kinetic equations are obtained as special cases, than by the 1st and 2nd order equations.

Volumetric-modulated arc therapy for the treatment of a large planning target volume in thoracic esophageal cancer.

PubMed

Abbas, Ahmar S; Moseley, Douglas; Kassam, Zahra; Kim, Sun Mo; Cho, Charles

2013-05-06

Recently, volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time compared to conventional intensity-modulated fixed-field treatment (IMRT). We applied the hypothesis of VMAT technique for the treatment of thoracic esophageal carcinoma to determine superior or equivalent conformal dose coverage for a large thoracic esophageal planning target volume (PTV) with superior or equivalent sparing of organs-at-risk (OARs) doses, and reduce delivery time and monitor units (MUs), in comparison with conventional fixed-field IMRT plans. We also analyzed and compared some other important metrics of treatment planning and treatment delivery for both IMRT and VMAT techniques. These metrics include: 1) the integral dose and the volume receiving intermediate dose levels between IMRT and VMATI plans; 2) the use of 4D CT to determine the internal motion margin; and 3) evaluating the dosimetry of every plan through patient-specific QA. These factors may impact the overall treatment plan quality and outcomes from the individual planning technique used. In this study, we also examined the significance of using two arcs vs. a single-arc VMAT technique for PTV coverage, OARs doses, monitor units and delivery time. Thirteen patients, stage T2-T3 N0-N1 (TNM AJCC 7th edn.), PTV volume median 395 cc (range 281-601 cc), median age 69 years (range 53 to 85), were treated from July 2010 to June 2011 with a four-field (n = 4) or five-field (n = 9) step-and-shoot IMRT technique using a 6 MV beam to a prescribed dose of 50 Gy in 20 to 25 F. These patients were retrospectively replanned using single arc (VMATI, 91 control points) and two arcs (VMATII, 182 control points). All treatment plans of the 13 study cases were evaluated using various dose-volume metrics. These included PTV D99, PTV D95, PTV V9547.5Gy(95%), PTV mean dose, Dmax, PTV dose conformity (Van't Riet conformation number (CN)), mean lung dose, lung V20 and V5, liver V30, and Dmax to the spinal canal prv3mm. Also examined were the total plan monitor units (MUs) and the beam delivery time. Equivalent target coverage was observed with both VMAT single and two-arc plans. The comparison of VMATI with fixed-field IMRT demonstrated equivalent target coverage; statistically no significant difference were found in PTV D99 (p = 0.47), PTV mean (p = 0.12), PTV D95 and PTV V9547.5Gy (95%) (p = 0.38). However, Dmax in VMATI plans was significantly lower compared to IMRT (p = 0.02). The Van't Riet dose conformation number (CN) was also statistically in favor of VMATI plans (p = 0.04). VMATI achieved lower lung V20 (p = 0.05), whereas lung V5 (p = 0.35) and mean lung dose (p = 0.62) were not significantly different. The other OARs, including spinal canal, liver, heart, and kidneys showed no statistically significant differences between the two techniques. Treatment time delivery for VMATI plans was reduced by up to 55% (p = 5.8E-10) and MUs reduced by up to 16% (p = 0.001). Integral dose was not statistically different between the two planning techniques (p = 0.99). There were no statistically significant differences found in dose distribution of the two VMAT techniques (VMATI vs. VMATII) Dose statistics for both VMAT techniques were: PTV D99 (p = 0.76), PTV D95 (p = 0.95), mean PTV dose (p = 0.78), conformation number (CN) (p = 0.26), and MUs (p = 0.1). However, the treatment delivery time for VMATII increased significantly by two-fold (p = 3.0E-11) compared to VMATI. VMAT-based treatment planning is safe and deliverable for patients with thoracic esophageal cancer with similar planning goals, when compared to standard IMRT. The key benefit for VMATI was the reduction in treatment delivery time and MUs, and improvement in dose conformality. In our study, we found no significant difference in VMATII over single-arc VMATI for PTV coverage or OARs doses. However, we observed significant increase in delivery time for VMATII compared to VMATI.

Dissolution and subsequent re-crystallization as zeroing mechanism, thermal properties and component resolved dose response of salt (NaCl) for retrospective dosimetry.

PubMed

Polymeris, George S; Kitis, George; Kiyak, Nafiye G; Sfamba, Ioanna; Subedi, Bhagawan; Pagonis, Vasilis

2011-09-01

In the present study we report dosimetric properties of iodized salt aiming at using it as an accidental luminescent dosimeter. It was found that the very good sensitivity of its main dosimetric peak is strongly affected by thermal treatments. This is also the case for OSL emission. The sensitivity loss due to heating implies that caution should be exercised while applying single aliquot protocols for dose evaluation. The sequence of dissolution and subsequent re-crystallization was established to be an extremely effective zeroing mechanism for the TL signal. The linearity in the dose response was also monitored in the case of dissolved and subsequently re-crystallized salt. In the case of naturally occurring salt, zeroing of the TL signal due to dissolution as well as the linearity of dose response up to doses as large as 100 Gy were found to be very promising features for dating applications. Copyright © 2011 Elsevier Ltd. All rights reserved.

Asynchronous data acquisition and on-the-fly analysis of dose fractionated cryoEM images by UCSFImage

PubMed Central

Li, Xueming; Zheng, Shawn; Agard, David A.; Cheng, Yifan

2015-01-01

Newly developed direct electron detection cameras have a high image output frame rate that enables recording dose fractionated image stacks of frozen hydrated biological samples by electron cryomicroscopy (cryoEM). Such novel image acquisition schemes provide opportunities to analyze cryoEM data in ways that were previously impossible. The file size of a dose fractionated image stack is 20 ~ 60 times larger than that of a single image. Thus, efficient data acquisition and on-the-fly analysis of a large number of dose-fractionated image stacks become a serious challenge to any cryoEM data acquisition system. We have developed a computer-assisted system, named UCSFImage4, for semi-automated cryo-EM image acquisition that implements an asynchronous data acquisition scheme. This facilitates efficient acquisition, on-the-fly motion correction, and CTF analysis of dose fractionated image stacks with a total time of ~60 seconds/exposure. Here we report the technical details and configuration of this system. PMID:26370395

Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation.

PubMed

Moulder, John E; Cohen, Eric P; Fish, Brian L

2011-01-01

It is known that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) can be used to mitigate radiation-induced renal injury. However, for a variety of reasons, these previous results are not directly applicable to the development of agents for the mitigation of injuries caused by terrorism-related radiation exposure. As part of an effort to develop an animal model that would fit the requirements of the U.S. Food and Drug Administration (FDA) "Animal Efficacy Rule", we designed new studies which used an FDA-approved ACEI (captopril) or an FDA-approved ARB (losartan, Cozaar®) started 10 days after a single total-body irradiation (TBI) at drug doses that are equivalent (on a g/m(2)/day basis) to the doses prescribed to humans. Captopril and losartan were equally effective as mitigators, with DMFs of 1.23 and 1.21, respectively, for delaying renal failure. These studies show that radiation nephropathy in a realistic rodent model can be mitigated with relevant doses of FDA-approved agents. This lays the necessary groundwork for pivotal rodent studies under the FDA Animal Efficacy Rule and provides an outline of how the FDA-required large-animal studies could be designed.

Captopril and Losartan for Mitigation of Renal Injury Caused by Single-Dose Total-Body Irradiation

PubMed Central

Moulder, John E.; Cohen, Eric P.; Fish, Brian L.

2011-01-01

It is known that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) can be used to mitigate radiation-induced renal injury. However, for a variety of reasons, these previous results are not directly applicable to the development of agents for the mitigation of injuries caused by terrorism-related radiation exposure. As part of an effort to develop an animal model that would fit the requirements of the U.S. Food and Drug Administration (FDA) “Animal Efficacy Rule”, we designed new studies which used an FDA-approved ACEI (captopril) or an FDA-approved ARB (losartan, Cozaar®) started 10 days after a single total-body irradiation (TBI) at drug doses that are equivalent (on a g/m2/day basis) to the doses prescribed to humans. Captopril and losartan were equally effective as mitigators, with DMFs of 1.23 and 1.21, respectively, for delaying renal failure. These studies show that radiation nephropathy in a realistic rodent model can be mitigated with relevant doses of FDA-approved agents. This lays the necessary groundwork for pivotal rodent studies under the FDA Animal Efficacy Rule and provides an outline of how the FDA-required large-animal studies could be designed. PMID:21175344

Single Enteral Loading Dose of Phenobarbital for Achieving Its Therapeutic Serum Levels in Neonates

PubMed Central

Turhan, Ali H.; Atici, Aytug; Okuyaz, Cetin; Uysal, Sercan

2010-01-01

Aim To investigate whether therapeutic serum drug levels may be achieved with a single enteral loading dose of phenobarbital. Methods The study was performed at the Mersin University Hospital in Turkey between April 2004 and August 2006, and included 29 newborn babies with seizure. After the acute treatment of the seizure with midazolam at a dose of 0.1 mg/kg, phenobarbital was administered by orogastric route at a loading dose of 20 mg/kg. Serum phenobarbital concentrations were measured at 0.5, 3, 6, and 12 hours after the loading. Serum phenobarbital levels between 10-30 μg/mL were considered as the therapeutic range. Results The serum phenobarbital levels reached therapeutic values in 9 (31%), 19 (66%), 21 (72%), and 23 (79%) patients at 0.5, 3, 6, and 12 hours after loading, respectively, while they did not reach therapeutic values in 6 patients (21%) after 12 hours. Four of the patients in whom there was no increase in serum phenobarbital levels had hypoxic-ischemic encephalopathy. Conclusion Enteral loading of phenobarbital can achieve therapeutic serum levels in the large majority of newborn babies with seizure and may be safely used in babies with the intact gastrointestinal tract. PMID:20564764

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

PubMed

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.

A single dose of inactivated hepatitis A vaccine promotes HAV-specific memory cellular response similar to that induced by a natural infection.

PubMed

Melgaço, Juliana Gil; Morgado, Lucas Nóbrega; Santiago, Marta Almeida; Oliveira, Jaqueline Mendes de; Lewis-Ximenez, Lia Laura; Hasselmann, Bárbara; Cruz, Oswaldo Gonçalves; Pinto, Marcelo Alves; Vitral, Claudia Lamarca

2015-07-31

Based on current studies on the effects of single dose vaccines on antibody production, Latin American countries have adopted a single dose vaccine program. However, no data are available on the activation of cellular response to a single dose of hepatitis A. Our study investigated the functional reactivity of the memory cell phenotype after hepatitis A virus (HAV) stimulation through administration of the first or second dose of HAV vaccine and compared the response to that of a baseline group to an initial natural infection. Proliferation assays showed that the first vaccine dose induced HAV-specific cellular response; this response was similar to that induced by a second dose or an initial natural infection. Thus, from the first dose to the second dose, increase in the frequencies of classical memory B cells, TCD8 cells, and central memory TCD4 and TCD8 cells were observed. Regarding cytokine production, increased IL-6, IL-10, TNF, and IFNγ levels were observed after vaccination. Our findings suggest that a single dose of HAV vaccine promotes HAV-specific memory cell response similar to that induced by a natural infection. The HAV-specific T cell immunity induced by primary vaccination persisted independently of the protective plasma antibody level. In addition, our results suggest that a single dose immunization system could serve as an alternative strategy for the prevention of hepatitis A in developing countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Pharmacogenetics-Based Warfarin Maintenance Dosing Algorithm from Northern Chinese Patients

PubMed Central

Luo, Fang; Wang, Jin'e; Shi, Yi; Tan, Yu; Chen, Qianlong; Zhang, Yu; Hui, Rutai; Wang, Yibo

2014-01-01

Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551), warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2 rs2108622 (0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236), the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, P<0.001). Our algorithm could improve the personalized management of warfarin use in Northern Chinese patients. PMID:25126975

Evaluation of Salmonella enterica serovar Typhi (Ty2 aroC-ssaV-) M01ZH09, with a defined mutation in the Salmonella pathogenicity island 2, as a live, oral typhoid vaccine in human volunteers.

PubMed

Kirkpatrick, B D; McKenzie, Robin; O'Neill, J Patrick; Larsson, Catherine J; Bourgeois, A Louis; Shimko, Janet; Bentley, Matthew; Makin, Jill; Chatfield, Steve; Hindle, Zoë; Fidler, Christine; Robinson, Brad E; Ventrone, Cassandra H; Bansal, Nivedita; Carpenter, Colleen M; Kutzko, Deborah; Hamlet, Sandra; LaPointe, Casey; Taylor, David N

2006-01-12

Salmonella enterica serovar Typhi strains with mutations in the Salmonella pathogenicity island-2 (SPI-2) may represent an effective strategy for human vaccine development, and a vectoring system for heterologous antigens. S. Typhi (Ty2 aroC-ssaV-) M01ZH09 is an attenuated, live, oral typhoid vaccine harboring defined deletion mutations in ssaV, which encodes an integral component in the SPI-2 type III secretion system (TTSS), as well as a mutation in an aromatic biosynthetic pathway needed for bacterial growth in vivo (aroC). SPI-2 mutant vaccines have yet to be evaluated in a large, randomized human trial. A simplified or single-oral dose oral typhoid vaccine using the SPI-2 strategy would offer significant advantages over the currently licensed typhoid vaccines. We performed a double-blinded, placebo-controlled, dose-escalating clinical trial in 60 healthy adult volunteers to determine the tolerability and immunogenicity of a single dose of M01ZH09. Three groups of 20 healthy adult volunteers were enrolled; 16 in each group received a single oral dose of the freeze-dried vaccine at 5 x 10(7), 5 x 10(8) or 5 x 10(9)CFU in a bicarbonate buffer. Four volunteers in each cohort received placebo in the same buffer. Adverse events were infrequent and not statistically different between vaccine and placebo recipients, although two subjects in the mid-range dose and three subjects in the highest dose had temperature measurements >37.5 degrees C. No blood or urine cultures were positive for M01ZH09, and fecal shedding was brief. The immune response was dose-related; the highest vaccine dose (5 x 10(9)CFU) was the most immunogenic. All tested subjects receiving the highest dose had a significant ASC response (mean 118 spots/10(6) cells). A >or=4-fold increase in antibody titer for S. Typhi LPS or flagellin was detected in 75% of volunteers in the highest-dose cohort by day 28. The SPI-2 mutant vaccine, M01ZH09, is a promising typhoid vaccine candidate and deserves further study as a vectoring system for heterologous vaccine antigens.

Establishment of institutional diagnostic reference level for computed tomography with automated dose-tracking software.

PubMed

Liang, Chong R; Chen, Priscilla X H; Kapur, Jeevesh; Ong, Michael K L; Quek, Swee T; Kapur, Subhash C

2017-06-01

The aim of this study was to establish institutional diagnostic reference levels (DRLs) by summarising doses collected across the five computed tomography (CT) system in our institution. CT dose data of 15940 patients were collected retrospectively from May 2015 to October 2015 in five institutional scanners. The mean, 75th percentile and 90th percentile of the dose spread were calculated according to anatomic region. The common CT examinations such as head, chest, combined abdomen/pelvis (A/P), and combined chest/abdomen/pelvis (C/A/P) were reviewed. Distribution of CT dose index (CTDIvol), dose-length product (DLP) and effective dose (ED) were extracted from the data for single-phasic and multiphasic examinations. The institutional DRL for our CT units were established as mean (50th percentile) of CTDIvol (mGy), DLP (mGy.cm) and ED (mSv) for single and multiphasic studies using the dose-tracking software. In single phasic examination, Head: (49.0 mGy), (978.0 mGy.cm), (2.4 mSv) respectively; Chest: (6.0 mGy), (254.0 mGy.cm), (4.9 mSv) respectively; CT A/P (10.0 mGy), (514.0 mGy.cm), (8.9 mSv) respectively; CT C/A/P (10.0 mGy), (674.0 mGy.cm), (11.8 mSv) respectively. In multiphasic studies: Head (45.0 mGy), (1822.0 mGy.cm), (5.0 mSv) respectively; Chest (8.0 mGy), (577.0 mGy.cm), (10.0 mSv) respectively; CT A/P: (10.0 mGy), (1153.0 mGy.cm), (20.2 mSv) respectively; CT C/A/P: (11.0 mGy), (1090.0 mGy.cm), (19.2 mSv) respectively. The reported metrics offer a variety of information that institutions can use for quality improvement activities. The variations in dose between scanners suggest a large potential for optimisation of radiation dose. © 2017 The Authors. Journal of Medical Radiation Sciences published by John Wiley & Sons Australia, Ltd on behalf of Australian Society of Medical Imaging and Radiation Therapy and New Zealand Institute of Medical Radiation Technology.

Replacing the Measles Ten-Dose Vaccine Presentation with the Single-Dose Presentation in Thailand

PubMed Central

Lee, Bruce Y.; Assi, Tina-Marie; Rookkapan, Korngamon; Connor, Diana L.; Rajgopal, Jayant; Sornsrivichai, Vorasith; Brown, Shawn T.; Welling, Joel S.; Norman, Bryan A.; Chen, Sheng-I; Bailey, Rachel R.; Wiringa, Ann E.; Wateska, Angela R.; Jana, Anirban; Van Panhuis, Willem G.; Burke, Donald S.

2011-01-01

Introduced to minimize open vial wastage, single-dose vaccine vials require more storage space and therefore may affect vaccine supply chains (i.e., the series of steps and processes entailed to deliver vaccines from manufacturers to patients). We developed a computational model of Thailand’s Trang province vaccine supply chain to analyze the effects of switching from a ten-dose measles vaccine presentation to each of the following: a single-dose Measles-Mumps-Rubella vaccine (which Thailand is currently considering) and a single-dose measles vaccine. While the Trang province vaccine supply chain would generally have enough storage and transport capacity to accommodate the switches, the added volume could push some locations’ storage and transport space utilization close to their limits. Single-dose vaccines would allow for more precise ordering and decrease open vial waste, but decrease reserves for unanticipated demand. Moreover, the added disposal and administration costs could far outweigh the costs saved from preventing open vial wastage. PMID:21439313

Evaluation of commercial ADC radiation tolerance for accelerator experiments

DOE PAGES

Chen, K.; Chen, H.; Kierstead, J.; ...

2015-08-17

Electronic components used in high energy physics experiments are subjected to a radiation background composed of high energy hadrons, mesons and photons. These particles can induce permanent and transient effects that affect the normal device operation. Ionizing dose and displacement damage can cause chronic damage which disable the device permanently. Transient effects or single event effects are in general recoverable with time intervals that depend on the nature of the failure. The magnitude of these effects is technology dependent with feature size being one of the key parameters. Analog to digital converters are components that are frequently used in detectormore » front end electronics, generally placed as close as possible to the sensing elements to maximize signal fidelity. We report on radiation effects tests conducted on 17 commercially available analog to digital converters and extensive single event effect measurements on specific twelve and fourteen bit ADCs that presented high tolerance to ionizing dose. We discuss mitigation strategies for single event effects (SEE) for their use in the large hadron collider environment.« less

Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers

PubMed Central

Chiesa, Joseph; Lückermann, Mark; Fischer, Carsten; Dalhoff, Axel; Fuhr, Uwe

2017-01-01

ABSTRACT Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.) PMID:28784673

Radiation damage in single-particle cryo-electron microscopy: effects of dose and dose rate.

PubMed

Karuppasamy, Manikandan; Karimi Nejadasl, Fatemeh; Vulovic, Milos; Koster, Abraham J; Ravelli, Raimond B G

2011-05-01

Radiation damage is an important resolution limiting factor both in macromolecular X-ray crystallography and cryo-electron microscopy. Systematic studies in macromolecular X-ray crystallography greatly benefited from the use of dose, expressed as energy deposited per mass unit, which is derived from parameters including incident flux, beam energy, beam size, sample composition and sample size. In here, the use of dose is reintroduced for electron microscopy, accounting for the electron energy, incident flux and measured sample thickness and composition. Knowledge of the amount of energy deposited allowed us to compare doses with experimental limits in macromolecular X-ray crystallography, to obtain an upper estimate of radical concentrations that build up in the vitreous sample, and to translate heat-transfer simulations carried out for macromolecular X-ray crystallography to cryo-electron microscopy. Stroboscopic exposure series of 50-250 images were collected for different incident flux densities and integration times from Lumbricus terrestris extracellular hemoglobin. The images within each series were computationally aligned and analyzed with similarity metrics such as Fourier ring correlation, Fourier ring phase residual and figure of merit. Prior to gas bubble formation, the images become linearly brighter with dose, at a rate of approximately 0.1% per 10 MGy. The gradual decomposition of a vitrified hemoglobin sample could be visualized at a series of doses up to 5500 MGy, by which dose the sample was sublimed. Comparison of equal-dose series collected with different incident flux densities showed a dose-rate effect favoring lower flux densities. Heat simulations predict that sample heating will only become an issue for very large dose rates (50 e(-)Å(-2) s(-1) or higher) combined with poor thermal contact between the grid and cryo-holder. Secondary radiolytic effects are likely to play a role in dose-rate effects. Stroboscopic data collection combined with an improved understanding of the effects of dose and dose rate will aid single-particle cryo-electron microscopists to have better control of the outcome of their experiments.

Radiation damage in single-particle cryo-electron microscopy: effects of dose and dose rate

PubMed Central

Karuppasamy, Manikandan; Karimi Nejadasl, Fatemeh; Vulovic, Milos; Koster, Abraham J.; Ravelli, Raimond B. G.

2011-01-01

Radiation damage is an important resolution limiting factor both in macromolecular X-ray crystallography and cryo-electron microscopy. Systematic studies in macromolecular X-ray crystallography greatly benefited from the use of dose, expressed as energy deposited per mass unit, which is derived from parameters including incident flux, beam energy, beam size, sample composition and sample size. In here, the use of dose is reintroduced for electron microscopy, accounting for the electron energy, incident flux and measured sample thickness and composition. Knowledge of the amount of energy deposited allowed us to compare doses with experimental limits in macromolecular X-ray crystallography, to obtain an upper estimate of radical concentrations that build up in the vitreous sample, and to translate heat-transfer simulations carried out for macromolecular X-ray crystallography to cryo-electron microscopy. Stroboscopic exposure series of 50–250 images were collected for different incident flux densities and integration times from Lumbricus terrestris extracellular hemoglobin. The images within each series were computationally aligned and analyzed with similarity metrics such as Fourier ring correlation, Fourier ring phase residual and figure of merit. Prior to gas bubble formation, the images become linearly brighter with dose, at a rate of approximately 0.1% per 10 MGy. The gradual decomposition of a vitrified hemoglobin sample could be visualized at a series of doses up to 5500 MGy, by which dose the sample was sublimed. Comparison of equal-dose series collected with different incident flux densities showed a dose-rate effect favoring lower flux densities. Heat simulations predict that sample heating will only become an issue for very large dose rates (50 e−Å−2 s−1 or higher) combined with poor thermal contact between the grid and cryo-holder. Secondary radiolytic effects are likely to play a role in dose-rate effects. Stroboscopic data collection combined with an improved understanding of the effects of dose and dose rate will aid single-particle cryo-electron microscopists to have better control of the outcome of their experiments. PMID:21525648

Effectiveness of Non-nucleoside Reverse-Transcriptase Inhibitor-Based Antiretroviral Therapy in Women Previously Exposed to a Single Intrapartum Dose of Nevirapine: A Multi-country, Prospective Cohort Study

PubMed Central

Stringer, Jeffrey S. A.; McConnell, Michelle S.; Kiarie, James; Bolu, Omotayo; Anekthananon, Thanomsak; Jariyasethpong, Tavatchai; Potter, Dara; Mutsotso, Winnie; Borkowf, Craig B.; Mbori-Ngacha, Dorothy; Muiruri, Peter; Ong'ech, John Odero; Zulu, Isaac; Njobvu, Lungowe; Jetsawang, Bongkoch; Pathak, Sonal; Bulterys, Marc; Shaffer, Nathan; Weidle, Paul J.

2010-01-01

Background Intrapartum and neonatal single-dose nevirapine (NVP) reduces the risk of mother-to-child HIV transmission but also induces viral resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. This drug resistance largely fades over time. We hypothesized that women with a prior single-dose NVP exposure would have no more than a 10% higher cumulative prevalence of failure of their NNRTI-containing antiretroviral therapy (ART) over the first 48 wk of therapy than would women without a prior exposure. Methods and Findings We enrolled 355 NVP-exposed and 523 NVP-unexposed women at two sites in Zambia, one site in Kenya, and two sites in Thailand into a prospective, non-inferiority cohort study and followed them for 48 wk on ART. Those who died, discontinued NNRTI-containing ART, or had a plasma viral load ≥400 copies/ml at either the 24 wk or 48 wk study visits and confirmed on repeat testing were characterized as having failed therapy. Overall, 114 of 355 NVP-exposed women (32.1%) and 132 of 523 NVP-unexposed women (25.2%) met criteria for treatment failure. The difference in failure rates between the exposure groups was 6.9% (95% confidence interval [CI] 0.8%–13.0%). The failure rates of women stratified by our predefined exposure interval categories were as follows: 47 of 116 women in whom less than 6 mo elapsed between exposure and starting ART failed therapy (40%; p<0.001 compared to unexposed women); 25 of 67 women in whom 7–12 mo elapsed between exposure and starting ART failed therapy (37%; p = 0.04 compared to unexposed women); and 42 of 172 women in whom more than 12 mo elapsed between exposure and starting ART failed therapy (24%; p = 0.82 compared to unexposed women). Locally weighted regression analysis also indicated a clear inverse relationship between virologic failure and the exposure interval. Conclusions Prior exposure to single-dose NVP was associated with an increased risk of treatment failure; however, this risk seems largely confined to women with a more recent exposure. Women requiring ART within 12 mo of NVP exposure should not be prescribed an NNRTI-containing regimen as first-line therapy. Please see later in the article for the Editors' Summary PMID:20169113

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

PubMed Central

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

Effect of Study Design on Sample Size in Studies Intended to Evaluate Bioequivalence of Inhaled Short-Acting β-Agonist Formulations.

PubMed

Zeng, Yaohui; Singh, Sachinkumar; Wang, Kai; Ahrens, Richard C

2018-04-01

Pharmacodynamic studies that use methacholine challenge to assess bioequivalence of generic and innovator albuterol formulations are generally designed per published Food and Drug Administration guidance, with 3 reference doses and 1 test dose (3-by-1 design). These studies are challenging and expensive to conduct, typically requiring large sample sizes. We proposed 14 modified study designs as alternatives to the Food and Drug Administration-recommended 3-by-1 design, hypothesizing that adding reference and/or test doses would reduce sample size and cost. We used Monte Carlo simulation to estimate sample size. Simulation inputs were selected based on published studies and our own experience with this type of trial. We also estimated effects of these modified study designs on study cost. Most of these altered designs reduced sample size and cost relative to the 3-by-1 design, some decreasing cost by more than 40%. The most effective single study dose to add was 180 μg of test formulation, which resulted in an estimated 30% relative cost reduction. Adding a single test dose of 90 μg was less effective, producing only a 13% cost reduction. Adding a lone reference dose of either 180, 270, or 360 μg yielded little benefit (less than 10% cost reduction), whereas adding 720 μg resulted in a 19% cost reduction. Of the 14 study design modifications we evaluated, the most effective was addition of both a 90-μg test dose and a 720-μg reference dose (42% cost reduction). Combining a 180-μg test dose and a 720-μg reference dose produced an estimated 36% cost reduction. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

SU-E-T-279: Realization of Three-Dimensional Conformal Dose Planning in Prostate Brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Z; Jiang, S; Yang, Z

2014-06-01

Purpose: Successful clinical treatment in prostate brachytherapy is largely dependent on the effectiveness of pre-surgery dose planning. Conventional dose planning method could hardly arrive at a satisfy result. In this abstract, a three-dimensional conformal localized dose planning method is put forward to ensure the accuracy and effectiveness of pre-implantation dose planning. Methods: Using Monte Carlo method, the pre-calculated 3-D dose map for single source is obtained. As for multiple seeds dose distribution, the maps are combined linearly to acquire the 3-D distribution. The 3-D dose distribution is exhibited in the form of isodose surface together with reconstructed 3-D organs groupmore » real-timely. Then it is possible to observe the dose exposure to target volume and normal tissues intuitively, thus achieving maximum dose irradiation to treatment target and minimum healthy tissues damage. In addition, the exfoliation display of different isodose surfaces can be realized applying multi-values contour extraction algorithm based on voxels. The needles could be displayed in the system by tracking the position of the implanted seeds in real time to conduct block research in optimizing insertion trajectory. Results: This study extends dose planning from two-dimensional to three-dimensional, realizing the three-dimensional conformal irradiation, which could eliminate the limitations of 2-D images and two-dimensional dose planning. A software platform is developed using VC++ and Visualization Toolkit (VTK) to perform dose planning. The 3-D model reconstruction time is within three seconds (on a Intel Core i5 PC). Block research could be conducted to avoid inaccurate insertion into sensitive organs or internal obstructions. Experiments on eight prostate cancer cases prove that this study could make the dose planning results more reasonable. Conclusion: The three-dimensional conformal dose planning method could improve the rationality of dose planning by safely reducing the large target margin and avoiding dose dead zones for prostate cancer treatment. 1) National Natural Science Foundation of People's Republic of China (No. 51175373); 2) New Century Educational Talents Plan of Chinese Education Ministry (NCET-10-0625); 3) Scientific and Technological Major Project, Tianjin (No. 12ZCDZSY10600)« less

Marrow toxicity of fractionated vs. single dose total body irradiation is identical in a canine model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Storb, R.; Raff, R.F.; Graham, T.

1993-03-20

The authors explored in dogs the marrow toxicity of single dose total body irradiation delivered from two opposing [sup 60]Co sources at a rate of 10 cGy/min and compared results to those seen with total body irradiation administered in 100 cGy fractions with minimum interfraction intervals of 6 hr. Dogs were not given marrow transplants. They found that 200 cGy single dose total body irradiation was sublethal, with 12 of 13 dogs showing hematopoietic recovery and survival. Seven of 21 dogs given 300 cGy single dose total body irradiation survived compared to 6 of 10 dogs given 300 cGy fractionatedmore » total body irradiation. One of 28 dogs given 400 cGy single dose total body irradiation survived compared to none of six given fractionated radiation. With granulocyte colony stimulating factor (GCSF) administered from day 0-21 after 400 cGy total body irradiation, most dogs survived with hematological recovery. Because of the almost uniform success with GCSF after 400 cGy single dose total body irradiation, a study of GCSF after 400 cGy fractionated total body irradiation was deemed not to be informative and, thus, not carried out. Additional comparisons between single dose and fractionated total body irradiation were carried out with GCSF administered after 500 and 600 cGy of total body irradiation. As with lower doses of total body irradiation, no significant survival differences were seen between the two modes of total body irradiation, and only 3 of 26 dogs studied survived with complete hematological recovery. Overall, therefore, survival among dogs given single dose total body irradiation was not different from that of dogs given fractionated total body irradiation (p = .67). Similarly, the slopes of the postirradiation declines of granulocyte and platelet counts and the rates of their recovery in surviving dogs given equal total doses of single versus fractionated total body irradiation were indistinguishable. 24 refs., 3 figs., 2 tabs.« less

The impact of histology and delivered dose on local control of spinal metastases treated with stereotactic radiosurgery.

PubMed

Yamada, Yoshiya; Katsoulakis, Evangelia; Laufer, Ilya; Lovelock, Michael; Barzilai, Ori; McLaughlin, Lily A; Zhang, Zhigang; Schmitt, Adam M; Higginson, Daniel S; Lis, Eric; Zelefsky, Michael J; Mechalakos, James; Bilsky, Mark H

2017-01-01

OBJECTIVE An analysis of factors contributing to durable radiographic control of spinal metastases was undertaken, drawing from a large single-institution database in an attempt to elucidate indications and dose requirements for successful treatment. METHODS All patients treated at a single institution with stereotactic radiosurgery (SRS) of the spine as first-line therapy were assessed for local progression of the treated site, defined as radiographic enlargement of the treated tumor and/or biopsy-proven evidence of active tumor cells. All patients were followed with CT, PET, or MR imaging every 3-6 months until death. Treatment decisions were made by a multidisciplinary team of radiation oncologists, neurosurgeons, and neuroradiologists. Target volumes were defined according to the international consensus guidelines and were reviewed in a multidisciplinary conference. Image-guided techniques and intensity modulation were used for every case. The tumor's histological type, gross tumor volume (GTV), dose that covers 95% of the GTV (GTV D95), percentage of GTV covered by 95% of the prescribed dose (GTV V95), planning target volume (PTV), dose that covers 95% of the PTV (PTV D95), and percentage of PTV covered by 95% of the prescribed dose (PTV V95) were analyzed for significance in relation to local control, based on time to local progression. RESULTS A total of 811 lesions were treated in 657 patients between 2003 and 2015 at a single institution. The mean follow-up and overall survival for the entire cohort was 26.9 months (range 2-141 months). A total of 28 lesions progressed and the mean time to failure was 26 months (range 9.7-57 months). The median prescribed dose was 2400 cGy (range 1600-2600 cGy). Both GTV D95 and PTV D95 were highly significantly associated with local failure in univariate analysis, but GTV and PTV and histological type did not reach statistical significance. The median GTV D95 for the cohort equal to or above the GTV D95 1830 cGy cut point (high dose) was 2356 cGy, and it was 1709 cGy for the cohort of patients who received less than 1830 cGy (low dose). In terms of PTV D95, the median dose for those equal to or above the cut point of 1740 cGy (high dose) was 2233 cGy, versus 1644 cGy for those lesions below the PTV D95 cut point of 1740 cGy (low dose). CONCLUSIONS High-dose single-session SRS provides durable long-term control, regardless of the histological findings or tumor size. In this analysis, the only significant factors predictive of local control were related to the actual dose of radiation given. Although the target volumes were well treated with the intended dose, those lesions irradiated to higher doses (median GTV D95 2356 cGy, minimum 1830 cGy) had a significantly higher probability of durable local control than those treated with lower doses (median PTV D95 2232 cGy, minimum of 1740 cGy) (p < 0.001). Patients in the high-dose cohort had a 2% cumulative rate of local failure. Histological findings were not associated with local failure, suggesting that radioresistant histological types benefit in particular from radiosurgery. For patients with a favorable prognosis, a higher dose of SRS is important for long-term outcomes.

The impact of histology and delivered dose on local control of spinal metastases treated with stereotactic radiosurgery

PubMed Central

Yamada, Yoshiya; Katsoulakis, Evangelia; Laufer, Ilya; Lovelock, Michael; Barzilai, Ori; McLaughlin, Lily A.; Zhang, Zhigang; Schmitt, Adam M.; Higginson, Daniel S.; Lis, Eric; Zelefsky, Michael J.; Mechalakos, James; Bilsky, Mark H.

2017-01-01

Objective An analysis of factors contributing to durable radiographic control of spinal metastases was undertaken, drawing from a large single-institution database in an attempt to elucidate indications and dose requirements for successful treatment. Methods All patients treated at a single institution with stereotactic radiosurgery (SRS) of the spine as first-line therapy were assessed for local progression of the treated site, defined as radiographic enlargement of the treated tumor and/or biopsy-proven evidence of active tumor cells. All patients were followed with CT, PET, or MR imaging every 3–6 months until death. Treatment decisions were made by a multidisciplinary team of radiation oncologists, neurosurgeons, and neuroradiologists. Target volumes were defined according to the international consensus guidelines and were reviewed in a multidisciplinary conference. Image-guided techniques and intensity modulation were used for every case. The tumor’s histological type, gross tumor volume (GTV), dose that covers 95% of the GTV (GTV D95), percentage of GTV covered by 95% of the prescribed dose (GTV V95), planning target volume (PTV), dose that covers 95% of the PTV (PTV D95), and percentage of PTV covered by 95% of the prescribed dose (PTV V95) were analyzed for significance in relation to local control, based on time to local progression. Results A total of 811 lesions were treated in 657 patients between 2003 and 2015 at a single institution. The mean follow-up and overall survival for the entire cohort was 26.9 months (range 2–141 months). A total of 28 lesions progressed and the mean time to failure was 26 months (range 9.7–57 months). The median prescribed dose was 2400 cGy (range 1600–2600 cGy). Both GTV D95 and PTV D95 were highly significantly associated with local failure in univariate analysis, but GTV and PTV and histological type did not reach statistical significance. The median GTV D95 for the cohort equal to or above the GTV D95 1830 cGy cut point (high dose) was 2356 cGy, and it was 1709 cGy for the cohort of patients who received less than 1830 cGy (low dose). In terms of PTV D95, the median dose for those equal to or above the cut point of 1740 cGy (high dose) was 2233 cGy, versus 1644 cGy for those lesions below the PTV D95 cut point of 1740 cGy (low dose). Conclusions High-dose single-session SRS provides durable long-term control, regardless of the histological findings or tumor size. In this analysis, the only significant factors predictive of local control were related to the actual dose of radiation given. Although the target volumes were well treated with the intended dose, those lesions irradiated to higher doses (median GTV D95 2356 cGy, minimum 1830 cGy) had a significantly higher probability of durable local control than those treated with lower doses (median PTV D95 2232 cGy, minimum of 1740 cGy) (p < 0.001). Patients in the high-dose cohort had a 2% cumulative rate of local failure. Histological findings were not associated with local failure, suggesting that radioresistant histological types benefit in particular from radiosurgery. For patients with a favorable prognosis, a higher dose of SRS is important for long-term outcomes. PMID:28041329

A single serving of caffeinated coffee impairs postprandial glucose metabolism in overweight men.

PubMed

Robertson, Tracey M; Clifford, Michael N; Penson, Simon; Chope, Gemma; Robertson, M Denise

2015-10-28

Previous studies regarding the acute effects of coffee on glycaemic control have used a single large dose of coffee, typically containing the caffeine equivalent of 2-4 servings of coffee. This study investigates whether the acute effects of coffee are dose-dependent, starting with a single serving. A total of ten healthy overweight males participated in a two-part randomised double-blind cross-over study. In the first part, they ingested 2, 4 or 8 g instant decaffeinated coffee (DC) dissolved in 400 ml water with caffeine added in proportion to the DC (total 100, 200 or 400 mg caffeine) or control (400 ml water) all with 50 g glucose. In the second part, they ingested the same amounts of DC (2, 4, 8 g) or control, but with a standard 100 mg caffeine added to each. Capillary blood samples were taken every 15 min for 2 h after each drink and glucose and insulin levels were measured. Repeated measures ANOVA on glucose results found an effect when caffeine was varied in line with DC (P=0·008). Post hoc analysis revealed that both 2 and 4 g DC with varied caffeine content increased the glycaemic response v. There was no effect of escalating doses of DC when caffeine remained constant at 100 mg. These results demonstrate that one standard serving of coffee (2 g) is sufficient to affect glucose metabolism. Furthermore, the amount of caffeine found in one serving (100 mg) is sufficient to mask any potential beneficial effects of increasing other components. No dose-dependent effect was found.

Performance of KCl:Eu2+ storage phosphor dosimeters for low dose measurements

PubMed Central

Li, H. Harold; Hansel, Rachael; Knutson, Nels; Yang, Deshan

2013-01-01

Recent research has demonstrated that europium doped potassium chloride (KCl:Eu2+) storage phosphor material has the potential to become the physical foundation of a novel and reusable dosimetry system using either film-like devices or devices similar to thermoluminescent dosimeter (TLD) chips. The purposes of this work are to quantify the performance of KCl:Eu2+ prototype dosimeters for low dose measurements and to demonstrate how it can be incorporated into clinical application for in vivo peripheral dose measurements. Pellet-style KCl:Eu2+ dosimeters, 6 mm in diameter, and 1 mm thick, were fabricated in-house for this study. The dosimeters were read using a laboratory photostimulated luminescence detection system. KCl:Eu2+ prototype storage phosphor dosimeter was capable of measuring a dose-to-water as low as 0.01 cGy from a 6 MV photon beam with a signal-to-noise ratio greater than 6. A pre-readout thermal annealing procedure enabled the dosimeter to be read within an hour post irradiation. After receiving large accumulated doses (~10 kGy), the dosimeters retained linear response in the low dose region with only a 20 percent loss of sensitivity comparing to a fresh sample (zero Gy history). The energy-dependence encountered during low dose peripheral measurements could be accounted for via a single point outside-field calibration per each beam quality. With further development the KCl:Eu2+− based dosimeter could become a versatile and durable dosimetry tool with large dynamic range (sub-cGy to 100 Gy). PMID:23735856

Dose fractionated gamma knife radiosurgery for large arteriovenous malformations on daily or alternate day schedule outside the linear quadratic model: Proof of concept and early results. A substitute to volume fractionation.

PubMed

Mukherjee, Kanchan Kumar; Kumar, Narendra; Tripathi, Manjul; Oinam, Arun S; Ahuja, Chirag K; Dhandapani, Sivashanmugam; Kapoor, Rakesh; Ghoshal, Sushmita; Kaur, Rupinder; Bhatt, Sandeep

2017-01-01

To evaluate the feasibility, safety and efficacy of dose fractionated gamma knife radiosurgery (DFGKRS) on a daily schedule beyond the linear quadratic (LQ) model, for large volume arteriovenous malformations (AVMs). Between 2012-16, 14 patients of large AVMs (median volume 26.5 cc) unsuitable for surgery or embolization were treated in 2-3 of DFGKRS sessions. The Leksell G frame was kept in situ during the whole procedure. 86% (n = 12) patients had radiologic evidence of bleed, and 43% (n = 6) had presented with a history of seizures. 57% (n = 8) patients received a daily treatment for 3 days and 43% (n = 6) were on an alternate day (2 fractions) regimen. The marginal dose was split into 2 or 3 fractions of the ideal prescription dose of a single fraction of 23-25 Gy. The median follow up period was 35.6 months (8-57 months). In the three-fraction scheme, the marginal dose ranged from 8.9-11.5 Gy, while in the two-fraction scheme, the marginal dose ranged from 11.3-15 Gy at 50% per fraction. Headache (43%, n = 6) was the most common early postoperative complication, which was controlled with short course steroids. Follow up evaluation of at least three years was achieved in seven patients, who have shown complete nidus obliteration in 43% patients while the obliteration has been in the range of 50-99% in rest of the patients. Overall, there was a 67.8% reduction in the AVM volume at 3 years. Nidus obliteration at 3 years showed a significant rank order correlation with the cumulative prescription dose (p 0.95, P value 0.01), with attainment of near-total (more than 95%) obliteration rates beyond 29 Gy of the cumulative prescription dose. No patient receiving a cumulative prescription dose of less than 31 Gy had any severe adverse reaction. In co-variate adjusted ordinal regression, only the cumulative prescription dose had a significant correlation with common terminology criteria for adverse events (CTCAE) severity (P value 0.04), independent of age, AVM volume, number of fractions and volume of brain receiving atleast 8 Gy of radiation. DFGKRS is feasible for large AVMs with a fair nidus obliteration rate and acceptable toxicity. Cumulative prescription dose seems to be the most significant independent predictor for outcome following DFGKRS with 29-30 Gy resulting in a fair nidus obliteration with least adverse events.

How accurately can the peak skin dose in fluoroscopy be determined using indirect dose metrics?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, A. Kyle, E-mail: kyle.jones@mdanderson.org; Ensor, Joe E.; Pasciak, Alexander S.

Purpose: Skin dosimetry is important for fluoroscopically-guided interventions, as peak skin doses (PSD) that result in skin reactions can be reached during these procedures. There is no consensus as to whether or not indirect skin dosimetry is sufficiently accurate for fluoroscopically-guided interventions. However, measuring PSD with film is difficult and the decision to do so must be madea priori. The purpose of this study was to assess the accuracy of different types of indirect dose estimates and to determine if PSD can be calculated within ±50% using indirect dose metrics for embolization procedures. Methods: PSD were measured directly using radiochromicmore » film for 41 consecutive embolization procedures at two sites. Indirect dose metrics from the procedures were collected, including reference air kerma. Four different estimates of PSD were calculated from the indirect dose metrics and compared along with reference air kerma to the measured PSD for each case. The four indirect estimates included a standard calculation method, the use of detailed information from the radiation dose structured report, and two simplified calculation methods based on the standard method. Indirect dosimetry results were compared with direct measurements, including an analysis of uncertainty associated with film dosimetry. Factors affecting the accuracy of the different indirect estimates were examined. Results: When using the standard calculation method, calculated PSD were within ±35% for all 41 procedures studied. Calculated PSD were within ±50% for a simplified method using a single source-to-patient distance for all calculations. Reference air kerma was within ±50% for all but one procedure. Cases for which reference air kerma or calculated PSD exhibited large (±35%) differences from the measured PSD were analyzed, and two main causative factors were identified: unusually small or large source-to-patient distances and large contributions to reference air kerma from cone beam computed tomography or acquisition runs acquired at large primary gantry angles. When calculated uncertainty limits [−12.8%, 10%] were applied to directly measured PSD, most indirect PSD estimates remained within ±50% of the measured PSD. Conclusions: Using indirect dose metrics, PSD can be determined within ±35% for embolization procedures. Reference air kerma can be used without modification to set notification limits and substantial radiation dose levels, provided the displayed reference air kerma is accurate. These results can reasonably be extended to similar procedures, including vascular and interventional oncology. Considering these results, film dosimetry is likely an unnecessary effort for these types of procedures when indirect dose metrics are available.« less

WE-E-18A-03: How Accurately Can the Peak Skin Dose in Fluoroscopy Be Determined Using Indirect Dose Metrics?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, A; Pasciak, A

Purpose: Skin dosimetry is important for fluoroscopically-guided interventions, as peak skin doses (PSD) that Result in skin reactions can be reached during these procedures. The purpose of this study was to assess the accuracy of different indirect dose estimates and to determine if PSD can be calculated within ±50% for embolization procedures. Methods: PSD were measured directly using radiochromic film for 41 consecutive embolization procedures. Indirect dose metrics from procedures were collected, including reference air kerma (RAK). Four different estimates of PSD were calculated and compared along with RAK to the measured PSD. The indirect estimates included a standard method,more » use of detailed information from the RDSR, and two simplified calculation methods. Indirect dosimetry was compared with direct measurements, including an analysis of uncertainty associated with film dosimetry. Factors affecting the accuracy of the indirect estimates were examined. Results: PSD calculated with the standard calculation method were within ±50% for all 41 procedures. This was also true for a simplified method using a single source-to-patient distance (SPD) for all calculations. RAK was within ±50% for all but one procedure. Cases for which RAK or calculated PSD exhibited large differences from the measured PSD were analyzed, and two causative factors were identified: ‘extreme’ SPD and large contributions to RAK from rotational angiography or runs acquired at large gantry angles. When calculated uncertainty limits [−12.8%, 10%] were applied to directly measured PSD, most indirect PSD estimates remained within ±50% of the measured PSD. Conclusions: Using indirect dose metrics, PSD can be determined within ±50% for embolization procedures, and usually to within ±35%. RAK can be used without modification to set notification limits and substantial radiation dose levels. These results can be extended to similar procedures, including vascular and interventional oncology. Film dosimetry is likely an unnecessary effort for these types of procedures.« less

Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block.

PubMed

Varghese, Anthony; Spindler, Anthony J; Paterson, David; Noble, Denis

2015-11-15

While it is well established that class-I antiarrhythmics block cardiac sodium channels, the mechanism of action of therapeutic levels of these drugs is not well understood. Using a combination of mathematical modeling and in vitro experiments, we studied the failure of activation of action potentials in single ventricular cells and in tissue caused by Na(+) channel block. Our computations of block and unblock of sodium channels by a theoretical class-Ib antiarrhythmic agent predict differences in the concentrations required to cause activation failure in single cells as opposed to multicellular preparations. We tested and confirmed these in silico predictions with in vitro experiments on isolated guinea-pig ventricular cells and papillary muscles stimulated at various rates (2-6.67 Hz) and exposed to various concentrations (5 × 10(-6) to 500 × 10(-6) mol/l) of lidocaine. The most salient result was that whereas large doses (5 × 10(-4) mol/l or higher) of lidocaine were required to inhibit action potentials temporarily in single cells, much lower doses (5 × 10(-6) mol/l), i.e., therapeutic levels, were sufficient to have the same effect in papillary muscles: a hundredfold difference. Our experimental results and mathematical analysis indicate that the syncytial nature of cardiac tissue explains the effects of clinically relevant doses of Na(+) channel blockers. Copyright © 2015 the American Physiological Society.

Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block

PubMed Central

Spindler, Anthony J.; Paterson, David; Noble, Denis

2015-01-01

While it is well established that class-I antiarrhythmics block cardiac sodium channels, the mechanism of action of therapeutic levels of these drugs is not well understood. Using a combination of mathematical modeling and in vitro experiments, we studied the failure of activation of action potentials in single ventricular cells and in tissue caused by Na+ channel block. Our computations of block and unblock of sodium channels by a theoretical class-Ib antiarrhythmic agent predict differences in the concentrations required to cause activation failure in single cells as opposed to multicellular preparations. We tested and confirmed these in silico predictions with in vitro experiments on isolated guinea-pig ventricular cells and papillary muscles stimulated at various rates (2–6.67 Hz) and exposed to various concentrations (5 × 10−6 to 500 × 10−6 mol/l) of lidocaine. The most salient result was that whereas large doses (5 × 10−4 mol/l or higher) of lidocaine were required to inhibit action potentials temporarily in single cells, much lower doses (5 × 10−6 mol/l), i.e., therapeutic levels, were sufficient to have the same effect in papillary muscles: a hundredfold difference. Our experimental results and mathematical analysis indicate that the syncytial nature of cardiac tissue explains the effects of clinically relevant doses of Na+ channel blockers. PMID:26342072

SU-E-I-15: Quantitative Evaluation of Dose Distributions From Axial, Helical and Cone-Beam CT Imaging by Measurement Using a Two-Dimensional Diode-Array Detector

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chacko, M; Aldoohan, S; Sonnad, J

2015-06-15

Purpose: To evaluate quantitatively dose distributions from helical, axial and cone-beam CT clinical imaging techniques by measurement using a two-dimensional (2D) diode-array detector. Methods: 2D-dose distributions from selected clinical protocols used for axial, helical and cone-beam CT imaging were measured using a diode-array detector (MapCheck2). The MapCheck2 is composed from solid state diode detectors that are arranged in horizontal and vertical lines with a spacing of 10 mm. A GE-Light-Speed CT-simulator was used to acquire axial and helical CT images and a kV on-board-imager integrated with a Varian TrueBeam-STx machine was used to acquire cone-beam CT (CBCT) images. Results: Themore » dose distributions from axial, helical and cone-beam CT were non-uniform over the region-of-interest with strong spatial and angular dependence. In axial CT, a large dose gradient was measured that decreased from lateral sides to the middle of the phantom due to large superficial dose at the side of the phantom in comparison with larger beam attenuation at the center. The dose decreased at the superior and inferior regions in comparison to the center of the phantom in axial CT. An asymmetry was found between the right-left or superior-inferior sides of the phantom which possibly to angular dependence in the dose distributions. The dose level and distribution varied from one imaging technique into another. For the pelvis technique, axial CT deposited a mean dose of 3.67 cGy, helical CT deposited a mean dose of 1.59 cGy, and CBCT deposited a mean dose of 1.62 cGy. Conclusions: MapCheck2 provides a robust tool to measure directly 2D-dose distributions for CT imaging with high spatial resolution detectors in comparison with ionization chamber that provides a single point measurement or an average dose to the phantom. The dose distributions measured with MapCheck2 consider medium heterogeneity and can represent specific patient dose.« less

SU-E-T-291: Dosimetric Accuracy of Multitarget Single Isocenter Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tannazi, F; Huang, M; Thomas, E

2015-06-15

Purpose: To evaluate the accuracy of single-isocenter multiple-target VMAT radiosurgery (SIMT-VMAT-SRS) by analysis of pre-treatment verification measurements. Methods: Our QA procedure used a phantom having a coronal plane for EDR2 film and a 0.125 cm3 ionization chamber. Film measurements were obtained for the largest and smallest targets for each plan. An ionization chamber measurement (ICM) was obtained for sufficiently large targets. Films were converted to dose using a patient-specific calibration curve and compared to treatment planning system calculations. Alignment error was estimated using image registration. The gamma index was calculated for 3%/3 and 3%/1 mm criteria. The median dose inmore » the target region and, for plans having an ICM, the average dose in the central 5 mm was calculated. Results: The average equivalent target diameter of the 48 targets was 15 mm (3–43 mm). Twenty of the 24 plans had an ICM for the plan corresponding to the largest target (diameter 11–43 mm) with a mean ratio of chamber reading to expected dose (ED) and the mean ratio of film to ED (averaged over the central 5 mm) was 1.001 (0.025 SD) and 1.000 (0.029 SD), respectively. For all plans, the mean film to ED (from the median dose in the target region) was 0.997 (0.027 SD). The mean registration vector was (0.15,0.29) mm, with an average magnitude of 0.96 mm. Before (after) registration, the average fraction of pixels having gamma < 1 was 99.3% (99.6%) and 89.1% (97.6%) for 3%/3mm and 3%/1mm, respectively. Conclusion: Our results demonstrate dosimetric accuracy of SIMT-VMAT-SRS for targets as small as 3 mm. Film dosimetry provides accurate assessment of the absolute dose delivered to targets too small for an ionization chamber measurement; however, the relatively large registration vector indicates that image-guidance should replace laser-based setup for patient-specific evaluation of geometric accuracy.« less

Analysis of stem cell apheresis products using intermediate-dose filgrastim plus large volume apheresis for allogeneic transplantation.

PubMed

Engelhardt, M; Bertz, H; Wäsch, R; Finke, J

2001-04-01

Previously, a dose-dependent influence of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on CD34+ mobilization was demonstrated. In this single-center prospective analysis, 52 healthy donors were investigated to determine the efficacy of intermediate-dose rhG-CSF 2x8 microg/kg donor body weight (bw) and intermediate large volume apheresis (LVA, median 12 l) to mobilize peripheral blood progenitor cells (PBPC) for allogeneic transplantation. The median number of CD34+ cells in apheresis products was 0.45% and 2.2x10(6)/kg recipient bw per single apheresis. A total of 5.4x10(6)/kg CD34+ cells were collected with two (range: one to three) LVA. In the analysis of donor subgroups, higher peripheral blood (PB) and apheresis results were obtained in male vs female donors; however, donor weight significantly differed in both groups. Heavier donors displayed higher PB and apheresis CD34+ counts; however, when CD34+ cells/kg were adjusted to a constant bw, similar harvest results were calculated in males and females, demonstrating that gender per se does not, whereas bw does affect apheresis results. Younger donors had significantly higher PB CD34+ counts, higher CD34+ numbers per single apheresis, increased CFU, more T, B, and CD61+, comparable NK, and less CD14+ cells. A correlation analysis of donor age and apheresis results displayed an age-related decline of 0.46x10(6)/kg CD34 cells per decade of donor aging. Cell subsets in apheresis products were CD14 (49%), CD3 (22%), CD4 (13%), CD8 (7%), CD61 (20%), CD19 (5%), and CD16/56+ (3%) cells, with increasing CD14+ cells and decreasing CD3, CD4, CD8, CD61, CD19, and CD16/56+ cells on subsequent days of apheresis. Compared to our previous analysis using high- (2x12 microg) and low-dose (1x10 microg) rhG-CSF for allogeneic PBPC mobilization, the intermediate-dose showed a similar CD34+ mobilization potential to 1x10 microg rhG-CSF; however, with use of LVA, two instead of three (p<0.05) aphereses were sufficient to mobilize > or =4x10(6)/kg bw CD34+ cells in most donors. Taken together, our results demonstrate that intermediate-dose rhG-CSF sufficiently mobilizes > or =4x10(6)/kg x bw CD34+ cells with use of LVA and that especially younger donors display increased CD34+ cell numbers.

Dose optimization of contrast-enhanced carotid MR angiography.

PubMed

Unterweger, M; Froehlich, J M; Kubik-Huch, R A; Seifert, B; Birrer, M; Huber, T; Otto, R

2005-09-01

The purpose of this work was to compare the diagnostic performance of a single-contrast or a double-contrast dose of carotid contrast-enhanced MR angiography (MRA). One-hundred nineteen patients (mean age 65+/-14.4 years) underwent carotid contrast-enhanced MRA with a standardized protocol (repetition time/echo 3.73 ms/1.38 ms, flip-angle 25 degrees, acquisition-time 19 s, voxel size 1.2 x 1.2 x 0.9 mm3) on a 1.5-T scanner (Sonata, Siemens-Medical-Systems) using a neck phased-array coil. Contrast agent was administered intravenously at a rate of 3.0 ml/s, either as a single dose (n=57; 0.1 mmol/kg body weight) or as a double dose (n=62; 0.2 mmol/kg body weight) of meglumine gadoterate (0.5 M/l), followed by 30 ml saline. Qualitative image analysis was performed on maximum intensity projections using a five-point scale. Signal intensities were measured at three different vascular levels on both sides to assess the contrast-to-noise ratios (CNRs). Image quality was rated as good or excellent in all cases. A double dose did not influence the efficacy of carotid enhancement (CNR single dose 69.12+/-19.8; CNR double dose 70.01+/-20.7; p = 0.81) compared with a single dose. In both dose groups the mean CNRs were inversely related to bodyweight, despite adjusted contrast volumes (p=0.0005). Double-dose contrast-enhanced carotid MRA is not superior to single-dose MRA, as overall diagnostic performance and quantitative contrast enhancement are equal. Being more cost-efficient, a single-dose administration of contrast agent is recommended for MRA of the carotid arteries.

Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population.

PubMed

Li, Xueqing; Wang, Rutao; Liu, Yang; Liu, Yun; Zheng, Heng; Feng, Yabo; Zhao, Na; Geng, Hongbin; Zhang, Wanzhi; Wen, Aidong

2017-11-16

Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C max showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t max of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed. Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The t max of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).

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

PubMed

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 published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

A single-gradient junction technique to replace multiple-junction shifts for craniospinal irradiation treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hadley, Austin; Ding, George X., E-mail: george.ding@vanderbilt.edu

2014-01-01

Craniospinal irradiation (CSI) requires abutting fields at the cervical spine. Junction shifts are conventionally used to prevent setup error–induced overdosage/underdosage from occurring at the same location. This study compared the dosimetric differences at the cranial-spinal junction between a single-gradient junction technique and conventional multiple-junction shifts and evaluated the effect of setup errors on the dose distributions between both techniques for a treatment course and single fraction. Conventionally, 2 lateral brain fields and a posterior spine field(s) are used for CSI with weekly 1-cm junction shifts. We retrospectively replanned 4 CSI patients using a single-gradient junction between the lateral brain fieldsmore » and the posterior spine field. The fields were extended to allow a minimum 3-cm field overlap. The dose gradient at the junction was achieved using dose painting and intensity-modulated radiation therapy planning. The effect of positioning setup errors on the dose distributions for both techniques was simulated by applying shifts of ± 3 and 5 mm. The resulting cervical spine doses across the field junction for both techniques were calculated and compared. Dose profiles were obtained for both a single fraction and entire treatment course to include the effects of the conventional weekly junction shifts. Compared with the conventional technique, the gradient-dose technique resulted in higher dose uniformity and conformity to the target volumes, lower organ at risk (OAR) mean and maximum doses, and diminished hot spots from systematic positioning errors over the course of treatment. Single-fraction hot and cold spots were improved for the gradient-dose technique. The single-gradient junction technique provides improved conformity, dose uniformity, diminished hot spots, lower OAR mean and maximum dose, and one plan for the entire treatment course, which reduces the potential human error associated with conventional 4-shifted plans.« less

Preclinical dose number and its application in understanding drug absorption risk and formulation design for preclinical species.

PubMed

Wuelfing, W Peter; Daublain, Pierre; Kesisoglou, Filippos; Templeton, Allen; McGregor, Caroline

2015-04-06

In the drug discovery setting, the ability to rapidly identify drug absorption risk in preclinical species at high doses from easily measured physical properties is desired. This is due to the large number of molecules being evaluated and their high attrition rate, which make resource-intensive in vitro and in silico evaluation unattractive. High-dose in vivo data from rat, dog, and monkey are analyzed here, using a preclinical dose number (PDo) concept based on the dose number described by Amidon and other authors (Pharm. Res., 1993, 10, 264-270). PDo, as described in this article, is simply calculated as dose (mg/kg) divided by compound solubility in FaSSIF (mg/mL) and approximates the volume of biorelevant media per kilogram of animal that would be needed to fully dissolve the dose. High PDo values were found to be predictive of difficulty in achieving drug exposure (AUC)-dose proportionality in in vivo studies, as could be expected; however, this work analyzes a large data set (>900 data points) and provides quantitative guidance to identify drug absorption risk in preclinical species based on a single solubility measurement commonly carried out in drug discovery. Above the PDo values defined, >50% of all in vivo studies exhibited poor AUC-dose proportionality in rat, dog, and monkey, and these values can be utilized as general guidelines in discovery and early development to rapidly assess risk of solubility-limited absorption for a given compound. A preclinical dose number generated by biorelevant dilutions of formulated compounds (formulated PDo) was also evaluated and defines solubility targets predictive of suitable AUC-dose proportionality in formulation development efforts. Application of these guidelines can serve to efficiently identify compounds in discovery that are likely to present extreme challenges with respect to solubility-limited absorption in preclinical species as well as reduce the testing of poor formulations in vivo, which is a key ethical and resource matter.

Effectiveness of Jeryl Lynn-containing vaccine in Spanish children.

PubMed

Castilla, Jesús; García Cenoz, Manuel; Arriazu, Maite; Fernández-Alonso, Mirian; Martínez-Artola, Víctor; Etxeberria, Jaione; Irisarri, Fátima; Barricarte, Aurelio

2009-03-26

We evaluated the effectiveness of the Jeryl Lynn strain vaccine in a large outbreak of mumps in Navarre, Spain, 2006-2008. Each of the 241 cases of mumps occurring in children over 15 months of age born between 1998 and 2005 was compared with 5 controls individually matched by sex, birth date, district of residence and paediatrician. Vaccination history was obtained blindly from clinical records. Conditional logistic regression was used to obtain the matched odds ratios (ORs), and effectiveness was calculated as 1-OR. Some 70% of cases had received one dose of measles-mumps-rubella vaccine, and 24% had received two doses. Overall vaccine effectiveness was 72% (95% CI, 39-87%). Two doses were more effective (83%; 54-94%) than a single dose (66%; 25-85%). Among vaccinated children, risk was higher in those who had received the first dose after 36 months of age (OR=3.1; 1.2-8.4) and those who had received the second dose 3 or more years before study enrolment (OR=10.2; 1.5-70.7). Early waning of immunity in children after the second dose may contribute to reduced vaccine effectiveness for mumps prevention.

Multicentre dose audit for clinical trials of radiation therapy in Asia

PubMed Central

Fukuda, Shigekazu; Fukumura, Akifumi; Nakamura, Yuzuru-Kutsutani; Jianping, Cao; Cho, Chul-Koo; Supriana, Nana; Dung, To Anh; Calaguas, Miriam Joy; Devi, C.R. Beena; Chansilpa, Yaowalak; Banu, Parvin Akhter; Riaz, Masooma; Esentayeva, Surya; Kato, Shingo; Karasawa, Kumiko; Tsujii, Hirohiko

2017-01-01

Abstract A dose audit of 16 facilities in 11 countries has been performed within the framework of the Forum for Nuclear Cooperation in Asia (FNCA) quality assurance program. The quality of radiation dosimetry varies because of the large variation in radiation therapy among the participating countries. One of the most important aspects of international multicentre clinical trials is uniformity of absolute dose between centres. The National Institute of Radiological Sciences (NIRS) in Japan has conducted a dose audit of participating countries since 2006 by using radiophotoluminescent glass dosimeters (RGDs). RGDs have been successfully applied to a domestic postal dose audit in Japan. The authors used the same audit system to perform a dose audit of the FNCA countries. The average and standard deviation of the relative deviation between the measured and intended dose among 46 beams was 0.4% and 1.5% (k = 1), respectively. This is an excellent level of uniformity for the multicountry data. However, of the 46 beams measured, a single beam exceeded the permitted tolerance level of ±5%. We investigated the cause for this and solved the problem. This event highlights the importance of external audits in radiation therapy. PMID:27864507

Evaluation of the new electron-transport algorithm in MCNP6.1 for the simulation of dose point kernel in water

NASA Astrophysics Data System (ADS)

Antoni, Rodolphe; Bourgois, Laurent

2017-12-01

In this work, the calculation of specific dose distribution in water is evaluated in MCNP6.1 with the regular condensed history algorithm the "detailed electron energy-loss straggling logic" and the new electrons transport algorithm proposed the "single event algorithm". Dose Point Kernel (DPK) is calculated with monoenergetic electrons of 50, 100, 500, 1000 and 3000 keV for different scoring cells dimensions. A comparison between MCNP6 results and well-validated codes for electron-dosimetry, i.e., EGSnrc or Penelope, is performed. When the detailed electron energy-loss straggling logic is used with default setting (down to the cut-off energy 1 keV), we infer that the depth of the dose peak increases with decreasing thickness of the scoring cell, largely due to combined step-size and boundary crossing artifacts. This finding is less prominent for 500 keV, 1 MeV and 3 MeV dose profile. With an appropriate number of sub-steps (ESTEP value in MCNP6), the dose-peak shift is almost complete absent to 50 keV and 100 keV electrons. However, the dose-peak is more prominent compared to EGSnrc and the absorbed dose tends to be underestimated at greater depths, meaning that boundaries crossing artifact are still occurring while step-size artifacts are greatly reduced. When the single-event mode is used for the whole transport, we observe the good agreement of reference and calculated profile for 50 and 100 keV electrons. Remaining artifacts are fully vanished, showing a possible transport treatment for energies less than a hundred of keV and accordance with reference for whatever scoring cell dimension, even if the single event method initially intended to support electron transport at energies below 1 keV. Conversely, results for 500 keV, 1 MeV and 3 MeV undergo a dramatic discrepancy with reference curves. These poor results and so the current unreliability of the method is for a part due to inappropriate elastic cross section treatment from the ENDF/B-VI.8 library in those energy ranges. Accordingly, special care has to be taken in setting choice for calculating electron dose distribution with MCNP6, in particular with regards to dosimetry or nuclear medicine applications.

Efficient Generation of an Array of Single Silicon-Vacancy Defects in Silicon Carbide

NASA Astrophysics Data System (ADS)

Wang, Junfeng; Zhou, Yu; Zhang, Xiaoming; Liu, Fucai; Li, Yan; Li, Ke; Liu, Zheng; Wang, Guanzhong; Gao, Weibo

2017-06-01

Color centers in silicon carbide have increasingly attracted attention in recent years owing to their excellent properties such as single-photon emission, good photostability, and long spin-coherence time even at room temperature. As compared to diamond, which is widely used for hosting nitrogen-vacancy centers, silicon carbide has an advantage in terms of large-scale, high-quality, and low-cost growth, as well as an advanced fabrication technique in optoelectronics, leading to prospects for large-scale quantum engineering. In this paper, we report an experimental demonstration of the generation of a single-photon-emitter array through ion implantation. VSi defects are generated in predetermined locations with high generation efficiency (approximately 19 % ±4 % ). The single emitter probability reaches approximately 34 % ±4 % when the ion-implantation dose is properly set. This method serves as a critical step in integrating single VSi defect emitters with photonic structures, which, in turn, can improve the emission and collection efficiency of VSi defects when they are used in a spin photonic quantum network. On the other hand, the defects are shallow, and they are generated about 40 nm below the surface which can serve as a critical resource in quantum-sensing applications.

Preoperative single fraction partial breast radiotherapy for early-stage breast cancer.

PubMed

Palta, Manisha; Yoo, Sua; Adamson, Justus D; Prosnitz, Leonard R; Horton, Janet K

2012-01-01

Several recent series evaluating external beam accelerated partial breast irradiation (PBI) have reported adverse cosmetic outcomes, possibly related to large volumes of normal tissue receiving near-prescription doses. We hypothesized that delivery of external beam PBI in a single fraction to the preoperative tumor volume would be feasible and result in a decreased dose to the uninvolved breast compared with institutional postoperative PBI historical controls. A total of 17 patients with unifocal Stage T1 breast cancer were identified. Contrast-enhanced subtraction magnetic resonance images were loaded into an Eclipse treatment planning system and used to define the target volumes. A "virtual plan" was created using four photon beams in a noncoplanar beam arrangement and optimized to deliver 15 Gy to the planning target volume. The median breast volume was 1,713 cm(3) (range: 1,014-2,140), and the median clinical target volume was 44 cm(3) (range: 26-73). In all cases, 100% of the prescription dose covered 95% of the clinical target volume. The median conformity index was 0.86 (range: 0.70-1.12). The median percentage of the ipsilateral breast volume receiving 100% and 50% of the prescribed dose was 3.8% (range: 2.2-6.9) and 13.3% (range: 7.5-20.8) compared with 18% (range: 3-42) and 53% (range: 24-65) in the institutional historical controls treated with postoperative external beam PBI (p = .002). The median maximum skin dose was 9 Gy. The median dose to 1 and 10 cm(3) of skin was 6.7 and 4.9 Gy. The doses to the heart and ipsilateral lung were negligible. Preoperative PBI resulted in a substantial reduction in ipsilateral breast tissue dose compared with postoperative PBI. The skin dose appeared reasonable, given the small volumes. A prospective Phase I trial evaluating this technique is ongoing. Copyright © 2012 Elsevier Inc. All rights reserved.

Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs

PubMed Central

Wickham, Kristina S.; Baresel, Paul C.; Sousa, Jason; Vuong, Chau T.; Reichard, Gregory A.; Campo, Brice; Tekwani, Babu L.; Walker, Larry A.

2016-01-01

Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) are at risk for developing hemolytic anemia when given the antimalarial drug primaquine (PQ). The WHO Evidence Review Group released a report suggesting that mass administration of a single dose of PQ at 0.25 mg of base/kg of body weight (mpk) (mouse equivalent of 3.125 mpk) could potentially reduce malaria transmission based on its gametocytocidal activity and could be safely administered to G6PD-deficient individuals, but there are limited safety data available confirming the optimum single dose of PQ. A single-dose administration of PQ was therefore assessed in our huRBC-SCID mouse model used to predict hemolytic toxicity with respect to G6PD deficiency. In this model, nonobese diabetic (NOD)/SCID mice are engrafted with human red blood cells (huRBC) from donors with the African or Mediterranean variant of G6PDd (A-G6PDd or Med-G6PDd, respectively) and demonstrate dose-dependent sensitivity to PQ. In mice engrafted with A-G6PD-deficient huRBC, single-dose PQ at 3.125, 6.25, or 12.5 mpk had no significant loss of huRBC compared to the vehicle control group. In contrast, in mice engrafted with Med-G6PDd huRBC, a single dose of PQ at 3.125, 6.25, or 12.5 mpk resulted in a significant, dose-dependent loss of huRBC compared to the value for the vehicle control group. Our data suggest that administration of a single low dose of 0.25 mpk of PQ could induce hemolytic anemia in Med-G6PDd individuals but that use of single-dose PQ at 0.25 mpk as a gametocytocidal drug to block transmission would be safe in areas where A-G6PDd predominates. PMID:27458212

Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs.

PubMed

Wickham, Kristina S; Baresel, Paul C; Marcsisin, Sean R; Sousa, Jason; Vuong, Chau T; Reichard, Gregory A; Campo, Brice; Tekwani, Babu L; Walker, Larry A; Rochford, Rosemary

2016-10-01

Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) are at risk for developing hemolytic anemia when given the antimalarial drug primaquine (PQ). The WHO Evidence Review Group released a report suggesting that mass administration of a single dose of PQ at 0.25 mg of base/kg of body weight (mpk) (mouse equivalent of 3.125 mpk) could potentially reduce malaria transmission based on its gametocytocidal activity and could be safely administered to G6PD-deficient individuals, but there are limited safety data available confirming the optimum single dose of PQ. A single-dose administration of PQ was therefore assessed in our huRBC-SCID mouse model used to predict hemolytic toxicity with respect to G6PD deficiency. In this model, nonobese diabetic (NOD)/SCID mice are engrafted with human red blood cells (huRBC) from donors with the African or Mediterranean variant of G6PDd (A-G6PDd or Med-G6PDd, respectively) and demonstrate dose-dependent sensitivity to PQ. In mice engrafted with A-G6PD-deficient huRBC, single-dose PQ at 3.125, 6.25, or 12.5 mpk had no significant loss of huRBC compared to the vehicle control group. In contrast, in mice engrafted with Med-G6PDd huRBC, a single dose of PQ at 3.125, 6.25, or 12.5 mpk resulted in a significant, dose-dependent loss of huRBC compared to the value for the vehicle control group. Our data suggest that administration of a single low dose of 0.25 mpk of PQ could induce hemolytic anemia in Med-G6PDd individuals but that use of single-dose PQ at 0.25 mpk as a gametocytocidal drug to block transmission would be safe in areas where A-G6PDd predominates. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Chemical Dosing and First-Order Kinetics

ERIC Educational Resources Information Center

Hladky, Paul W.

2011-01-01

College students encounter a variety of first-order phenomena in their mathematics and science courses. Introductory chemistry textbooks that discuss first-order processes, usually in conjunction with chemical kinetics or radioactive decay, stop at single, discrete dose events. Although single-dose situations are important, multiple-dose events,…

Cs2AgBiBr6 single-crystal X-ray detectors with a low detection limit

NASA Astrophysics Data System (ADS)

Pan, Weicheng; Wu, Haodi; Luo, Jiajun; Deng, Zhenzhou; Ge, Cong; Chen, Chao; Jiang, Xiaowei; Yin, Wan-Jian; Niu, Guangda; Zhu, Lujun; Yin, Lixiao; Zhou, Ying; Xie, Qingguo; Ke, Xiaoxing; Sui, Manling; Tang, Jiang

2017-11-01

Sensitive X-ray detection is crucial for medical diagnosis, industrial inspection and scientific research. The recently described hybrid lead halide perovskites have demonstrated low-cost fabrication and outstanding performance for direct X-ray detection, but they all contain toxic Pb in a soluble form. Here, we report sensitive X-ray detectors using solution-processed double perovskite Cs2AgBiBr6 single crystals. Through thermal annealing and surface treatment, we largely eliminate Ag+/Bi3+ disordering and improve the crystal resistivity, resulting in a detector with a minimum detectable dose rate as low as 59.7 nGyair s-1, comparable to the latest record of 0.036 μGyair s-1 using CH3NH3PbBr3 single crystals. Suppressed ion migration in Cs2AgBiBr6 permits relatively large external bias, guaranteeing efficient charge collection without a substantial increase in noise current and thus enabling the low detection limit.

Management of urinary tract infections in pregnancy: a review with comments on single dose therapy.

PubMed

Zinner, S H

1992-01-01

Most investigators agree that the adverse effects of urinary tract infections in pregnancy can be abrogated by effective early detection and treatment. However, the optimal methods for screening and treatment remain controversial. Although single-dose therapy has not been applied to pregnant women with acute pyelonephritis, most but not all studies which have compared single-dose with longer courses of beta-lactam or other antibiotics in pregnant asymptomatic bacteriuric women have shown no differences in outcome. This paper reviews recent trials of single-dose treatment of bacteriuria in pregnant women.

Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study)

PubMed Central

Hegarty, Joanne Elizabeth; Harding, Jane Elizabeth; Gamble, Gregory David; Crowther, Caroline Anne; Edlin, Richard; Alsweiler, Jane Marie

2016-01-01

Background Neonatal hypoglycaemia is common, affecting up to 15% of newborns, and can cause brain damage. Currently, there are no strategies, beyond early feeding, to prevent neonatal hypoglycaemia. Our aim was to determine a dose of 40% oral dextrose gel that will prevent neonatal hypoglycaemia in newborn babies at risk. Methods and Findings We conducted a randomised, double-blind, placebo-controlled dose-finding trial of buccal dextrose gel to prevent neonatal hypoglycaemia at two hospitals in New Zealand. Babies at risk of hypoglycaemia (infant of a mother with diabetes, late preterm delivery, small or large birthweight, or other risk factors) but without indication for admission to a neonatal intensive care unit (NICU) were randomly allocated either to one of four treatment groups: 40% dextrose at one of two doses (0.5 ml/kg = 200 mg/kg, or 1 ml/kg = 400 mg/kg), either once at 1 h of age or followed by three additional doses of dextrose (0.5 ml/kg before feeds in the first 12 h); or to one of four corresponding placebo groups. Treatments were administered by massaging gel into the buccal mucosa. The primary outcome was hypoglycaemia (<2.6 mM) in the first 48 h. Secondary outcomes included admission to a NICU, admission for hypoglycaemia, and breastfeeding at discharge and at 6 wk. Prespecified potential dose limitations were tolerance of gel, time taken to administer, messiness, and acceptability to parents. From August 2013 to November 2014, 416 babies were randomised. Compared to babies randomised to placebo, the risk of hypoglycaemia was lowest in babies randomised to a single dose of 200 mg/kg dextrose gel (relative risk [RR] 0.68; 95% confidence interval [CI] 0.47–0.99, p = 0.04) but was not significantly different between dose groups (p = 0.21). Compared to multiple doses, single doses of gel were better tolerated, quicker to administer, and less messy, but these limitations were not different between dextrose and placebo gel groups. Babies who received any dose of dextrose gel were less likely to develop hypoglycaemia than those who received placebo (RR 0.79; 95% CI 0.64–0.98, p = 0.03; number needed to treat = 10, 95% CI 5–115). Rates of NICU admission were similar (RR 0.64; 95% CI 0.33–1.25, p = 0.19), but admission for hypoglycaemia was less common in babies randomised to dextrose gel (RR 0.46; 95% CI 0.21–1.01, p = 0.05). Rates of breastfeeding were similar in both groups. Adverse effects were uncommon and not different between groups. A limitation of this study was that most of the babies in the trial were infants of mothers with diabetes (73%), which may reduce the applicability of the results to babies from other risk groups. Conclusions The incidence of neonatal hypoglycaemia can be reduced with a single dose of buccal 40% dextrose gel 200 mg/kg. A large randomised trial (Hypoglycaemia Prevention with Oral Dextrose [hPOD]) is under way to determine the effects on NICU admission and later outcomes. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12613000322730 PMID:27780197

On the interplay effects with proton scanning beams in stage III lung cancer.

PubMed

Li, Yupeng; Kardar, Laleh; Li, Xiaoqiang; Li, Heng; Cao, Wenhua; Chang, Joe Y; Liao, Li; Zhu, Ronald X; Sahoo, Narayan; Gillin, Michael; Liao, Zhongxing; Komaki, Ritsuko; Cox, James D; Lim, Gino; Zhang, Xiaodong

2014-02-01

To assess the dosimetric impact of interplay between spot-scanning proton beam and respiratory motion in intensity-modulated proton therapy (IMPT) for stage III lung cancer. Eleven patients were sampled from 112 patients with stage III nonsmall cell lung cancer to well represent the distribution of 112 patients in terms of target size and motion. Clinical target volumes (CTVs) and planning target volumes (PTVs) were defined according to the authors' clinical protocol. Uniform and realistic breathing patterns were considered along with regular- and hypofractionation scenarios. The dose contributed by a spot was fully calculated on the computed tomography (CT) images corresponding to the respiratory phase that the spot is delivered, and then accumulated to the reference phase of the 4DCT to generate the dynamic dose that provides an estimation of what might be delivered under the influence of interplay effect. The dynamic dose distributions at different numbers of fractions were compared with the corresponding 4D composite dose which is the equally weighted average of the doses, respectively, computed on respiratory phases of a 4DCT image set. Under regular fractionation, the average and maximum differences in CTV coverage between the 4D composite and dynamic doses after delivery of all 35 fractions were no more than 0.2% and 0.9%, respectively. The maximum differences between the two dose distributions for the maximum dose to the spinal cord, heart V40, esophagus V55, and lung V20 were 1.2 Gy, 0.1%, 0.8%, and 0.4%, respectively. Although relatively large differences in single fraction, correlated with small CTVs relative to motions, were observed, the authors' biological response calculations suggested that this interfractional dose variation may have limited biological impact. Assuming a hypofractionation scenario, the differences between the 4D composite and dynamic doses were well confined even for single fraction. Despite the presence of interplay effect, the delivered dose may be reliably estimated using the 4D composite dose. In general the interplay effect may not be a primary concern with IMPT for lung cancers for the authors' institution. The described interplay analysis tool may be used to provide additional confidence in treatment delivery.

Molecular biology of botulinum neurotoxin serotype A: a cosmetic perspective.

PubMed

Eapen, Bell Raj

2008-09-01

Cosmetic use of botulinum neurotoxin serotype A (BoNT/A) involves low doses of toxin administered for facial wrinkles and hyperhidrosis. The structural and functional properties of BoNT/A can affect the degree and duration of effect. Actively using the injected muscle is favorable as it exposes more receptors to BoNT/A. Divided doses of BoNT/A at an interval of more than 3 days may be longer lasting than single dose by blocking nascent neuronal sprouts. Antibodies are unlikely to be effective in BoNT/A neutralization because of the large area of receptor interaction. Several commonly used drugs including zinc and chloroquine can interact with BoNT/A, necessitating dosage adjustment for optimum effect. Serotype E (BoNT/E) can emerge as an antidote for BoNT/A for cosmetic use.

A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-05-01

A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects. Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a minimum of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatography-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated. Δ(9)-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concentration (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concentration (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported. The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.

Influence of plasma cholesterol and triglyceride concentrations and eritoran (E5564) micelle size on its plasma pharmacokinetics and ex vivo activity following single intravenous bolus dose into healthy female rabbits.

PubMed

Wasan, Kishor M; Risovic, Verica; Sivak, Olena; Lee, Stephen D; Mason, Douglas X; Chiklis, Gregory R; McShane, Jim; Lynn, Melvyn; Wong, Nancy; Rossignol, Daniel P

2008-01-01

Eritoran (E5564) is a glycophospholipid that acts as a toll-like receptor 4 (TLR4) antagonist that is being tested as a treatment for severe sepsis and septic shock. In the blood, eritoran binds to plasma lipoproteins altering its pharmacokinetic and pharmacodynamic (PD) effects in vivo. The purpose of this study was to determine the influence of changes in plasma cholesterol and triglyceride concentrations on the plasma pharmacokinetics and ex vivo activity of eritoran following single intravenous bolus dosing of eritoran to healthy female rabbits fed either a regular chow diet or a cholesterol-enriched diet. This was done with eritoran administered as stable micelle formulations of mean hydrodynamic diameters of 8 or 27 nm). Female New Zealand White rabbits were fed a standard diet for 7 days and then randomly assigned either a regular chow diet [regular-diet (n = 9)] or a cholesterol-enriched diet [cholesterol-diet (n = 12)] for an additional 7 days. Following feeding of these diets a single intravenous bolus dose of eritoran (0.5 mg/kg) formulated into either "small micelles" (8 nm in diameter) or "large micelles" (27 nm in diameter) was administered to regular-fed and cholesterol-fed rabbits. Serial blood samples were obtained prior to eritoran administration and at the following times post injection: 0.083 (5 min), 1, 2, 4, 8, 10, 24, 48 and 72 h. Plasma was analyzed for eritoran concentrations using LC/MS/MS. Total plasma cholesterol (TC) and triglyceride (TG) levels were quantified using enzymatic kits. Plasma eritoran pharmacokinetic (PK) parameters were estimated by non-compartmental analysis using the WinNonlin nonlinear estimation program. To analyze PD activity, whole blood obtained at 0.083 (5 min), 2, 24, 48 and 72 h following eritoran administration was assessed for ex vivo activity by measuring the ability of 1 and 10 ng/ml LPS to elicit TNF-alpha release. Total plasma cholesterol and triglyceride levels were significantly higher in cholesterol-fed rabbits compared to the rabbits fed a regular chow diet. Diet had no effect on the estimated plasma PK parameters. However, PD activity of both small and large micelle eritoran as measured by an ex vivo challenge dose of 1 ng/ml LPS was reduced in blood of cholesterol-fed rabbits compared to normal-fed rabbits. Comparison of PK parameters for small and large micelles indicated that small micelles had increased AUC(0-72 h), decreased plasma clearance and increased initial concentration (measured at 5 min post administration) compared to the large micelle formulation. Consistent with this observation, eritoran formulated into small micelles had significantly greater ex vivo activity than large micelles and was independent of TC and TG concentrations. These findings suggest that plasma pharmacokinetics and activity of eritoran maybe influenced by eritoran micelle size and plasma TC and TG concentrations.

Dose optimization of total or partial skin electron irradiation by thermoluminescent dosimetry.

PubMed

Schüttrumpf, Lars; Neumaier, Klement; Maihoefer, Cornelius; Niyazi, Maximilian; Ganswindt, Ute; Li, Minglun; Lang, Peter; Reiner, Michael; Belka, Claus; Corradini, Stefanie

2018-05-01

Due to the complex surface of the human body, total or partial skin irradiation using large electron fields is challenging. The aim of the present study was to quantify the magnitude of dose optimization required after the application of standard fields. Total skin electron irradiation (TSEI) was applied using the Stanford technique with six dual-fields. Patients presenting with localized lesions were treated with partial skin electron irradiation (PSEI) using large electron fields, which were individually adapted. In order to verify and validate the dose distribution, in vivo dosimetry with thermoluminescent dosimeters (TLD) was performed during the first treatment fraction to detect potential dose heterogeneity and to allow for an individual dose optimization with adjustment of the monitor units (MU). Between 1984 and 2017, a total of 58 patients were treated: 31 patients received TSEI using 12 treatment fields, while 27 patients underwent PSEI and were treated with 4-8 treatment fields. After evaluation of the dosimetric results, an individual dose optimization was necessary in 21 patients. Of these, 7 patients received TSEI (7/31). Monitor units (MU) needed to be corrected by a mean value of 117 MU (±105, range 18-290) uniformly for all 12 treatment fields, corresponding to a mean relative change of 12% of the prescribed MU. In comparison, the other 14 patients received PSEI (14/27) and the mean adjustment of monitor units was 282 MU (±144, range 59-500) to single or multiple fields, corresponding to a mean relative change of 22% of the prescribed MU. A second dose optimization to obtain a satisfying dose at the prescription point was need in 5 patients. Thermoluminescent dosimetry allows an individual dose optimization in TSEI and PSEI to enable a reliable adjustment of the MUs to obtain the prescription dose. Especially in PSEI in vivo dosimetry is of fundamental importance.

Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects.

PubMed

Togawa, Michinori; Yamaya, Hidetoshi; Rodríguez, Mónica; Nagashima, Hirotaka

2016-12-01

Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). After single oral doses, maximum plasma concentrations (C max ) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies.

QMRA for Drinking Water: 2. The Effect of Pathogen Clustering in Single-Hit Dose-Response Models.

PubMed

Nilsen, Vegard; Wyller, John

2016-01-01

Spatial and/or temporal clustering of pathogens will invalidate the commonly used assumption of Poisson-distributed pathogen counts (doses) in quantitative microbial risk assessment. In this work, the theoretically predicted effect of spatial clustering in conventional "single-hit" dose-response models is investigated by employing the stuttering Poisson distribution, a very general family of count distributions that naturally models pathogen clustering and contains the Poisson and negative binomial distributions as special cases. The analysis is facilitated by formulating the dose-response models in terms of probability generating functions. It is shown formally that the theoretical single-hit risk obtained with a stuttering Poisson distribution is lower than that obtained with a Poisson distribution, assuming identical mean doses. A similar result holds for mixed Poisson distributions. Numerical examples indicate that the theoretical single-hit risk is fairly insensitive to moderate clustering, though the effect tends to be more pronounced for low mean doses. Furthermore, using Jensen's inequality, an upper bound on risk is derived that tends to better approximate the exact theoretical single-hit risk for highly overdispersed dose distributions. The bound holds with any dose distribution (characterized by its mean and zero inflation index) and any conditional dose-response model that is concave in the dose variable. Its application is exemplified with published data from Norovirus feeding trials, for which some of the administered doses were prepared from an inoculum of aggregated viruses. The potential implications of clustering for dose-response assessment as well as practical risk characterization are discussed. © 2016 Society for Risk Analysis.

Absorption and distribution of lycopene in rat colon.

PubMed

Oshima, S; Inakuma, T; Narisawa, T

1999-01-01

Colonic absorption and distribution of lycopene, which inhibited rat colon carcinogenesis in our previous studies, were investigated in Sprague-Dawley rats. Three groups of six rats each with or without a single-barreled colostomy at the mid colon were given a single intragastric or intracolonic dose of 0.2 mL of corn oil containing 12 mg of lycopene. Twenty-four hours later, all rats were sacrificed and the blood and some tissues were collected. The contents of lycopene in the samples were assayed by HPLC. Lycopene was detected in an appreciable amount in the liver, but only in trace amount in the serum of all rats treated with an intracolonic dose of lycopene and in rats with an intragastric dose. After an intragastric lycopene treatment, lycopene was detected in the mucosa of the proximal colon and of the distal colon of the colostomized rats, whose distal colon had been excluded from the fecal stream. A large amount of lycopene was recovered in the feces. None was detected in any sample from the control rats treated with an intragastric or intracolonic dose of plain corn oil. The results suggest that lycopene is absorbed from the colon and also from the small intestine. It might be concluded that both ways of absorption contribute to a comparative amount of lycopene accumulation in the colon mucosa after ingestion of this carotenoid.

RadioImmunotherapy for adenoid cystic carcinoma: a single-institution series of combined treatment with cetuximab

PubMed Central

2010-01-01

Background Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent. However, some clinical situations do not allow application of tumouricidal doses (i.e. re-irradiation) hence radiation sensitization by exploitation of high endothelial growth factor receptor (EGFR)-expression in ACC seems beneficial. This is a single-institution experience of combined radioimmunotherapy (RIT) with the EGFR-inhibitor cetuximab. Methods Between 2006 and 2010, 9 pts received RIT for advanced/recurrent ACC, 5/9 pts as re-irradiation. Baseline characteristics as well as treatment parameters were retrieved to evaluate efficacy and toxicity of the combination regimen were evaluated. Control rates (local/distant) and overall survival were calculated using Kaplan-Meier estimation. Results Median dose was 65 Gy, pts received a median of 6 cycles cetuximab. RIT was tolerated well with only one °III mucositis/dysphagia. Overall response/remission rates were high (77,8%); 2-year estimate of local control was 80% hence reaching local control levels comparable to high-dose RT. Progression-free survival (PFS) at 2 years and median overall survival were only 62,5% and 22,2 mo respectively. Conclusion While local control and treatment response in RIT seems promising, PFS and overall survival are still hampered by distant failure. The potential benefit of RIT with cetuximab warrants exploration in a prospective controlled clinical trial. PMID:21047402

Four-Dimensional Patient Dose Reconstruction for Scanned Ion Beam Therapy of Moving Liver Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richter, Daniel; TU Darmstadt, Darmstadt; Saito, Nami

2014-05-01

Purpose: Estimation of the actual delivered 4-dimensional (4D) dose in treatments of patients with mobile hepatocellular cancer with scanned carbon ion beam therapy. Methods and Materials: Six patients were treated with 4 fractions to a total relative biological effectiveness (RBE)–weighted dose of 40 Gy (RBE) using a single field. Respiratory motion was addressed by dedicated margins and abdominal compression (5 patients) or gating (1 patient). 4D treatment dose reconstructions based on the treatment records and the measured motion monitoring data were performed for the single-fraction dose and a total of 17 fractions. To assess the impact of uncertainties in the temporalmore » correlation between motion trajectory and beam delivery sequence, 3 dose distributions for varying temporal correlation were calculated per fraction. For 3 patients, the total treatment dose was formed from the fractional distributions using all possible combinations. Clinical target volume (CTV) coverage was analyzed using the volumes receiving at least 95% (V{sub 95}) and 107% (V{sub 107}) of the planned doses. Results: 4D dose reconstruction based on daily measured data is possible in a clinical setting. V{sub 95} and V{sub 107} values for the single fractions ranged between 72% and 100%, and 0% and 32%, respectively. The estimated total treatment dose to the CTV exhibited improved and more robust dose coverage (mean V{sub 95} > 87%, SD < 3%) and overdose (mean V{sub 107} < 4%, SD < 3%) with respect to the single-fraction dose for all analyzed patients. Conclusions: A considerable impact of interplay effects on the single-fraction CTV dose was found for most of the analyzed patients. However, due to the fractionated treatment, dose heterogeneities were substantially reduced for the total treatment dose. 4D treatment dose reconstruction for scanned ion beam therapy is technically feasible and may evolve into a valuable tool for dose assessment.« less

Generalized field-splitting algorithms for optimal IMRT delivery efficiency.

PubMed

Kamath, Srijit; Sahni, Sartaj; Li, Jonathan; Ranka, Sanjay; Palta, Jatinder

2007-09-21

Intensity-modulated radiation therapy (IMRT) uses radiation beams of varying intensities to deliver varying doses of radiation to different areas of the tissue. The use of IMRT has allowed the delivery of higher doses of radiation to the tumor and lower doses to the surrounding healthy tissue. It is not uncommon for head and neck tumors, for example, to have large treatment widths that are not deliverable using a single field. In such cases, the intensity matrix generated by the optimizer needs to be split into two or three matrices, each of which may be delivered using a single field. Existing field-splitting algorithms used the pre-specified arbitrary split line or region where the intensity matrix is split along a column, i.e., all rows of the matrix are split along the same column (with or without the overlapping of split fields, i.e., feathering). If three fields result, then the two splits are along the same two columns for all rows. In this paper we study the problem of splitting a large field into two or three subfields with the field width as the only constraint, allowing for an arbitrary overlap of the split fields, so that the total MU efficiency of delivering the split fields is maximized. Proof of optimality is provided for the proposed algorithm. An average decrease of 18.8% is found in the total MUs when compared to the split generated by a commercial treatment planning system and that of 10% is found in the total MUs when compared to the split generated by our previously published algorithm.

Irradiation autogenous mandibular grafts in primary reconstructions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamaker, R.C.

1981-07-01

The procedure, irradiated mandibular autografts, for primary reconstruction, is presented with an immediate success rate of 88%. Eight cases have undergone primary mandibular reconstruction with the tumorous mandible irradiated to 10,000 rads in a single dose. The longest follow-up is 2 3/4 years. The autograft has proven to be an ideal implant. Major resections of the mandible in conjunction with large myocutaneous flaps have been reconstructed utilizing this implant.

Cellular dosimetry of (111)In using monte carlo N-particle computer code: comparison with analytic methods and correlation with in vitro cytotoxicity.

PubMed

Cai, Zhongli; Pignol, Jean-Philippe; Chan, Conrad; Reilly, Raymond M

2010-03-01

Our objective was to compare Monte Carlo N-particle (MCNP) self- and cross-doses from (111)In to the nucleus of breast cancer cells with doses calculated by reported analytic methods (Goddu et al. and Farragi et al.). A further objective was to determine whether the MCNP-predicted surviving fraction (SF) of breast cancer cells exposed in vitro to (111)In-labeled diethylenetriaminepentaacetic acid human epidermal growth factor ((111)In-DTPA-hEGF) could accurately predict the experimentally determined values. MCNP was used to simulate the transport of electrons emitted by (111)In from the cell surface, cytoplasm, or nucleus. The doses to the nucleus per decay (S values) were calculated for single cells, closely packed monolayer cells, or cell clusters. The cell and nucleus dimensions of 6 breast cancer cell lines were measured, and cell line-specific S values were calculated. For self-doses, MCNP S values of nucleus to nucleus agreed very well with those of Goddu et al. (ratio of S values using analytic methods vs. MCNP = 0.962-0.995) and Faraggi et al. (ratio = 1.011-1.024). MCNP S values of cytoplasm and cell surface to nucleus compared fairly well with the reported values (ratio = 0.662-1.534 for Goddu et al.; 0.944-1.129 for Faraggi et al.). For cross doses, the S values to the nucleus were independent of (111)In subcellular distribution but increased with cluster size. S values for monolayer cells were significantly different from those of single cells and cell clusters. The MCNP-predicted SF for monolayer MDA-MB-468, MDA-MB-231, and MCF-7 cells agreed with the experimental data (relative error of 3.1%, -1.0%, and 1.7%). The single-cell and cell cluster models were less accurate in predicting the SF. For MDA-MB-468 cells, relative error was 8.1% using the single-cell model and -54% to -67% using the cell cluster model. Individual cell-line dimensions had large effects on S values and were needed to estimate doses and SF accurately. MCNP simulation compared well with the reported analytic methods in the calculation of subcellular S values for single cells and cell clusters. Application of a monolayer model was most accurate in predicting the SF of breast cancer cells exposed in vitro to (111)In-DTPA-hEGF.

Evidence for single-dose protection by the bivalent HPV vaccine-Review of the Costa Rica HPV vaccine trial and future research studies.

PubMed

Kreimer, Aimée R; Herrero, Rolando; Sampson, Joshua N; Porras, Carolina; Lowy, Douglas R; Schiller, John T; Schiffman, Mark; Rodriguez, Ana Cecilia; Chanock, Stephen; Jimenez, Silvia; Schussler, John; Gail, Mitchell H; Safaeian, Mahboobeh; Kemp, Troy J; Cortes, Bernal; Pinto, Ligia A; Hildesheim, Allan; Gonzalez, Paula

2018-01-20

The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose. Published by Elsevier Ltd.

Predictive factors for the methotrexate treatment outcome in ectopic pregnancy: A comparative study of 400 cases.

PubMed

Bonin, Lucie; Pedreiro, Cécile; Moret, Stéphanie; Chene, Gautier; Gaucherand, Pascal; Lamblin, Géry

2017-01-01

We sought to evaluate the global success rate of intramuscular methotrexate for the treatment of ectopic pregnancy, identify factors predictive of treatment success or failure, and study methotrexate tolerability in a large patient cohort. For this single-center retrospective observational study, we retrieved the records of all women who had a clinically or echographically confirmed ectopic pregnancy with a Fernandez score <13 and who were treated according to a 1mg/kg intramuscular single-dose methotrexate protocol. Medical treatment failure was defined by an obligation to proceed to laparoscopy. Needing a second injection was not considered to be medical treatment failure. Between February 2008 and November 2013 (69 months), 400 women received methotrexate for ectopic pregnancy. The medical treatment protocol was effective for 314 patients, i.e., an overall success rate of 78.5%. A single methotrexate dose was sufficient for 63.5% of the women and a second dose was successful for 73.2% of the remaining women. The medical treatment success rate fell as initial hCG levels climbed. The main factors associated with methotrexate failure included day (D) 0, D4 and D7 hCG levels, pretherapeutic blood progesterone, hematosalpinx at D0 and pain at D7. Early favorable kinetics of hCG levels was predictive of success. Methotrexate treatment was successful in 90% of women who had D0 hCG <1000IU/l. Methotrexate tolerability was good, with only 9% of the women reporting non-severe adverse effects. The fertility rate with delivery after medical treatment for ectopic pregnancy was 80.7%. In this study, we showed that an initial hCG value <1000IU/l and favorable early HCG kinetics were predictive factors for the successful medical treatment of ectopic pregnancy by methotrexate, and hematosalpinx and pretherapeutic blood progesterone >5ng/ml at diagnosis were predictive of its failure. We also confirmed good tolerability for single-dose methotrexate protocols. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Protection of intestinal damage by pretreatment with cytarabine (cytosine arabinoside)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phelps, T.A.; Blackett, N.M.

The circumstances in which cytarabine (cytosine arabinoside) ''protects'' intestinal epithelial stem cells against radiation have been investigated. Special attention has been given to this protective effect with radiation doses in the clinically used range in order to determine whether the protective effect might be of use in radiotherapy. It has been shown that 12 hours after cytarabine the D/sub 0/ and extrapolation number are increased when large single doses of radiation are used. To determine the effect of cytarabine at lower doses, it is necessary to use a second irradiation as an ''assay'' dose. By this means it is shownmore » that there is more protection than can be accounted for by the change in D/sub 0/ and extrapolation number at the time of the first dose. Evidence is presented indicating that the rate of stem cell regeneration is not increased by cytarabine pretreatment. Finally, the relation between intestinal protection, bone marrow stem cell enhanced recovery and improved animal survival as a result of cytarabine pretreatment is discussed.« less

High-speed large angle mammography tomosynthesis system

NASA Astrophysics Data System (ADS)

Eberhard, Jeffrey W.; Staudinger, Paul; Smolenski, Joe; Ding, Jason; Schmitz, Andrea; McCoy, Julie; Rumsey, Michael; Al-Khalidy, Abdulrahman; Ross, William; Landberg, Cynthia E.; Claus, Bernhard E. H.; Carson, Paul; Goodsitt, Mitchell; Chan, Heang-Ping; Roubidoux, Marilyn; Thomas, Jerry A.; Osland, Jacqueline

2006-03-01

A new mammography tomosynthesis prototype system that acquires 21 projection images over a 60 degree angular range in approximately 8 seconds has been developed and characterized. Fast imaging sequences are facilitated by a high power tube and generator for faster delivery of the x-ray exposure and a high speed detector read-out. An enhanced a-Si/CsI flat panel digital detector provides greater DQE at low exposure, enabling tomo image sequence acquisitions at total patient dose levels between 150% and 200% of the dose of a standard mammographic view. For clinical scenarios where a single MLO tomographic acquisition per breast may replace the standard CC and MLO views, total tomosynthesis breast dose is comparable to or below the dose in standard mammography. The system supports co-registered acquisition of x-ray tomosynthesis and 3-D ultrasound data sets by incorporating an ultrasound transducer scanning system that flips into position above the compression paddle for the ultrasound exam. Initial images acquired with the system are presented.

Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial ▿

PubMed Central

Dunbar, Lala M.; Milata, Joe; McClure, Ty; Wasilewski, Margaret M.

2011-01-01

Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA. PMID:21537018

Interplay effects in proton scanning for lung: a 4D Monte Carlo study assessing the impact of tumor and beam delivery parameters.

PubMed

Dowdell, S; Grassberger, C; Sharp, G C; Paganetti, H

2013-06-21

Relative motion between a tumor and a scanning proton beam results in a degradation of the dose distribution (interplay effect). This study investigates the relationship between beam scanning parameters and the interplay effect, with the goal of finding parameters that minimize interplay. 4D Monte Carlo simulations of pencil beam scanning proton therapy treatments were performed using the 4DCT geometry of five lung cancer patients of varying tumor size (50.4-167.1 cc) and motion amplitude (2.9-30.1 mm). Treatments were planned assuming delivery in 35 × 2.5 Gy(RBE) fractions. The spot size, time to change the beam energy (τes), time required for magnet settling (τss), initial breathing phase, spot spacing, scanning direction, scanning speed, beam current and patient breathing period were varied for each of the five patients. Simulations were performed for a single fraction and an approximation of conventional fractionation. For the patients considered, the interplay effect could not be predicted using the superior-inferior motion amplitude alone. Larger spot sizes (σ ~ 9-16 mm) were less susceptible to interplay, giving an equivalent uniform dose (EUD) of 99.0 ± 4.4% (1 standard deviation) in a single fraction compared to 86.1 ± 13.1% for smaller spots (σ ~ 2-4 mm). The smaller spot sizes gave EUD values as low as 65.3% of the prescription dose in a single fraction. Reducing the spot spacing improved the target dose homogeneity. The initial breathing phase can have a significant effect on the interplay, particularly for shorter delivery times. No clear benefit was evident when scanning either parallel or perpendicular to the predominant axis of motion. Longer breathing periods decreased the EUD. In general, longer delivery times led to lower interplay effects. Conventional fractionation showed significant improvement in terms of interplay, giving a EUD of at least 84.7% and 100.0% of the prescription dose for the small and larger spot sizes respectively. The interplay effect is highly patient specific, depending on the motion amplitude, tumor location and the delivery parameters. Large degradations of the dose distribution in a single fraction were observed, but improved significantly using conventional fractionation.

Interplay effects in proton scanning for lung: A 4D Monte Carlo study assessing the impact of tumor and beam delivery parameters

PubMed Central

Dowdell, S; Grassberger, C; Sharp, G C; Paganetti, H

2013-01-01

Relative motion between a tumor and a scanning proton beam results in a degradation of the dose distribution (interplay effect). This study investigates the relationship between beam scanning parameters and the interplay effect, with the goal of finding parameters that minimize interplay. 4D Monte Carlo simulations of pencil beam scanning proton therapy treatments were performed using the 4DCT geometry of 5 lung cancer patients of varying tumor size (50.4–167.1cc) and motion amplitude (2.9–30.1mm). Treatments were planned assuming delivery in 35×2.5Gy(RBE) fractions. The spot size, time to change the beam energy (τes), time required for magnet settling (τss), initial breathing phase, spot spacing, scanning direction, scanning speed, beam current and patient breathing period were varied for each of the 5 patients. Simulations were performed for a single fraction and an approximation of conventional fractionation. For the patients considered, the interplay effect could not be predicted using the superior-inferior (SI) motion amplitude alone. Larger spot sizes (σ ~9–16mm) were less susceptible to interplay, giving an equivalent uniform dose (EUD) of 99.0±4.4% (1 standard deviation) in a single fraction compared to 86.1±13.1% for smaller spots (σ ~2–4mm). The smaller spot sizes gave EUD values as low as 65.3% of the prescription dose in a single fraction. Reducing the spot spacing improved the target dose homogeneity. The initial breathing phase can have a significant effect on the interplay, particularly for shorter delivery times. No clear benefit was evident when scanning either parallel or perpendicular to the predominant axis of motion. Longer breathing periods decreased the EUD. In general, longer delivery times led to lower interplay effects. Conventional fractionation showed significant improvement in terms of interplay, giving a EUD of at least 84.7% and 100.0% of the prescription dose for the small and larger spot sizes respectively. The interplay effect is highly patient specific, depending on the motion amplitude, tumor location and the delivery parameters. Large degradations of the dose distribution in a single fraction were observed, but improved significantly using conventional fractionation. PMID:23689035

Pharmacokinetics interaction between imatinib and genistein in rats.

PubMed

Wang, Zhe; Wang, Li; Xia, Meng-Ming; Sun, Wei; Huang, Cheng-Ke; Cui, Xiao; Hu, Guo-Xin; Lian, Qing-Quan; Wang, Zeng-Shou

2015-01-01

The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly (P < 0.05) decreased the AUC0-t and C max of imatinib. AUC0-t and the C max of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect.

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

PubMed Central

Cui, Yimin; Song, Yan; Wang, Jessie; Yu, Zhigang; Schuster, Alan; Barrett, Yu Chen; Frost, Charles

2013-01-01

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. PMID:24353445

Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose

PubMed Central

Marciani, L; Garsed, K C; Hoad, C L; Fields, A; Fordham, I; Pritchard, S E; Placidi, E; Murray, K; Chaddock, G; Costigan, C; Lam, C; Jalanka-Tuovinen, J; De Vos, W M; Gowland, P A; Spiller, R C

2014-01-01

Background Most methods of assessing colonic motility are poorly acceptable to patients. Magnetic resonance imaging (MRI) can monitor gastrointestinal motility and fluid distributions. We predicted that a dose of oral polyethylene glycol (PEG) and electrolyte solution would increase ileo-colonic inflow and stimulate colonic motility. We aimed to investigate the colonic response to distension by oral PEG electrolyte in healthy volunteers (HVs) and to evaluate the effect of single 2 L vs split (2 × 1 L) dosing. Methods Twelve HVs received a split dose (1 L the evening before and 1 L on the study day) and another 12 HVs a single dose (2 L on the main study day) of PEG electrolyte. They underwent MRI scans, completed symptom questionnaires, and provided stool samples. Outcomes included small bowel water content, ascending colon motility index, and regional colonic volumes. Key Results Small bowel water content increased fourfold from baseline after ingesting both split (p = 0.0010) and single dose (p = 0.0005). The total colonic volume increase from baseline was smaller for the split dose at 35 ± 8% than for the single dose at 102 ± 27%, p = 0.0332. The ascending colon motility index after treatment was twofold higher for the single dose group (p = 0.0103). Conclusions & Inferences Ingestion of 1 and 2 L PEG electrolyte solution caused a rapid increase in the small bowel and colonic volumes and a robust rise in colonic motility. The increase in both volumes and motility was dose dependent. Such a challenge, being well-tolerated, could be a useful way of assessing colonic motility in future studies. PMID:25060551

Multistage stereotactic radiosurgery for large cerebral arteriovenous malformations using the Gamma Knife platform.

PubMed

Ding, Chuxiong; Hrycushko, Brian; Whitworth, Louis; Li, Xiang; Nedzi, Lucien; Weprin, Bradley; Abdulrahman, Ramzi; Welch, Babu; Jiang, Steve B; Wardak, Zabi; Timmerman, Robert D

2017-10-01

Radiosurgery is an established technique to treat cerebral arteriovenous malformations (AVMs). Obliteration of larger AVMs (> 10-15 cm 3 or diameter > 3 cm) in a single session is challenging with current radiosurgery platforms due to toxicity. We present a novel technique of multistage stereotactic radiosurgery (SRS) for large intracranial arteriovenous malformations (AVM) using the Gamma Knife system. Eighteen patients with large (> 10-15 cm 3 or diameter > 3 cm) AVMs, which were previously treated using a staged SRS technique on the Cyberknife platform, were retrospectively selected for this study. The AVMs were contoured and divided into 3-8 subtargets to be treated sequentially in a staged approach at half to 4 week intervals. The prescription dose ranged from 15 Gy to 20 Gy, depending on the subtarget number, volume, and location. Gamma Knife plans using multiple collimator settings were generated and optimized. The coordinates of each shot from the initial plan covering the total AVM target were extracted based on their relative positions within the frame system. The shots were regrouped based on their location with respect to the subtarget contours to generate subplans for each stage. The delivery time of each shot for a subtarget was decay corrected with 60 Co for staging the treatment course to generate the same dose distribution as that planned for the total AVM target. Conformality indices and dose-volume analysis were performed to evaluate treatment plans. With the shot redistribution technique, the composite dose for the multistaged treatment of multiple subtargets is equivalent to the initial plan for total AVM target. Gamma Knife plans resulted in an average PTV coverage of 96.3 ± 0.9% and a PITV of 1.23 ± 0.1. The resulting Conformality indices, V 12Gy and R 50 dose spillage values were 0.76 ± 0.05, 3.4 ± 1.8, and 3.1 ± 0.5 respectively. The Gamma Knife system can deliver a multistaged conformal dose to treat large AVMs when correcting for translational setup errors of each shot at each staged treatment. © 2017 American Association of Physicists in Medicine.

Treatment of chancroid, 1997.

PubMed

Schmid, G P

1999-01-01

Since the 1993 treatment guidelines for sexually transmitted diseases were published by the Centers for Disease Control and Prevention, experience has indicated that the regimens recommended then remain largely effective. The recommended therapies--with azithromycin (1 g orally, once), ceftriaxone (250 mg intramuscularly, once), or erythromycin (500 mg orally, four times a day for 7 days)--appear highly effective in the United States; limited data from Kenya suggest that the ceftriaxone regimen may not be as effective there as it once was. The alternative regimen of ciprofloxacin proposed in 1993 (500 mg orally, twice a day for 3 days) is as effective as the recommended therapies, but new information indicates that single-dose therapy with 500 mg orally is not as effective as the use of either larger single doses or more prolonged therapy. Persons who are infected with human immunodeficiency virus (HIV) do not respond as well as those who are not HIV-infected, and males who are uncircumcised appear not to respond as well as those who are circumcised.

Chromosome Aberrations in Astronauts

NASA Technical Reports Server (NTRS)

George, Kerry A.; Durante, M.; Cucinotta, Francis A.

2007-01-01

A review of currently available data on in vivo induced chromosome damage in the blood lymphocytes of astronauts proves that, after protracted exposure of a few months or more to space radiation, cytogenetic biodosimetry analyses of blood collected within a week or two of return from space provides a reliable estimate of equivalent radiation dose and risk. Recent studies indicate that biodosimetry estimates from single spaceflights lie within the range expected from physical dosimetry and biophysical models, but very large uncertainties are associated with single individual measurements and the total sample population remains low. Retrospective doses may be more difficult to estimate because of the fairly rapid time-dependent loss of "stable" aberrations in blood lymphocytes. Also, biodosimetry estimates from individuals who participate in multiple missions, or very long (interplanetary) missions, may be complicated by an adaptive response to space radiation and/or changes in lymphocyte survival and repopulation. A discussion of published data is presented and specific issues related to space radiation biodosimetry protocols are discussed.

Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model.

PubMed

Yamazaki, Shinji; Johnson, Theodore R; Smith, Bill J

2015-10-01

An orally available multiple tyrosine kinase inhibitor, crizotinib (Xalkori), is a CYP3A substrate, moderate time-dependent inhibitor, and weak inducer. The main objectives of the present study were to: 1) develop and refine a physiologically based pharmacokinetic (PBPK) model of crizotinib on the basis of clinical single- and multiple-dose results, 2) verify the crizotinib PBPK model from crizotinib single-dose drug-drug interaction (DDI) results with multiple-dose coadministration of ketoconazole or rifampin, and 3) apply the crizotinib PBPK model to predict crizotinib multiple-dose DDI outcomes. We also focused on gaining insights into the underlying mechanisms mediating crizotinib DDIs using a dynamic PBPK model, the Simcyp population-based simulator. First, PBPK model-predicted crizotinib exposures adequately matched clinically observed results in the single- and multiple-dose studies. Second, the model-predicted crizotinib exposures sufficiently matched clinically observed results in the crizotinib single-dose DDI studies with ketoconazole or rifampin, resulting in the reasonably predicted fold-increases in crizotinib exposures. Finally, the predicted fold-increases in crizotinib exposures in the multiple-dose DDI studies were roughly comparable to those in the single-dose DDI studies, suggesting that the effects of crizotinib CYP3A time-dependent inhibition (net inhibition) on the multiple-dose DDI outcomes would be negligible. Therefore, crizotinib dose-adjustment in the multiple-dose DDI studies could be made on the basis of currently available single-dose results. Overall, we believe that the crizotinib PBPK model developed, refined, and verified in the present study would adequately predict crizotinib oral exposures in other clinical studies, such as DDIs with weak/moderate CYP3A inhibitors/inducers and drug-disease interactions in patients with hepatic or renal impairment. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Design and statistical considerations for studies evaluating the efficacy of a single dose of the human papillomavirus (HPV) vaccine.

PubMed

Sampson, Joshua N; Hildesheim, Allan; Herrero, Rolando; Gonzalez, Paula; Kreimer, Aimee R; Gail, Mitchell H

2018-05-01

Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix ® or Gardasil ®, prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomédicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution. Copyright © 2018. Published by Elsevier Inc.

Modulation of distinct asthmatic phenotypes in mice by dose-dependent inhalation of microbial products.

PubMed

Whitehead, Gregory S; Thomas, Seddon Y; Cook, Donald N

2014-01-01

Humans with asthma display considerable heterogeneity with regard to T helper (Th) 2-associated eosinophilic and Th17-associated neutrophilic inflammation, but the impact of the environment on these different forms of asthma is poorly understood. We studied the nature and longevity of asthma-like responses triggered by inhalation of allergen together with environmentally relevant doses of inhaled lipopolysaccharide (LPS). Ovalbumin (OVA) was instilled into the airways of mice together with a wide range of LPS doses. Following a single OVA challenge, or multiple challenges, animals were assessed for pulmonary cytokine production, airway inflammation, and airway hyperresponsiveness (AHR). Mice instilled with OVA together with very low doses (≤10⁻³ μg) of LPS displayed modest amounts of Th2 cytokines, with associated airway eosinophilia and AHR after a single challenge, and these responses were sustained after multiple OVA challenges. When the higher but still environmentally relevant dose of 10⁻¹ μg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia. After multiple OVA challenges, however, the 10⁻¹ μg LPS animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells with high levels of inducible co-stimulatory molecule (ICOS). As a result, asthma-like features in these mice were shorter-lived than in mice sensitized using lower doses of LPS. The nature and longevity of Th2, Th17, and Treg immune responses to inhaled allergen are dependent on the quantity of LPS inhaled at the time of allergic sensitization. These findings might account in part for the heterogeneity of inflammatory infiltrates seen in lungs of asthmatics.

High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies.

PubMed

Zohar, Joseph; Yahalom, Hila; Kozlovsky, Nitsan; Cwikel-Hamzany, Shlomit; Matar, Michael A; Kaplan, Zeev; Yehuda, Rachel; Cohen, Hagit

2011-11-01

High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100-140 mg) or placebo within 6 h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. In parallel, a comparative study of morphological arborization in dentate gyrus and its modulating molecules was performed in stress-exposed animals treated with high-dose hydrocortisone. Steroid-treated stressed animals displayed significantly increased dendritic growth and spine density, with increased levels of brain-derived neurotrophic factor (BDNF) and obtunded postsynaptic density-95 (PSD-95) levels. The animal study provided insights into the potential mechanism of this intervention, as it identified relevant morphological and biochemical associations to the clinical observations. Thus, evidence from clinical and animal studies suggests that there is a "window of opportunity" in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD. Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.

Studies on the fate of flocoumafen in the Japanese quail (Coturnix coturnix japonica).

PubMed

Huckle, K R; Warburton, P A; Forbes, S; Logan, C J

1989-01-01

1. 14C-Flocoumafen, administered to Japanese quail as a single oral or i.p. dose, was rapidly and extensively eliminated in excreta; most was eliminated within 24 h. Extensive metabolism of the rodenticide was seen, with at least 8 metabolites detected; unchanged flocoumafen comprised 9% dose. The elimination kinetics and metabolic profiles were qualitatively similar after oral and i.p. dosing. 2. The major metabolites (60% dose) were labile to beta-glucuronidase, liberating aglycones with identical chromatographic mobilities to those of the unchanged flocoumafen isomers. 3. Radioactivity was retained mostly in the liver; largely as unchanged flocoumafen associated with the mitochondrial and microsomal fractions. Elimination of radioactivity from most tissues was biphasic with an initially rapid depletion (5 days) followed by a slow terminal elimination phase. The elimination half life from liver was greater than 100 days. 4. Livers of quail receiving extended dietary exposure to flocoumafen at 5, 15 and 50 ppm had concentrations of flocoumafen (1.0 nmol/g) that were independent of dose, indicating a capacity-limited binding site. These hepatic concentrations were similar to those after a single oral dose and were also similar to those in rats. The data indicate the presence in quail liver of a saturable high affinity flocoumafin binding site with similar characteristics and capacity to that in the rat. 5. The selective toxicity of flocoumafen to rats (highly toxic) and quail (moderately toxic) appears to arise from differences in metabolism rather than from anticoagulant binding in the liver. When hepatic binding sites of rats are saturated anticoagulant action becomes lethal, whereas quail are able to survive and extensively metabolize the compound.

Comparison of two methods for measuring γ-H2AX nuclear fluorescence as a marker of DNA damage in cultured human cells: applications for microbeam radiation therapy

NASA Astrophysics Data System (ADS)

Anderson, D.; Andrais, B.; Mirzayans, R.; Siegbahn, E. A.; Fallone, B. G.; Warkentin, B.

2013-06-01

Microbeam radiation therapy (MRT) delivers single fractions of very high doses of synchrotron x-rays using arrays of microbeams. In animal experiments, MRT has achieved higher tumour control and less normal tissue toxicity compared to single-fraction broad beam irradiations of much lower dose. The mechanism behind the normal tissue sparing of MRT has yet to be fully explained. An accurate method for evaluating DNA damage, such as the γ-H2AX immunofluorescence assay, will be important for understanding the role of cellular communication in the radiobiological response of normal and cancerous cell types to MRT. We compare two methods of quantifying γ-H2AX nuclear fluorescence for uniformly irradiated cell cultures: manual counting of γ-H2AX foci by eye, and an automated, MATLAB-based fluorescence intensity measurement. We also demonstrate the automated analysis of cell cultures irradiated with an array of microbeams. In addition to offering a relatively high dynamic range of γ-H2AX signal versus irradiation dose ( > 10 Gy), our automated method provides speed, robustness, and objectivity when examining a series of images. Our in-house analysis facilitates the automated extraction of the spatial distribution of the γ-H2AX intensity with respect to the microbeam array — for example, the intensities in the peak (high dose area) and valley (area between two microbeams) regions. The automated analysis is particularly beneficial when processing a large number of samples, as is needed to systematically study the relationship between the numerous dosimetric and geometric parameters involved with MRT (e.g., microbeam width, microbeam spacing, microbeam array dimensions, peak dose, valley dose, and geometric arrangement of multiple arrays) and the resulting DNA damage.

Medical management of ectopic pregnancy with single-dose and 2-dose methotrexate protocols: human chorionic gonadotropin trends and patient outcomes.

PubMed

Mergenthal, Michelle C; Senapati, Suneeta; Zee, Jarcy; Allen-Taylor, Lynne; Whittaker, Paul G; Takacs, Peter; Sammel, Mary D; Barnhart, Kurt T

2016-11-01

Ectopic pregnancy, although rare, is an important cause of female morbidity and mortality and early, effective treatment is critical. Systemic methotrexate has become widely accepted as a safe and effective alternative to surgery in the stable patient. As the number and timing of methotrexate doses differ in the 3 main medical treatment regimens, one might expect trends in serum human chorionic gonadotropin and time to resolution to vary depending on protocol. Furthermore, human chorionic gonadotropin trends and time to resolution may predict ultimate treatment success. This study hypothesized that the 2-dose methotrexate protocol would be associated with a faster initial decline in serum human chorionic gonadotropin levels and a shorter time to resolution compared to the single-dose protocol. A prospective multicenter cohort study included clinical data from women who received medical management for ectopic pregnancy. Rates of human chorionic gonadotropin change and successful pregnancy resolution were assessed. Propensity score modeling addressed confounding by indication, the potential for differential assignment of patients with better prognosis to the single-dose methotrexate protocol. In all, 162 ectopic pregnancies were in the final analysis; 114 (70%) were treated with the single-dose methotrexate and 48 (30%) with the 2-dose protocol. Site, race, ethnicity, and reported pain level were associated with differential protocol allocation (P < .001, P = .011, P < .001, and P = .035, respectively). Women had similar initial human chorionic gonadotropin levels in either protocol but the mean rate of decline of human chorionic gonadotropin from day 0 (day of administration of first dose of methotrexate) to day 7 was significantly more rapid in women who received the single-dose protocol compared to those treated with the 2-dose protocol (mean change -31.3% vs -10.4%, P = .037, adjusted for propensity score and site). The 2 protocols had no significant differences in success rate or time to resolution. In a racially and geographically diverse group of women, the single- and double-dose methotrexate protocols had comparable outcomes. The more rapid human chorionic gonadotropin initial decline in the single-dose group suggested these patients were probably at lower risk for ectopic rupture than those getting the 2-dose protocol. A prospective randomized controlled design is needed to remove confounding by indication. Copyright © 2016 Elsevier Inc. All rights reserved.

Experimental re-evaluation of flunarizine as add-on antiepileptic therapy.

PubMed

Thakur, Anamika; Sahai, A K; Thakur, J S

2011-04-01

Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy. Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD(50) and CD(99) values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100-300 mg/kg), lamotrigine (3-12 mg/kg) and flunarizine (5-20 mg/kg), and then each group of mice was injected with CD(99) dose of PTZ (65mg/kg i.p.). Another group of mice received single ED(50) dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal-Wallis ANOVA on Ranks test. As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection. As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials involving large sample size are needed to establish flunarizine as add-on therapy in refractory epilepsy.

The effects of repetitious topical use of mitomycin C on antrostomy patency in maxillary antrostomy created rabbit model.

PubMed

Kavuzlu, Ali; Arslan, Necmi; Tastan, Eren; Islam, Ahmet; Ustun, Huseyin; Aydogan, Filiz

2011-11-01

The aim of our study was to investigate the effect of the topical use of mitomycin C (MMC) intraoperatively in single dose and intra-postoperatively in two doses on the narrowing of antrostomy in maxillary rabbit sinus antrostomies created experimentally. And also to determine the local and systemic side effects of topical MMC. With this objective, 0.6 mg/ml MMC was used to the first group at single dose and to the second group intraoperatively and on third day postoperatively in two doses topically for 5 min. After 8 weeks, although the mean area of antrostomy was larger than that in the control side in the first group, which received single dose MMC, the difference was not statistically significant (p = 0.287). The second group received two doses, and the antrostomy areas were found to be significantly larger than the controls (p = 0.05). Overall, the sides that received MMC were significantly larger (p = 0.029). From the point of histopathological examination of the tissue, it was seen that two-dose MMC increased the edema indicating inflammation and antrostomy resolved with normal respiratory tract epithelium. It was shown by measuring the blood values that nephrotoxic and myelosupressant effect of MMC occurring in systemic use did not occur with single or double dose topical use. Our results demonstrate that even if the number of cases was low, two doses of topical MMC usage prevent the narrowing of antrostomy while single dose MMC does not. And two-dose topical MMC usage does not have local and systemic side effects.

Evaluation of a single-scan protocol for radiochromic film dosimetry.

PubMed

Shimohigashi, Yoshinobu; Araki, Fujio; Maruyama, Masato; Nakaguchi, Yuji; Kuwahara, Satoshi; Nagasue, Nozomu; Kai, Yudai

2015-03-08

The purpose of this study was to evaluate a single-scan protocol using Gafchromic EBT3 film (EBT3) by comparing it with the commonly used 24-hr measurement protocol for radiochromic film dosimetry. Radiochromic film is generally scanned 24 hr after film exposure (24-hr protocol). The single-scan protocol enables measurement results within a short time using only the verification film, one calibration film, and unirradiated film. The single-scan protocol was scanned 30 min after film irradiation. The EBT3 calibration curves were obtained with the multichannel film dosimetry method. The dose verifications for each protocol were performed with the step pattern, pyramid pattern, and clinical treatment plans for intensity-modulated radiation therapy (IMRT). The absolute dose distributions for each protocol were compared with those calculated by the treatment planning system (TPS) using gamma evaluation at 3% and 3 mm. The dose distribution for the single-scan protocol was within 2% of the 24-hr protocol dose distribution. For the step pattern, the absolute dose discrepancies between the TPS for the single-scan and 24-hr protocols were 2.0 ± 1.8 cGy and 1.4 ± 1.2 cGy at the dose plateau, respectively. The pass rates were 96.0% for the single-scan protocol and 95.9% for the 24-hr protocol. Similarly, the dose discrepancies for the pyramid pattern were 3.6 ± 3.5cGy and 2.9 ± 3.3 cGy, respectively, while the pass rates for the pyramid pattern were 95.3% and 96.4%, respectively. The average pass rates for the four IMRT plans were 96.7% ± 1.8% for the single-scan protocol and 97.3% ± 1.4% for the 24-hr protocol. Thus, the single-scan protocol measurement is useful for dose verification of IMRT, based on its accuracy and efficiency.

Effects of food and grapefruit juice on single-dose pharmacokinetics of blonanserin in healthy Chinese subjects.

PubMed

Shang, De-Wei; Wang, Zhan-Zhang; Hu, Hai-Tang; Zhang, Yue-Feng; Ni, Xiao-Jia; Lu, Hao-Yang; Zhang, Ming; Hu, Jin-Qing; Qiu, Chang; Peng, Huan; Shen, Ling-Fang; Wen, Yu-Guan

2018-01-01

The purpose of this study was to investigate the potential effects of a meal and grapefruit juice on the pharmacokinetics of blonanserin and its metabolite N-desethyl blonanserin in healthy Chinese volunteers. This was a single-centre, open-label, fixed-sequence study, where 12 healthy Chinese volunteers received a single dose of 8 mg blonanserin after an overnight fast in period 1 (reference), a high-fat meal during period 2 and with co-administration of 250 mL of grapefruit juice in period 3. The washout period was 7 days. Series of plasma samples were collected after each dose to determine concentrations of blonanserin and its metabolite N-desethyl blonanserin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis and compared between periods by standard average bioequivalence ANOVA. Adverse events were monitored throughout the study. All subjects completed the study. High-fat meals significantly increased blonanserin exposure (AUC t ) 2.58-fold (90% CI 2.21, 3.02), relative to the reference period. Co-administration of blonanserin with grapefruit juice remarkably prolonged elimination half-life of blonanserin (from 9.7 to 21.4 h) and significantly increased exposures to blonanserin and N-desethyl blonanserin by 5.82-fold (90% CI 4.57, 7.42) and 1.81-fold (90% CI 1.65, 1.98), respectively. These results suggested that blonanserin was largely metabolised in the intestinal tract before becoming systemically available, and both food and grapefruit juice enhanced exposure to blonanserin and N-desethyl blonanserin. Grapefruit juice increased bioavailability and may have reduced systemic clearance of blonanserin. Further intestinal CYP3A4 and hepatic CYP3A4 might be postulated to explain the delayed elimination of blonanserin. Dose adjustment of blonanserin is needed on the basis of co-intake of known strong CYP3A4 inhibitor. Patients taking high-dose blonanserin also need to be cautious about the ingestion of grapefruit juice.

Estimating systemic exposure to levonorgestrel from an oral contraceptive.

PubMed

Basaraba, Cale N; Westhoff, Carolyn L; Pike, Malcolm C; Nandakumar, Renu; Cremers, Serge

2017-04-01

The gold standard for measuring oral contraceptive (OC) pharmacokinetics is the 24-h steady-state area under the curve (AUC). We conducted this study to assess whether limited sampling at steady state or measurements following use of one or two OCs could provide an adequate proxy in epidemiological studies for the progestin 24-h steady-state AUC of a particular OC. We conducted a 13-sample, 24-h pharmacokinetic study on both day 1 and day 21 of the first cycle of a monophasic OC containing 30-mcg ethinyl estradiol and 150-mcg levonorgestrel (LNG) in 17 normal-weight healthy White women and a single-dose 9-sample study of the same OC after a 1-month washout. We compared the 13-sample steady-state results with several steady-state and single-dose results calculated using parsimonious sampling schemes. The 13-sample steady-state 24-h LNG AUC was highly correlated with the steady-state 24-h trough value [r=0.95; 95% confidence interval (0.85, 0.98)] and with the steady-state 6-, 8-, 12- and 16-h values (0.92≤r≤0.95). The trough values after one or two doses were moderately correlated with the steady-state 24-h AUC value [r=0.70; 95% CI (0.27, 0.90) and 0.77; 95% CI (0.40, 0.92), respectively]. Single time-point concentrations at steady state and after administration of one or two OCs gave highly to moderately correlated estimates of steady-state LNG AUC. Using such measures could facilitate prospective pharmaco-epidemiologic studies of the OC and its side effects. A single time-point LNG concentration at steady state is an excellent proxy for complete and resource-intensive steady-state AUC measurement. The trough level after two single doses is a fair proxy for steady-state AUC. These results provide practical tools to facilitate large studies to investigate the relationship between systemic LNG exposure and side effects in a real-life setting. Copyright © 2017 Elsevier Inc. All rights reserved.

Nitrosamine-induced carcinogenesis. The alkylation of N-7 of guanine of nucleic acids of the rat by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate

PubMed Central

Swann, P. F.; Magee, P. N.

1971-01-01

1. The extent of ethylation of N-7 of guanine in the nucleic acids of rat tissue in vivo by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate was measured. 2. All compounds produced measurable amounts of 7-ethyl-guanine. 3. A single dose of diethylnitrosamine or N-ethyl-N-nitrosourea produced tumours of the kidney in the rat. Three doses of ethyl methanesulphonate produced kidney tumours, but a single dose did not. 4. A single dose of diethylnitrosamine produced twice as much ethylation of N-7 of guanine in DNA of kidney as did N-ethyl-N-nitrosourea. A single dose of both compounds induced kidney tumours, although of a different histological type. 5. A single dose of ethyl methanesulphonate produced ten times as much ethylation of N-7 of guanine in kidney DNA as did N-ethyl-N-nitrosourea without producing tumours. 6. The relevance of these findings to the hypothesis that alkylation of a cellular component is the mechanism of induction of tumours by nitroso compounds is discussed. PMID:5145908

Evidence of reduced oral bioavailability of paracetamol in rats following multiple ingestion of grapefruit juice.

PubMed

Qinna, Nidal A; Ismail, Obbei A; Alhussainy, Tawfiq M; Idkaidek, Nasir M; Arafat, Tawfiq A

2016-04-01

The aim of the current investigation was to assess the ability GFJ to modulate the pharmacokinetic profile of paracetamol following single or repeated administrations of GFJ in Sprague-Dawley rats. Diclofenac and carbamazepine were both used as positive controls. Rats received single GFJ or single distilled water doses or pretreated with three doses of GFJ prior to test drug administration. Blood samples were collected, processed and analyzed using validated HPLC methods, and pharmacokinetic data were constructed for each group. Increase in the bioavailability of both diclofenac and carbamazepine following multiple GFJ ingestion was revealed. Conversely, the bioavailability of paracetamol was significantly reduced following multiple GFJ administration. The percentage of reduction in the C max and AUC of paracetamol were calculated as 31 and 51 %, respectively, compared to none-GFJ-treated control (P < 0.05). The T(max) was not essentially changed. In conclusion, frequent administration of GFJ was confirmed to modulate the pharmacokinetics of paracetamol in rats by reducing its bioavailability. Meanwhile, it may be advisable not to ingest large amounts of GFJ along with paracetamol to avoid a possible potential loss of the efficacy.

Simulation and parametric study of a film-coated controlled-release pharmaceutical.

PubMed

Borgquist, Per; Zackrisson, Gunnar; Nilsson, Bernt; Axelsson, Anders

2002-04-23

Pharmaceutical formulations can be designed as Multiple Unit Systems, such as Roxiam CR, studied in this work. The dose is administrated as a capsule, which contains about 100 individual pellets, which in turn contain the active drug remoxipride. Experimental data for a large number of single pellets can be obtained by studying the release using microtitre plates. This makes it possible to study the release of the individual subunits making up the total dose. A mathematical model for simulating the release of remoxipride from single film-coated pellets is presented including internal and external mass transfer hindrance apart from the most important film resistance. The model can successfully simulate the release of remoxipride from single film-coated pellets if the lag phase of the experimental data is ignored. This was shown to have a minor influence on the release rate. The use of the present model is demonstrated by a parametric study showing that the release process is film-controlled, i.e. is limited by the mass transport through the polymer coating. The model was used to fit the film thickness and the drug loading to the experimental release data. The variation in the fitted values was similar to that obtained in the experiments.

Peri-exposure protection against Nipah virus disease using a single-dose recombinant vesicular stomatitis virus-based vaccine

PubMed Central

DeBuysscher, Blair L; Scott, Dana; Thomas, Tina; Feldmann, Heinz; Prescott, Joseph

2016-01-01

Nipah virus is a zoonotic paramyxovirus that causes severe disease in humans and animals. Due to almost yearly outbreaks in Bangladesh, and a large outbreak in Malaysia that lead to the shutdown of swine export, Nipah virus is both a threat to public health and the economy. Infection is associated with respiratory distress, encephalitis and human-to-human transmission, resulting in high case fatality rates during outbreaks. This study aims to address the amount of time needed until protection from a recombinant vesicular stomatitis virus-based vaccine candidate expressing the Nipah virus glycoprotein (G), which we have previously shown to protect hamsters and non-human primates when administered 28 days before challenge. We found that a single-dose vaccination, when administered 1 day before challenge, reduced viral load, limited pathology and fully protected hamsters from Nipah virus infection. The vaccine was even partially protective when administered at early time points following challenge with Nipah virus. These data indicate that a single administration of this vaccine to high-risk individuals, such as family members and health-care workers of infected patients, could be protective and useful for reducing human-to-human transmission and curbing an outbreak. PMID:28706736

Peri-exposure protection against Nipah virus disease using a single-dose recombinant vesicular stomatitis virus-based vaccine.

PubMed

DeBuysscher, Blair L; Scott, Dana; Thomas, Tina; Feldmann, Heinz; Prescott, Joseph

2016-01-01

Nipah virus is a zoonotic paramyxovirus that causes severe disease in humans and animals. Due to almost yearly outbreaks in Bangladesh, and a large outbreak in Malaysia that lead to the shutdown of swine export, Nipah virus is both a threat to public health and the economy. Infection is associated with respiratory distress, encephalitis and human-to-human transmission, resulting in high case fatality rates during outbreaks. This study aims to address the amount of time needed until protection from a recombinant vesicular stomatitis virus-based vaccine candidate expressing the Nipah virus glycoprotein (G), which we have previously shown to protect hamsters and non-human primates when administered 28 days before challenge. We found that a single-dose vaccination, when administered 1 day before challenge, reduced viral load, limited pathology and fully protected hamsters from Nipah virus infection. The vaccine was even partially protective when administered at early time points following challenge with Nipah virus. These data indicate that a single administration of this vaccine to high-risk individuals, such as family members and health-care workers of infected patients, could be protective and useful for reducing human-to-human transmission and curbing an outbreak.

Safety, Tolerability, and Pharmacokinetic Properties of Intravenous Delafloxacin After Single and Multiple Doses in Healthy Volunteers.

PubMed

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

2016-01-01

The objective of this report was to determine the pharmacokinetic properties, safety, and tolerability of single and multiple doses of intravenous delafloxacin. In addition, the absolute bioavailability (BA) of the 450-mg tablet formulation of delafloxacin was determined. Three clinical trials are summarized. The first study was a randomized, double-blind, placebo-controlled, single- (300, 450, 600, 750, 900, and 1200 mg) ascending-dose study of IV delafloxacin in 62 (52 active, 10 placebo) healthy volunteers. The second study was a randomized, double-blind, placebo-controlled study of IV delafloxacin (300 mg) given as a single dose on day 1, followed by twice-daily dosing on days 2 through 14; 12 (8 active, 4 placebo) healthy volunteers were enrolled. The third study was an open-label, randomized, 2-period, 2-sequence crossover study in which 56 healthy volunteers were randomly assigned to 1 of 2 sequences of a single oral dose of delafloxacin (450-mg tablet) or IV delafloxacin (300 mg). Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were calculated. Delafloxacin Cmax values increased proportionally with increasing single IV dose for the dose range of 300 to 1200 mg, whereas the AUC values increased more than proportionally to dose for the same dose range. The mean terminal half-life of delafloxacin was approximately 12 hours (ranging from 8 to 17 hours). The volume of distribution (Vd) at steady state was approximately 35 L, which is similar to the volume of total body water. There was minimal accumulation of delafloxacin after twice-daily IV administration of 300 mg with an accumulation ratio of 1.09. The delafloxacin total exposure after a single 1-hour IV infusion of 300 mg and a single oral dose of a 450-mg tablet were equivalent with geometric least square mean ratio (90% CI) of 0.8768 (0.8356-0.9200) for AUC0-∞ and 0.8445 (0.8090-0.8815) for AUC0-t, respectively. The Cmax values of delafloxacin were not equivalent for the 2 formulations with a ratio (90% CI) of 0.5516 (0.5150-0.5908), respectively. The mean absolute bioavailability of delafloxacin was 58.8%. Delafloxacin was well tolerated in healthy volunteers after single and multiple IV doses. The total systemic exposure to IV (300 mg) and oral (450 mg) delafloxacin is comparable, supporting that a switch between the 2 formulations is appropriate. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Clinical outcomes from an innovative protocol using serial ultrasound imaging and a single MR image to guide brachytherapy for locally advanced cervix cancer.

PubMed

van Dyk, Sylvia; Narayan, Kailash; Bernshaw, David; Kondalsamy-Chennakesavan, Srinivas; Khaw, Pearly; Lin, Ming Yin; Schneider, Michal

The aim of this study was to report clinical outcomes in a series of patients who underwent serial ultrasound and a single MRI to plan and verify intracavitary brachytherapy. Data for patients who were referred for curative intent radiotherapy for International Federation of Gynecology and Obstetrics (FIGO) Stage 1-1V cervix cancer between January 2007 and March 2012 were analyzed. All patients received external beam radiotherapy with concurrent chemotherapy and sequential high-dose rate brachytherapy. Brachytherapy was planned and verified using serial ultrasound imaging and a single MRI. Data from 191 patients were available for analyses. The median (range) followup time was 5.08 (0.25-8.25) years. Five-year local control, failure-free survival, cancer-specific survival, and overall survival were 86%, 57.3%, 70% and 63%, respectively. Mean (standard deviation) combined external beam radiotherapy and brachytherapy target doses, equivalent to doses in 2 Gy fractions were 80.4 Gy10 (3.89), median (range) 80 (49-96) Gy10. Grade 3 or greater gastrointestinal, genitourinary, or vaginal late toxicity occurred in 3%, 1.6%, and 2% of patients, respectively. Survival, patterns of failure, and late complication rates were similar to published series of MRI/CT-based brachytherapy practices. This large study demonstrates that favorable treatment outcomes can be obtained using a pragmatic and innovative combination of ultrasound and MR imaging. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

The pharmacokinetic and safety profiles of blonanserin in healthy Chinese volunteers after single fasting doses and single and multiple postprandial doses.

PubMed

Chen, Xia; Wang, Hongyun; Jiang, Ji; Chen, Rui; Zhou, Ying; Zhong, Wen; Liu, Hongzhong; Hu, Pei

2014-03-01

Blonanserin is a novel atypical antipsychotic drug acting as a mixed serotonin 5-HT2A and dopamine D2 receptor antagonist. This study investigated the pharmacokinetics and safety of blonanserin in healthy Chinese males. This was an open-label trial with two parts. Twenty-four subjects were enrolled in part A to receive a single fasting dose of 4 or 8 mg blonanserin (each n = 12); part B recruited 12 subjects and administered single and sequentially twice-daily multiple postprandial doses of blonanserin 2 mg for 9 days. Serial blood samples were taken for the bioassay of plasma blonanserin and its four metabolites during both sub-studies. Safety was assessed, including repeat measurements of fasting serum prolactin, insulin, triglyceride and cholesterol. Blonanserin was rapidly absorbed, accompanied with immediate plasma concentration elevation of the N-oxide form (M2) and gradual rises of the N-deethylated form (M1) and its downstream metabolites. The mean elimination half-life of blonanserin (7.7-11.9 h) was much longer than that of M2 (1.2-1.3 h) but shorter than that of M1 (26.4-31.4 h) after single fasting doses. After food intake, a single dose of 2 mg blonanserin resulted in total exposure and peak concentrations of blonanserin similar to those observed with a single fasting dose of blonanserin 4 mg. Moreover, the relationship of metabolite over parent compound ratio was different between M1 and M2 after single and multiple postprandial administrations (single dose vs multiple dose: M1, 0.33 vs 0.75; M2, 0.13 vs 0.067). Mild but transient increases of prolactin, insulin and triglyceride were observed. The pharmacokinetics of blonanserin in Chinese subjects were similar to those observed in Japanese subjects. This study suggested that food intake not only increases the bioavailability of blonanserin but differently affects the pharmacokinetics of its metabolites as well. The drug was safe and well tolerated in healthy Chinese males.

Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients.

PubMed

Pfister, C U; Martoni, A; Zamagni, C; Lelli, G; De Braud, F; Souppart, C; Duval, M; Hornberger, U

2001-07-01

Letrozole (trademark Femara) is a new orally active, potent and selective aromatase inhibitor for the hormonal treatment of advanced breast cancer in postmenopausal women. The pharmacokinetics of letrozole and the suppression of peripheral estrogens were studied in 28 breast cancer patients after a single dose and at steady state. The pharmacokinetics of two distinct age groups (> or =50, < or =65, N=15 and > or =70 years old, N=9) were compared. There were no significant differences in area under the curve (AUC) or terminal half-life between the two age groups neither after a single dose nor at steady state. However, when comparing steady state to single dose kinetics, half-life and AUC increased significantly by 42% (90% CI: 1.13, 1.78) and 28% (90% CI: 1.12, 1.47), respectively. This deviation from linearity was probably due to a partial saturation or auto-inhibition of the dominant metabolic clearance mechanism of letrozole. At steady state, approximately 70% of the administered dose was excreted in urine as unchanged letrozole (6.0+/-3.8%) or as the glucuronide of the major, pharmacologically inactive metabolite CGP44645 (64.2+/-22.7%). A single dose of letrozole caused suppression of serum estrogen levels close to the quantification limit of the assay. No difference between single dose suppression and suppression at steady state could be detected. Copyright 2001 John Wiley & Sons, Ltd.

Low efficacy of mebendazole against hookworm in Vietnam: two randomized controlled trials.

PubMed

Flohr, Carsten; Tuyen, Luc Nguyen; Lewis, Sarah; Minh, Truong Tan; Campbell, Jim; Britton, John; Williams, Hywel; Hien, Tran Tinh; Farrar, Jeremy; Quinnell, Rupert J

2007-04-01

Vietnam is participating in a global de-worming effort that aims to treat 650 million school children regularly by 2010. The treatment used in Vietnam is single dose oral mebendazole (Phardazone) 500 mg. We tested the efficacy of single dose mebendazole 500 mg in the therapy of hookworm infection in a randomized double-blind placebo-controlled trial among 271 Vietnamese schoolchildren. The treatment efficacy of single dose mebendazole in children did not differ significantly from placebo, with a reduction in mean eggs per gram of feces relative to placebo of 31% (95% CI -9 to 56%, P = 0.1). In light of these findings we then carried out a similar randomized trial comparing triple dose mebendazole, single dose albendazole, and triple dose albendazole against placebo in 209 adults in the same area. The estimated reduction in mean post-treatment eggs per gram of feces relative to placebo was 63% (95% CI 30-81%) for triple mebendazole, 75% (47-88%) for single albendazole, and 88% (58-97%) for triple albendazole. Our results suggest that single dose oral mebendazole has low efficacy against hookworm infection in Vietnam, and that it should be replaced by albendazole. These findings are of major public health relevance given the opportunity costs of treating entire populations with ineffective therapies. We recommend that efficacy of anti-helminth therapies is pilot tested before implementation of national gut worm control programs.

Pharmacokinetics, Biotransformation, and Excretion of [14C]Etelcalcetide (AMG 416) Following a Single Microtracer Intravenous Dose in Patients with Chronic Kidney Disease on Hemodialysis.

PubMed

Subramanian, Raju; Zhu, Xiaochun; Hock, M Benjamin; Sloey, Bethlyn J; Wu, Benjamin; Wilson, Sarah F; Egbuna, Ogo; Slatter, J Greg; Xiao, Jim; Skiles, Gary L

2017-02-01

Etelcalcetide (AMG 416) is a novel synthetic peptide calcium-sensing receptor activator in clinical development as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. Etelcalcetide is composed of seven D-aminoacids with an L-cysteine linked to a D-cysteine by a disulfide bond. A single intravenous dose of [ 14 C]etelcalcetide (10 mg; 26.3 kBq; 710 nCi) was administered to patients with CKD on hemodialysis to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in this setting. Blood, dialysate, urine, and feces were collected to characterize the pharmacokinetics, biotransformation product profiles, mass balance, and formation of anti-etelcalcetide antibodies. Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [ 14 C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces. Biotransformation resulted from disulfide exchange with endogenous thiols, and preserved the etelcalcetide D-amino acid backbone. Drug-related radioactivity circulated primarily as serum albumin peptide conjugate (SAPC). Following removal of plasma etelcalcetide by hemodialysis, re-equilibration occurred between SAPC and L-cysteine present in blood to partially restore the etelcalcetide plasma concentrations between dialysis sessions. No unanticipated safety signals or anti-etelcalcetide or anti-SAPC antibodies were detected.

Systematic literature review comparing rapid 3-dose administration of the GSK tick-borne encephalitis vaccine with other primary immunization schedules.

PubMed

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.

Optimizing drug-dose alerts using commercial software throughout an integrated health care system.

PubMed

Saiyed, Salim M; Greco, Peter J; Fernandes, Glenn; Kaelber, David C

2017-11-01

All default electronic health record and drug reference database vendor drug-dose alerting recommendations (single dose, daily dose, dose frequency, and dose duration) were silently turned on in inpatient, outpatient, and emergency department areas for pediatric-only and nonpediatric-only populations. Drug-dose alerts were evaluated during a 3-month period. Drug-dose alerts fired on 12% of orders (104 098/834 911). System-level and drug-specific strategies to decrease drug-dose alerts were analyzed. System-level strategies included: (1) turning off all minimum drug-dosing alerts, (2) turning off all incomplete information drug-dosing alerts, (3) increasing the maximum single-dose drug-dose alert threshold to 125%, (4) increasing the daily dose maximum drug-dose alert threshold to 125%, and (5) increasing the dose frequency drug-dose alert threshold to more than 2 doses per day above initial threshold. Drug-specific strategies included changing drug-specific maximum single and maximum daily drug-dose alerting parameters for the top 22 drug categories by alert frequency. System-level approaches decreased alerting to 5% (46 988/834 911) and drug-specific approaches decreased alerts to 3% (25 455/834 911). Drug-dose alerts varied between care settings and patient populations. © The Author 2017. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Multicentre dose audit for clinical trials of radiation therapy in Asia.

PubMed

Mizuno, Hideyuki; Fukuda, Shigekazu; Fukumura, Akifumi; Nakamura, Yuzuru-Kutsutani; Jianping, Cao; Cho, Chul-Koo; Supriana, Nana; Dung, To Anh; Calaguas, Miriam Joy; Devi, C R Beena; Chansilpa, Yaowalak; Banu, Parvin Akhter; Riaz, Masooma; Esentayeva, Surya; Kato, Shingo; Karasawa, Kumiko; Tsujii, Hirohiko

2017-05-01

A dose audit of 16 facilities in 11 countries has been performed within the framework of the Forum for Nuclear Cooperation in Asia (FNCA) quality assurance program. The quality of radiation dosimetry varies because of the large variation in radiation therapy among the participating countries. One of the most important aspects of international multicentre clinical trials is uniformity of absolute dose between centres. The National Institute of Radiological Sciences (NIRS) in Japan has conducted a dose audit of participating countries since 2006 by using radiophotoluminescent glass dosimeters (RGDs). RGDs have been successfully applied to a domestic postal dose audit in Japan. The authors used the same audit system to perform a dose audit of the FNCA countries. The average and standard deviation of the relative deviation between the measured and intended dose among 46 beams was 0.4% and 1.5% (k = 1), respectively. This is an excellent level of uniformity for the multicountry data. However, of the 46 beams measured, a single beam exceeded the permitted tolerance level of ±5%. We investigated the cause for this and solved the problem. This event highlights the importance of external audits in radiation therapy. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schnell, E; Ferreira, C; Ahmad, S

Purpose: Accuracy of a RSP-HU calibration curve produced for proton treatment planning is tested by comparing the treatment planning system dose grid to physical doses delivered on film by a Mevion S250 double-scattering proton unit. Methods: A single batch of EBT3 Gafchromic film was used for calibration and measurements. The film calibration curve was obtained using Mevion proton beam reference option 20 (15cm range, 10cm modulation). Paired films were positioned at the center of the spread out Bragg peak (SOBP) in solid water. The calibration doses were verified with an ion chamber, including background and doses from 20cGy to 350cGy.more » Films were scanned in a flatbed Epson-Expression 10000-XL scanner, and analyzed using the red channel. A Rando phantom was scanned with a GE LightSpeed CT Simulator. A single-field proton plan (Eclipse, Varian) was calculated to deliver 171cGy to the pelvis section (heterogeneous region), using a standard 4×4cm aperture without compensator, 7.89cm beam range, and 5.36cm SOBP. Varied depths of the calculated distal 90% isodose-line were recorded and compared. The dose distribution from film irradiated between Rando slices was compared with the calculated plans using RIT v.6.2. Results: Distal 90% isodose-line depth variation between CT scans was 2mm on average, and 4mm at maximum. Fine calculation of this variation was restricted by the dose calculation grid, as well as the slice thickness. Dose differences between calibrated film measurements and calculated doses were on average 5.93cGy (3.5%), with the large majority of differences forming a normal distribution around 3.5cGy (2%). Calculated doses were almost entirely greater than those measured. Conclusion: RSP to HU calibration curve is shown to produce distal depth variation within the margin of tolerance (±4.3mm) across all potential scan energies and protocols. Dose distribution calculation is accurate to 2–4% within the SOBP, including areas of high tissue heterogeneity.« less

Alternative methods for CYP2D6 phenotyping: comparison of dextromethorphan metabolic ratios from AUC, single point plasma, and urine.

PubMed

Chen, Rui; Wang, Haotian; Shi, Jun; Hu, Pei

2016-05-01

CYP2D6 is a high polymorphic enzyme. Determining its phenotype before CYP2D6 substrate treatment can avoid dose-dependent adverse events or therapeutic failures. Alternative phenotyping methods of CYP2D6 were compared to aluate the appropriate and precise time points for phenotyping after single-dose and ultiple-dose of 30-mg controlled-release (CR) dextromethorphan (DM) and to explore the antimodes for potential sampling methods. This was an open-label, single and multiple-dose study. 21 subjects were assigned to receive a single dose of CR DM 30 mg orally, followed by a 3-day washout period prior to oral administration of CR DM 30 mg every 12 hours for 6 days. Metabolic ratios (MRs) from AUC∞ after single dosing and from AUC0-12h at steady state were taken as the gold standard. The correlations of metabolic ratios of DM to dextrorphan (MRDM/DX) values based on different phenotyping methods were assessed. Linear regression formulas were derived to calculate the antimodes for potential sample methods. In the single-dose part of the study statistically significant correlations were found between MRDM/DX from AUC∞ and from serial plasma points from 1 to 30 hours or from urine (all p-values < 0.001). In the multiple-dose part, statistically significant correlations were found between MRDM/DX from AUC0-12h on day 6 and MRDM/DX from serial plasma points from 0 to 36 hours after the last dosing (all p-values < 0.001). Based on reported urinary antimode and linear regression analysis, the antimodes of AUC and plasma points were derived to profile the trend of antimodes as the drug concentrations changed. MRDM/DX from plasma points had good correlations with MRDM/DX from AUC. Plasma points from 1 to 30 hours after single dose of 30-mg CR DM and any plasma point at steady state after multiple doses of CR DM could potentially be used for phenotyping of CYP2D6.

Evaluation of a novel triple-channel radiochromic film analysis procedure using EBT2.

PubMed

van Hoof, Stefan J; Granton, Patrick V; Landry, Guillaume; Podesta, Mark; Verhaegen, Frank

2012-07-07

A novel approach to read out radiochromic film was introduced recently by the manufacturer of GafChromic film. In this study, the performance of this triple-channel film dosimetry method was compared against the conventional single-red-channel film dosimetry procedure, with and without inclusion of a pre-irradiation (pre-IR) film scan, using EBT2 film and kilo- and megavoltage photon beams up to 10 Gy. When considering regions of interest averaged doses, the triple-channel method and both single-channel methods produced equivalent results. Absolute dose discrepancies between the triple-channel method, both single-channel methods and the treatment planning system calculated dose values, were no larger than 5 cGy for dose levels up to 2.2 Gy. Signal to noise in triple-channel dose images was found to be similar to signal to noise in single-channel dose images. The accuracy of resulting dose images from the triple- and single-channel methods with inclusion of pre-IR film scan was found to be similar. Results of a comparison of EBT2 data from a kilovoltage depth dose experiment to corresponding Monte Carlo depth dose data produced dose discrepancies of 9.5 ± 12 cGy and 7.6 ± 6 cGy for the single-channel method with inclusion of a pre-IR film scan and the triple-channel method, respectively. EBT2 showed to be energy sensitive at low kilovoltage energies with response differences of 11.9% and 15.6% in the red channel at 2 Gy between 50-225 kVp and 80-225 kVp photon spectra, respectively. We observed that the triple-channel method resulted in non-uniformity corrections of ±1% and consistency values of 0-3 cGy for the batches and dose levels studied. Results of this study indicate that the triple-channel radiochromic film read-out method performs at least as well as the single-channel method with inclusion of a pre-IR film scan, reduces film non-uniformity and saves time with elimination of a pre-IR film scan.

Efficacy and Safety of Single and Double Doses of Ivermectin versus 7-Day High Dose Albendazole for Chronic Strongyloidiasis

PubMed Central

Suputtamongkol, Yupin; Premasathian, Nalinee; Bhumimuang, Kid; Waywa, Duangdao; Nilganuwong, Surasak; Karuphong, Ekkapun; Anekthananon, Thanomsak; Wanachiwanawin, Darawan; Silpasakorn, Saowaluk

2011-01-01

Background Strongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. It remains an important health problem due to autoinfection, which may result in hyperinfection and disseminated infection in immunosuppressed patients, especially patients receiving chemotherapy or corticosteroid treatment. Ivermectin and albendazole are effective against strongyloidiasis. However, the efficacy and the most effective dosing regimen are to be determined. Methods A prospective, randomized, open study was conducted in which a 7-day course of oral albendazole 800 mg daily was compared with a single dose (200 microgram/kilogram body weight), or double doses, given 2 weeks apart, of ivermectin in Thai patients with chronic strongyloidiasis. Patients were followed-up with 2 weeks after initiation of treatment, then 1 month, 3 months, 6 months, 9 months, and 1 year after treatment. Combination of direct microscopic examination of fecal smear, formol-ether concentration method, and modified Koga agar plate culture were used to detect strongyloides larvae in two consecutive fecal samples in each follow-up visit. The primary endpoint was clearance of strongyloides larvae from feces after treatment and at one year follow-up. Results Ninety patients were included in the analysis (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). All except one patient in this study had at least one concomitant disease. Diabetes mellitus, systemic lupus erythrematosus, nephrotic syndrome, hematologic malignancy, solid tumor and human immunodeficiency virus infection were common concomitant diseases in these patients. The median (range) duration of follow-up were 19 (2–76) weeks in albendazole group, 39 (2–74) weeks in single dose ivermectin group, and 26 (2–74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin, and double doses of oral ivermectin respectively (P = 0.006) in modified intention to treat analysis. No serious adverse event associated with treatment was found in any of the groups. Conclusion/Significance This study confirms that both a single, and a double dose of oral ivermectin taken two weeks apart, is more effective than a 7-day course of high dose albendazole for patients with chronic infection due to S. stercoralis. Double dose of ivermectin, taken two weeks apart, might be more effective than a single dose in patients with concomitant illness. Trial Registration ClinicalTrials.gov NCT00765024 PMID:21572981

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

PubMed Central

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

2017-01-01

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. PMID:29089656

A strategy to reduce cardiovascular disease by more than 80%

PubMed Central

Wald, N J; Law, M R

2003-01-01

Objectives To determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels. Design We quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta-analysis of 15 trials of low dose (50-125 mg/day) aspirin. Outcome measures Proportional reduction in ischaemic heart disease (IHD) events and strokes; life years gained; and prevalence of adverse effects. Results The formulation which met our objectives was: a statin (for example, atorvastatin (daily dose 10 mg) or simvastatin (40 mg)); three blood pressure lowering drugs (for example, a thiazide, a β blocker, and an angiotensin converting enzyme inhibitor), each at half standard dose; folic acid (0.8 mg); and aspirin (75 mg). We estimate that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%). One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke. Summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation). Conclusion The Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention. PMID:12829553

Intraoperative vancomycin use in spinal surgery: single institution experience and microbial trends.

PubMed

Ghobrial, George M; Thakkar, Vismay; Andrews, Edward; Lang, Michael; Chitale, Ameet; Oppenlander, Mark E; Maulucci, Christopher M; Sharan, Ashwini D; Heller, Joshua; Harrop, James S; Jallo, Jack; Prasad, Srinivas

2014-04-01

Retrospective case series. To demonstrate the microbial trends of spinal surgical site infections in patients who had previously received crystallized vancomycin in the operative bed. Prior large, case control series demonstrate the significant decrease in surgical site infection with the administration of vancomycin in the wound bed. A single institution, electronic database search was conducted for all patients who underwent spinal surgery who had received prophylactic crystalline vancomycin powder in the wound bed. Patients with a prior history of wound infection, intrathecal pumps, or spinal stimulators were excluded. A total of 981 consecutive patients (494 males, 487 females; mean age, 59.4 yr; range, 16-95 yr) were identified from January 2011 to June 2013. The average dose of vancomycin powder was 1.13 g (range, 1-6 g). Sixty-six patients (6.71%) were diagnosed with a surgical site infection, of which 51 patients had positive wound cultures (5.2%). Of the 51 positive cultures, the most common organism was Staphylococcus aureus. The average dose of vancomycin was 1.3 g in the 38 cases where a gram-positive organism was cultured. A number of gram-negative infections were encountered such as Serratia marcescens, Enterobacter aerogenes, Bacteroides fragilis, Enterobacter cloacae, Citrobacter koseri, and Pseudomonas aeruginosa. The average dose of vancomycin was 1.2 g in 23 cases where a gram-negative infection was cultured. Fifteen of the 51 positive cultures (29.4%) were polymicrobial. Eight (53%) of these 15 polymicrobial cultures contained 3 or more distinct organisms. Prophylactic intraoperative vancomycin use in the wound bed in spinal surgery may increase the incidence of gram-negative or polymicrobial spinal infections. The use of intraoperative vancomycin may correlate with postoperative seromas, due to the high incidence of nonpositive cultures. Large, randomized, prospective trials are needed to demonstrate causation and dose-response relationship.

Fractionated External Beam Radiotherapy as a Suitable Preparative Regimen for Hepatocyte Transplantation After Partial Hepatectomy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krause, Petra; Wolff, Hendrik A.; Rave-Frank, Margret

2011-07-15

Purpose: Hepatocyte transplantation is strongly considered to be a promising option to correct chronic liver failure through repopulation of the diseased organ. We already reported on extensive liver repopulation by hepatocytes transplanted into rats preconditioned with 25-Gy single dose selective external beam irradiation (IR). Herein, we tested lower radiation doses and fractionated protocols, which would be applicable in clinical use. Methods and Material: Livers of dipeptidylpeptidase IV (DPPIV)-deficient rats were preconditioned with partial liver external beam single dose IR at 25 Gy, 8 Gy, or 5 Gy, or fractionated IR at 5 x 5 Gy or 5 x 2 Gy.more » Four days after completion of IR, a partial hepatectomy (PH) was performed to resect the untreated liver section. Subsequently, 12 million wild-type (DPPIV{sup +}) hepatocytes were transplanted via the spleen into the recipient livers. The degree of donor cell integration and liver repopulation was studied 16 weeks after transplantation by means of immunofluorescence and DPPIV-luminescence assay. Results: Donor hepatocyte integration and liver repopulation were more effective in the irradiated livers following pretreatment with the IR doses 1 x 25 Gy and 5 x 5 Gy (formation of large DPPIV-positive cell clusters) than single-dose irradiation at 8 Gy or 5 Gy (DPPIV-positive clusters noticeably smaller and less frequent). Quantitative analysis of extracted DPPIV revealed signals exceeding the control level in all transplanted animals treated with IR and PH. Compared with the standard treatment of 1 x 25 Gy, fractionation with 5 x 5 Gy was equally efficacious, the Mann-Whitney U test disclosing no statistically significant difference (p = 0.146). The lower doses of 1 x 5 Gy, 1 x 8 Gy, and 5 x 2 Gy were significantly less effective with p < 0.05. Conclusion: This study suggests that fractionated radiotherapy in combination with PH is a conceivable pretreatment approach to prime the host liver for hepatocyte transplantation, thus bringing the experimental model a step closer to clinical application.« less

The Efficacy of Single-Dose versus Double-Dose Praziquantel Treatments on Schistosoma mansoni Infections: Its Implication on Undernutrition and Anaemia among Primary Schoolchildren in Two On-Shore Communities, Northwestern Tanzania

PubMed Central

Buza, Joram; Mpolya, Emmanuel A.; Angelo, Teckla; Kinung'hi, Safari M.

2017-01-01

Administering more than one treatment may increase Praziquantel cure and egg reduction rates, thereby hastening achievement of schistosomiasis transmission control. A total of 431 S. mansoni-infected schoolchildren were randomized to receive either a single or repeated 40 mg/kg Praziquantel dose. Heights, weights, and haemoglobin levels were determined using a stadiometer, weighing scale, and HemoCue, respectively. At 8 weeks, cure rate was higher on repeated dose (93.10%) compared to single dose (68.68%) (p < 0.001). The egg reduction rate was higher on repeated dose (97.54%) compared to single dose (87.27%) (p = 0.0062). Geometric mean egg intensity was lower among those on repeated dose (1.30 epg) compared to single dose (3.18 epg) (p = 0.036) but not at 5 (p > 0.05) and 8 (p > 0.05) months with no difference in reinfection rate. No difference in the prevalence of stunting was observed between the two treatment regimens (p > 0.05) at 8 months, but there was an increase in the prevalence of wasting among those on repeated dose (p < 0.001). There was an increase in the mean haemoglobin levels at 8 months with no difference between the two arms (p > 0.05). To achieve reduction of transmission intensity and disease control in highly endemic areas, repeated treatments alone may not be sufficient. This trial was registered with PACTR201601001416338. PMID:29094048

Comparison of the Efficacy and Safety of 2 Acetaminophen Dosing Regimens in Febrile Infants and Children: A Report on 3 Legacy Studies.

PubMed

Temple, Anthony R; Zimmerman, Brenda; Gelotte, Cathy; Kuffner, Edwin K

2017-01-01

Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to ≤ 11 years from 3 double-blind, randomized, single or multiple dose studies. Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study. A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses. Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours.

Oral Tranexamic Acid Reduces Transfusions in Total Knee Arthroplasty.

PubMed

Perreault, Roger E; Fournier, Christine A; Mattingly, David A; Junghans, Richard P; Talmo, Carl T

2017-10-01

Tranexamic acid (TXA) reduces intraoperative blood loss and transfusions in patients undergoing total knee arthroplasty. Although numerous studies demonstrate the efficacy of intravenous and topical TXA in these patients, few demonstrate the effectiveness and appropriate dosing recommendations of oral formulations. A retrospective cohort study was performed to evaluate differences in transfusion requirements in patients undergoing primary unilateral total knee arthroplasty with either no TXA (n = 866), a single-dose of oral TXA (n = 157), or both preoperative and postoperative oral TXA (n = 1049). Secondary outcomes included postoperative hemoglobin drop, total units transfused, length of stay, drain output, and cell salvage volume. Transfusion rates decreased from 15.4% in the no-oral tranexamic acid (OTA) group to 9.6% in the single-dose OTA group (P < .001) and 7% in the 2-dose group (P < .001), with no difference in transfusion rates between the single- and 2-dose groups (P = .390). In addition, postoperative hemoglobin drop was reduced from 4.2 g/dL in the no-OTA group to 3.5 g/dL in the single-dose group (P < .01) and to 3.4 g/dL in the 2-dose group (P < .01), without a difference between the single- and 2-dose groups (P = .233). OTA reduces transfusions, with greater ease of administration and improved cost-effectiveness relative to other forms of delivery. Copyright © 2017 Elsevier Inc. All rights reserved.

Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.

PubMed

Zhang, Y; Roberts, J; Tortorici, M; Veldman, A; St Ledger, K; Feussner, A; Sidhu, J

2017-06-01

Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week. Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for < 12 years) who had participated in a single-dose PK investigation with rVIII-SingleChain 50 IU kg -1 . PK sampling was performed for up to 96 h. Results A two-compartment population PK model with first-order elimination adequately described FVIII activity. Body weight and predose level of von Willebrand factor were significant covariates on clearance, and body weight was a significant covariate on the central distribution volume. Simulations using the model with various dosing scenarios estimated that > 85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL -1 , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg -1 ) and highest (50 IU kg -1 ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg -1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL -1 at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Quantitative assessment of the accuracy of dose calculation using pencil beam and Monte Carlo algorithms and requirements for clinical quality assurance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ali, Imad, E-mail: iali@ouhsc.edu; Ahmad, Salahuddin

2013-10-01

To compare the doses calculated using the BrainLAB pencil beam (PB) and Monte Carlo (MC) algorithms for tumors located in various sites including the lung and evaluate quality assurance procedures required for the verification of the accuracy of dose calculation. The dose-calculation accuracy of PB and MC was also assessed quantitatively with measurement using ionization chamber and Gafchromic films placed in solid water and heterogeneous phantoms. The dose was calculated using PB convolution and MC algorithms in the iPlan treatment planning system from BrainLAB. The dose calculation was performed on the patient's computed tomography images with lesions in various treatmentmore » sites including 5 lungs, 5 prostates, 4 brains, 2 head and necks, and 2 paraspinal tissues. A combination of conventional, conformal, and intensity-modulated radiation therapy plans was used in dose calculation. The leaf sequence from intensity-modulated radiation therapy plans or beam shapes from conformal plans and monitor units and other planning parameters calculated by the PB were identical for calculating dose with MC. Heterogeneity correction was considered in both PB and MC dose calculations. Dose-volume parameters such as V95 (volume covered by 95% of prescription dose), dose distributions, and gamma analysis were used to evaluate the calculated dose by PB and MC. The measured doses by ionization chamber and EBT GAFCHROMIC film in solid water and heterogeneous phantoms were used to quantitatively asses the accuracy of dose calculated by PB and MC. The dose-volume histograms and dose distributions calculated by PB and MC in the brain, prostate, paraspinal, and head and neck were in good agreement with one another (within 5%) and provided acceptable planning target volume coverage. However, dose distributions of the patients with lung cancer had large discrepancies. For a plan optimized with PB, the dose coverage was shown as clinically acceptable, whereas in reality, the MC showed a systematic lack of dose coverage. The dose calculated by PB for lung tumors was overestimated by up to 40%. An interesting feature that was observed is that despite large discrepancies in dose-volume histogram coverage of the planning target volume between PB and MC, the point doses at the isocenter (center of the lesions) calculated by both algorithms were within 7% even for lung cases. The dose distributions measured with EBT GAFCHROMIC films in heterogeneous phantoms showed large discrepancies of nearly 15% lower than PB at interfaces between heterogeneous media, where these lower doses measured by the film were in agreement with those by MC. The doses (V95) calculated by MC and PB agreed within 5% for treatment sites with small tissue heterogeneities such as the prostate, brain, head and neck, and paraspinal tumors. Considerable discrepancies, up to 40%, were observed in the dose-volume coverage between MC and PB in lung tumors, which may affect clinical outcomes. The discrepancies between MC and PB increased for 15 MV compared with 6 MV indicating the importance of implementation of accurate clinical treatment planning such as MC. The comparison of point doses is not representative of the discrepancies in dose coverage and might be misleading in evaluating the accuracy of dose calculation between PB and MC. Thus, the clinical quality assurance procedures required to verify the accuracy of dose calculation using PB and MC need to consider measurements of 2- and 3-dimensional dose distributions rather than a single point measurement using heterogeneous phantoms instead of homogenous water-equivalent phantoms.« less

Online 3D EPID-based dose verification: Proof of concept.

PubMed

Spreeuw, Hanno; Rozendaal, Roel; Olaciregui-Ruiz, Igor; González, Patrick; Mans, Anton; Mijnheer, Ben; van Herk, Marcel

2016-07-01

Delivery errors during radiotherapy may lead to medical harm and reduced life expectancy for patients. Such serious incidents can be avoided by performing dose verification online, i.e., while the patient is being irradiated, creating the possibility of halting the linac in case of a large overdosage or underdosage. The offline EPID-based 3D in vivo dosimetry system clinically employed at our institute is in principle suited for online treatment verification, provided the system is able to complete 3D dose reconstruction and verification within 420 ms, the present acquisition time of a single EPID frame. It is the aim of this study to show that our EPID-based dosimetry system can be made fast enough to achieve online 3D in vivo dose verification. The current dose verification system was sped up in two ways. First, a new software package was developed to perform all computations that are not dependent on portal image acquisition separately, thus removing the need for doing these calculations in real time. Second, the 3D dose reconstruction algorithm was sped up via a new, multithreaded implementation. Dose verification was implemented by comparing planned with reconstructed 3D dose distributions delivered to two regions in a patient: the target volume and the nontarget volume receiving at least 10 cGy. In both volumes, the mean dose is compared, while in the nontarget volume, the near-maximum dose (D2) is compared as well. The real-time dosimetry system was tested by irradiating an anthropomorphic phantom with three VMAT plans: a 6 MV head-and-neck treatment plan, a 10 MV rectum treatment plan, and a 10 MV prostate treatment plan. In all plans, two types of serious delivery errors were introduced. The functionality of automatically halting the linac was also implemented and tested. The precomputation time per treatment was ∼180 s/treatment arc, depending on gantry angle resolution. The complete processing of a single portal frame, including dose verification, took 266 ± 11 ms on a dual octocore Intel Xeon E5-2630 CPU running at 2.40 GHz. The introduced delivery errors were detected after 5-10 s irradiation time. A prototype online 3D dose verification tool using portal imaging has been developed and successfully tested for two different kinds of gross delivery errors. Thus, online 3D dose verification has been technologically achieved.

Discovery of cryptophycin-1 and BCN-183577: examples of strategies and problems in the detection of antitumor activity in mice.

PubMed

Corbett, T H; Valeriote, F A; Demchik, L; Lowichik, N; Polin, L; Panchapor, C; Pugh, S; White, K; Kushner, J; Rake, J; Wentland, M; Golakoti, T; Hetzel, C; Ogino, J; Patterson, G; Moore, R

1997-01-01

Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected i.v.

[Pharmacokinetics of digoxin in hyperthyroidism. Effect of methimazole].

PubMed

Izbicka, Maria; Gasińska, Teresa; Dec, Renata

2010-01-01

Cardiovascular abnormalities may be the only manifestations of overt hyperthyroidism. In patients with heart failure and atrial fibrillation digoxin can be beneficial in controlling the symptoms and signs, but hyperthyroid patients show an impaired response or even resistance to digoxin treatment. The aim of the study is to establish: 1. Are there any differences in the pharmacokinetics of a single oral dose of digoxin between hypertyroid and euthyroid patients? 2. Does simultaneous administration of digoxin and methimazole affect the pharmacokinetics of a single oral dose of dogoxin? 3. Does methimazole-induced euthyroidism change the pharmacokinetics of a single oral dose of digoxin? The subject of the study were 28 patients with hyperthyroidism and 15 healthy persons. We evaluated the pharmacokinetics of a single oral dose of digoxin. Moreover we evaluated pharmacokinetics of a single dose of digoxin after simultaneous administration of digoxin and methimazole in 12 patients and 12 methimazole treated patients werere-assessed once they had become euthyroid. Hyperthyroid patients showed significantly lower serum digoxin concentrations, shorter T1/2 beta and a significantly smaller area under the concentration curve (AUC) that the control group. Administration of methimazole did not affect digoxin pharmacokinetics. In hyperthyroid patients: 1. the pharmacokinetics of a single oral dose of digoxin does differ from that observed in healthy subjects. 2.methimazole do not alter digoxin pharmacokinetics.

The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study

PubMed Central

Azman, Andrew S.; Luquero, Francisco J.; Ciglenecki, Iza; Grais, Rebecca F.; Sack, David A.; Lessler, Justin

2015-01-01

Background In 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both. Methods and Findings Using mathematical models we determined the minimum relative single-dose efficacy (MRSE) at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%–56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%). This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%–88%) for two doses and 44% (95% CI −27% to 76%) for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%–88%), which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943–86,205) cases in Zimbabwe, 78,317 (95% PI 57,435–100,150) in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490–3,170) cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture uncertainty due to imperfect surveillance data and uncertainty about the transmission dynamics of cholera in each setting. Conclusions Reactive vaccination campaigns using a single dose of OCV may avert more cases and deaths than a standard two-dose campaign when vaccine supplies are limited, while at the same time reducing logistical complexity. These findings should motivate consideration of the trade-offs between one- and two-dose campaigns in resource-constrained settings, though further field efficacy data are needed and should be a priority in any one-dose campaign. PMID:26305226

Disposition of styrene-acrylonitrile (SAN) trimer in female rats: single dose intravenous and gavage studies.

PubMed

Gargas, Michael L; Collins, Brad; Fennell, Timothy R; Gaudette, Norman F; Sweeney, Lisa M

2008-04-21

Styrene-acrylonitrile trimer (SAN Trimer), a mixture of six isomers (four isomers of 4-cyano-1,2,3,4-tetrahydro-alpha-methyl-1-naphthaleneacetonitrile [THAN] and two isomers of 4-cyano-1,2,3,4-tetrahydro-1-naphthaleneproprionitrile [THNP]), is a by-product of a specific production process of styrene-acrylonitrile polymer. Disposition studies in female rats were conducted to evaluate the pharmacokinetic behavior of [3H]SAN Trimer following a single intravenous administration (26 mg/kg) to nonpregnant rats; a single gavage administration (nominal doses of 25 mg/kg, 75 mg/kg, or 200 mg/kg in corn oil) to nonpregnant rats; and a single gavage administration (nominal dose of 200 mg/kg in corn oil) to pregnant and lactating rats. SAN Trimer was rapidly eliminated from blood (T1/2 approximately 1h) following a single intravenous dose and following single oral doses (T1/2 approximately 3-4h). SAN Trimer was also rapidly excreted in the urine and feces following single oral doses, while total radioactivity was cleared more slowly. In pregnant rats, the concentrations of both radioactivity and SAN Trimer 2h after dosing were highest in the blood, followed by the placenta, with the lowest levels in the fetus. In lactating rats, the concentrations of both radioactivity and SAN Trimer were higher in milk than in maternal blood. Total radioactivity and SAN Trimer blood concentrations in nonpregnant, pregnant, and lactating rats were both higher in lactating rats compared to nonpregnant and pregnant rats.

Repaglinide pharmacokinetics in healthy young adult and elderly subjects.

PubMed

Hatorp, V; Huang, W C; Strange, P

1999-04-01

In this open-label, single-center, pharmacokinetic study of repaglinide, 12 healthy volunteers (6 men, 6 women) were enrolled in each of 2 groups (total, 24 volunteers). One group consisted of young adult subjects (18 to 40 years), and the other group consisted of elderly subjects (> or = 65 years). On day 1, after a 10-hour fast, all 24 subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, subjects received a 2-mg dose of repaglinide 15 minutes before each of 3 meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve, maximum concentration (Cmax), time to Cmax, and half-life, were determined at completion of the single-dose and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7 to assess steady state. The single-dose and multiple-dose pharmacokinetic variables of serum repaglinide were not significantly different between young adult and elderly subjects. Repaglinide was well tolerated in both groups. Hypoglycemic events occurred in 5 young adult and 5 elderly subjects. This study demonstrates that the pharmacokinetics of repaglinide are similar in healthy young adult and elderly subjects.

Single Low-Dose Ionizing Radiation Induces Genotoxicity in Adult Zebrafish and its Non-Irradiated Progeny.

PubMed

Lemos, J; Neuparth, T; Trigo, M; Costa, P; Vieira, D; Cunha, L; Ponte, F; Costa, P S; Metello, L F; Carvalho, A P

2017-02-01

This study investigated to what extent a single exposure to low doses of ionizing radiation can induce genotoxic damage in irradiated adult zebrafish (Danio rerio) and its non-irradiated F1 progeny. Four groups of adult zebrafish were irradiated with a single dose of X-rays at 0 (control), 100, 500 and 1000 mGy, respectively, and couples of each group were allowed to reproduce following irradiation. Blood of parental fish and whole-body offspring were analysed by the comet assay for detection of DNA damage. The level of DNA damage in irradiated parental fish increased in a radiation dose-dependent manner at day 1 post-irradiation, but returned to the control level thereafter. The level of DNA damage in the progeny was directly correlated with the parental irradiation dose. Results highlight the genotoxic risk of a single exposure to low-dose ionizing radiation in irradiated individuals and also in its non-irradiated progeny.

Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

PubMed

Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

2014-05-01

In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

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

PubMed

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.

Pharmacokinetics and tolerability of intravenous ibuprofen injection in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose study
.

PubMed

Zhou, Huili; Xu, Wei; Wu, Guolan; Wu, Lihua; Shentu, Jianzhong; Pan, Zhengfei; Hu, Shuai; Liu, Yang

2016-11-01

Recently a formulation of intravenous (IV) ibuprofen was developed in China for management of mild to moderate pain in patients who could not take oral medications or where intravenous administration was preferable. The aim of this study was to evaluate the pharmacokinetic properties and tolerability of single and multiple doses of ibuprofen injection in healthy Chinese volunteers. This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. In the single-dose phase, subjects were randomized to receive a single dose of ibuprofen injection 0.2, 0.4, or 0.8 g administered as a 30-minute IV infusion with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 12.5 hours after drug administration and were analyzed using a validated LC-MS/MS method. In the multiple-dose phase, subjects received 0.4 g ibuprofen every 6 hours for 9 doses. Blood samples were obtained before the 7^th, 8^th, and 9^th administration to determine the C_min at steady state; on the 9^th intravenous administration, blood samples were also collected for 12.5 hours after drug administration. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). A total of 12 healthy male (n = 6) and female (n = 6) Chinese volunteers were enrolled and completed the trial. After IV administration of single dose, the mean (SD) C_max value increased from 35.77 (6.98) to 117.12 (19.78) µg/mL, and the mean (SD) AUC_0-t value increased from 67.63 (10.30) to 230.50 (33.55) µg×h/mL in the range of 0.2-g to 0.8-g dose. The terminal half-life in plasma was ~ 2.0 hours. After IV administration of 9 doses of ibuprofen 400 mg every 6 hours, the mean (SD) C_max was 66.49 (8.49) µg/mL, the AUC_0-t was 135.65 (26.91) µg×h/mL, the t_1/2 was 2.14 (0.34) hours, the Cl/F was 3.34 (0.68) L/h, and the Vz/F was 10.32 (2.69) L, which were comparable with those after single dosing. The accumulation index was 1.17 (0.06), and the fluctuation was 304.0 (57.7) %. Results of the t-tests of C_max and AUC found no significant differences between the male and female groups. No serious AEs were reported, and there were no discontinuations due to AEs. The pharmacokinetics of ibuprofen exhibited dose-related kinetics from the 0.2- to the 0.8-g dose. After multiple doses, the pharmacokinetic parameters of ibuprofen were consistent with those after single doses. There was no accumulation in ibuprofen exposure in healthy Chinese between multiple doses and single dose. At the doses studied, ibuprofen appeared to be well tolerated in these healthy volunteers.
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SU-E-T-457: Impact of Interfractional Variations On Anterior Vs. Lateral-Field Proton Therapy of Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moteabbed, M; Trofimov, A; Sharp, G C

2015-06-15

Purpose: To investigate the effects of interfractional anatomy and setup variations on plans with anterior-oblique vs. lateral beams for prostate cancer pencil beam scanning (PBS) and passive scattered (PS) proton therapy. Methods: Six patients with low/intermediate risk prostate cancer treated with PS proton therapy at our institution were selected. All patients underwent weekly verification CT scans. Implanted fiducials were used for localization, and endorectal balloons for prostate immobilization. New PBS plans with lateral beams, as well as PBS and PS plans with anterior-oblique beams (±35 deg) were created. PBS plans used two different spot sizes: ∼10mm (large) and ∼5mm (medium)more » sigma at 25cm range and optimized as single-field-uniform-dose with ∼8% non-uniformity. No range uncertainty margins were applied in PBS plans to maximize rectal sparing. Field-specific apertures were used when planning with large spots to sharpen the penumbrae. The planned dose was recomputed on each weekly CT with fiducials aligned to the simulation CT, scaled and accumulated via deformable image registration. Results: The dose volume analysis showed that although difference between planned and accumulated dose remains negligible for plans with conventional lateral beams using both PS and PBS, this is not the case for plans with anterior beams. The target coverage in anterior plans was largely degraded due to the variations in the beam path length and the absence of range margins. The average prostate D95 was reduced by 7.5/15.9% (using PS/PBS) after accumulation for anterior plans, compared with 0/0.4% for lateral plans. The average mean dose in organs-at-risk decreased by 1% for lateral and 2% for anterior plans, similarly for PS and PBS. Spot size did not affect the dose changes. Conclusion: Prostate plans using anterior beams may undergo clinically relevant interfractional dose degradation. Corrective strategies guided by in-vivo range measurements should be studied before clinical application of this technique.« less

A study on comparison of Gafchromic EBT2 film response under single and cumulative exposure conditions

PubMed Central

Ganapathy, K.; Kurup, P.G.G.; Murali, V.; Muthukumaran, M.; Velmurugan, J.

2013-01-01

Gafchromic films are used as dosimeter for in vivo and in phantom dose measurements. The dose response of Gafchromic EBT2 film under single and repeated exposure conditions is compared in this study to analyze the usability of Gafchromic EBT2 films in cumulative dose measurements. The post-irradiation change in response of the film is studied for up to 4 days after irradiation. The effect of repeated exposure to scanner light on the response of the film is also studied. To check usability of Gafchromic EBT2 films in cumulative dose measurements, three EBT2 films were exposed to a daily fraction dose of 100 cGy, 150 cGy and 200 cGy, respectively, for 4 days. The dose response of the films exposed to cumulative irradiation was compared with the dose measured from films exposed to the same dose but in a single exposure. It is observed that the post-irradiation darkening of the film does not saturate and continue to take place even 4 days after irradiation. The dose measured from the EBT2 films after 4 days from irradiation was around 2% higher than the dose measured from the same films at 24 hours post-irradiation. It was also observed that the repeated exposure to scanner light does not produce any significant change in the film response. The dose response of films exposed to cumulative irradiation agrees with the dose response of films exposed to the same dose in a single irradiation with less than 3% difference. Gafchromic EBT2 films can be used to measure the cumulative dose delivered over multiple fractions, when the delivered dose is uniform across the film. PMID:24672151

Quantitative evaluation of local pulmonary distribution of TiO2 in rats following single or multiple intratracheal administrations of TiO2 nanoparticles using X-ray fluorescence microscopy.

PubMed

Zhang, Guihua; Shinohara, Naohide; Kano, Hirokazu; Senoh, Hideki; Suzuki, Masaaki; Sasaki, Takeshi; Fukushima, Shoji; Gamo, Masashi

2016-10-01

Uneven pulmonary nanoparticle (NP) distribution has been described when using single-dose intratracheal administration tests. Multiple-dose intratracheal administrations with small quantities of NPs are expected to improve the unevenness of each dose. The differences in local pulmonary NP distribution (called microdistribution) between single- and multiple-dose administrations may cause differential pulmonary responses; however, this has not been evaluated. Here, we quantitatively evaluated the pulmonary microdistribution (per mesh: 100 μm × 100 μm) of TiO2 in lung sections from rats following one, two, three, or four doses of TiO2 NPs at a same total dosage of 10 mg kg(-1) using X-ray fluorescence microscopy. The results indicate that: (i) multiple-dose administrations show lower variations in TiO2 content (ng mesh(-1) ) for sections of each lobe; (ii) TiO2 appears to be deposited more in the right caudal and accessory lobes located downstream of the administration direction of NP suspensions, and less so in the right middle lobes, irrespective of the number of doses; (iii) there are not prominent differences in the pattern of pulmonary TiO2 microdistribution between rats following single and multiple doses of TiO2 NPs. Additionally, the estimation of pulmonary TiO2 deposition for multiple-dose administrations imply that every dose of TiO2 would be randomly deposited only in part of the fixed 30-50% of lung areas. The evidence suggests that multiple-dose administrations do not offer remarkable advantages over single-dose administration on the pulmonary NP microdistribution, although multiple-dose administrations may reduce variations in the TiO2 content for each lung lobe. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Exploring proximity effects and large depth of field in helium ion beam lithography: large-area dense patterns and tilted surface exposure.

PubMed

Flatabø, Ranveig; Agarwal, Akshay; Hobbs, Richard; Greve, Martin M; Holst, Bodil; Berggren, Karl K

2018-07-06

Helium ion beam lithography (HIL) is an emerging nanofabrication technique. It benefits from a reduced interaction volume compared to that of an electron beam of similar energy, and hence reduced long-range scattering (proximity effect), higher resist sensitivity and potentially higher resolution. Furthermore, the small angular spread of the helium ion beam gives rise to a large depth of field. This should enable patterning on tilted and curved surfaces without the need of any additional adjustments, such as laser-auto focus. So far, most work on HIL has been focused on exploiting the reduced proximity effect to reach single-digit nanometer resolution, and has thus been concentrated on single-pixel exposures over small areas. Here we explore two new areas of application. Firstly, we investigate the proximity effect in large-area exposures and demonstrate HIL's capabilities in fabricating precise high-density gratings on large planar surfaces (100 μm × 100 μm, with pitch down to 35 nm) using an area dose for exposure. Secondly, we exploit the large depth of field by making the first HIL patterns on tilted surfaces (sample stage tilted 45°). We demonstrate a depth of field greater than 100 μm for a resolution of about 20 nm.

A Single-Dose Crossover Pharmacokinetic Comparison Study of Oral, Rectal and Topical Quetiapine in Healthy Adults.

PubMed

Leung, Jonathan G; Nelson, Sarah; Cunningham, Julie L; Thompson, Virginia H; Bobo, William V; Kung, Simon; Dierkhising, Ross A; Plevak, Matthew F; Lapid, Maria I

2016-08-01

Quetiapine is an oral atypical antipsychotic drug commonly used to treat a large number of neuropsychiatric disorders and conditions. However, a substantial number of patients who may benefit from treatment with quetiapine are unable to ingest quetiapine or other medications by mouth and thus require alternative routes of administration. There are currently no studies evaluating non-oral compounded dosage forms of quetiapine. We conducted a single-dose open-label crossover pharmacokinetic study in 10 healthy adults to determine whether quetiapine compounded as a rectal suppository or a topical cream achieved absorption similar to that achieved by a commercially available oral formulation. Rectal quetiapine produced an area under the plasma concentration-time curve from time zero to infinity (AUC∞) approximately 90 % greater than that produced by an equal (milligram per milligram) dose of oral quetiapine (15,333 ng/mL versus 8118.8 ng/mL, p = 0.005). However, only two of ten subjects who received topical quetiapine had detectable serum levels. When detected, serum levels achieved with topical quetiapine were delayed and low in comparison with those produced by the oral and rectal dosage forms. Our results suggest that rectal, but not topical, quetiapine may be useful in clinical settings. Clinical outcome studies of rectal quetiapine are needed.

Contemporary Parenteral Antiplatelet Bridging Strategies: A Single-Center Real-World Experience at a Tertiary Care Center.

PubMed

Stern, Gretchen; Rimsans, Jessica; Qamar, Arman; Vaduganathan, Muthiah; Bhatt, Deepak L

2018-03-13

Oral antiplatelet therapy may require interruption soon after percutaneous coronary intervention (PCI) or acute coronary syndrome. The optimal parenteral antiplatelet bridge strategy with glycoprotein IIb/IIIa inhibitors or cangrelor, a P2Y12 inhibitor, is unclear. We explore real-world use of cangrelor or eptifibatide for antiplatelet bridging at a large tertiary-care center. Thirty-one patients (9 eptifibatide, 20 cangrelor, and 2 both) received bridge therapy from October 2015 to June 2017. Primary bridge therapy indications included surgery (68%), limited enteral access/absorption (16%), and high-perceived bleed risk (16%). Median duration of bridge therapy was 61 (20-100) hours for cangrelor and 83 (19-98) hours for eptifibatide. Severe/life-threatening bleeding or stent thrombosis was not observed. GUSTO-defined bleeding occurred in 30% (cangrelor) and 27% (eptifibatide). Initial dosing errors occurred in 23% of patients. Death during hospitalization occurred in 16% of patients. Parenteral antiplatelet bridging was used for ~3 days in this single-center, tertiary care experience, commonly for unplanned surgery following PCI. Despite high-risk presentations with >15% in-hospital mortality, efficacy profiles were reassuring with no identified stent thrombosis, but bleeding and dosing errors were common. Antiplatelet bridging should only be used in well-selected patients at the appropriate dose for the minimal necessary duration.

21 CFR 522.914 - Fenprostalene solution.

Code of Federal Regulations, 2010 CFR

2010-04-01

... this chapter. (d) Special considerations. Labeling shall bear the following statements: Women of.... Feedlot heifers to induce abortion, single dose. Beef or nonlactating dairy cattle for estrus synchronization, a single dose or two doses 11 to 13 days apart. Do not use in pregnant animals unless abortion is...

Magnetization transfer proportion: a simplified measure of dose response for polymer gel dosimetry.

PubMed

Whitney, Heather M; Gochberg, Daniel F; Gore, John C

2008-12-21

The response to radiation of polymer gel dosimeters has most often been described by measuring the nuclear magnetic resonance transverse relaxation rate as a function of dose. This approach is highly dependent upon the choice of experimental parameters, such as the echo spacing time for Carr-Purcell-Meiboom-Gill-type pulse sequences, and is difficult to optimize in imaging applications where a range of doses are applied to a single gel, as is typical for practical uses of polymer gel dosimetry. Moreover, errors in computing dose can arise when there are substantial variations in the radiofrequency (B1) field or resonant frequency, as may occur for large samples. Here we consider the advantages of using magnetization transfer imaging as an alternative approach and propose the use of a simplified quantity, the magnetization transfer proportion (MTP), to assess doses. This measure can be estimated through two simple acquisitions and is more robust in the presence of some sources of system imperfections. It also has a dependence upon experimental parameters that is independent of dose, allowing simultaneous optimization at all dose levels. The MTP is shown to be less susceptible to B1 errors than are CPMG measurements of R2. The dose response can be optimized through appropriate choices of the power and offset frequency of the pulses used in magnetization transfer imaging.

Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers▿

PubMed Central

Di Stefano, A. F. D.; Rusca, A.; Loprete, L.; Dröge, M. J.; Moro, L.; Assandri, A.

2011-01-01

The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fecal elimination of rifamycin SV after single- and multiple-dose regimens of the new formulation were investigated. Concentrations in plasma of >2 ng/ml were infrequently and randomly quantifiable after single and multiple oral doses. The systemic exposure to rifamycin SV after single and multiple oral doses of MMX tablets under fasting and fed conditions or following a four-times-a-day (q.i.d.) or a twice-a-day (b.i.d.) regimen could be considered negligible. With both oral regimens, the drug was confirmed to be very poorly absorbable systemically. The amount of systemically absorbed antibiotic excreted by the renal route is far lower than 0.01% of the administered dose after both the single- and multiple-dose regimens. The absolute bioavailability, calculated as the mean percent ratio between total urinary excretion amounts (ΣXu) after a single intravenous injection and after a single oral dose under fasting conditions, was 0.0410 ± 0.0617. The total elimination of the unchanged rifamycin SV with feces was 87% of the administered oral dose. No significant effect of rifamycin SV on vital signs, electrocardiograms, or laboratory parameters was observed. PMID:21402860

A Case of Community-Acquired Pneumonia Due to Legionella pneumophila Serogroup 9 Wherein Initial Treatment with Single-Dose Oral Azithromycin Appeared Useful.

PubMed

Ito, Akihiro; Ishida, Tadashi; Tachibana, Hiromasa; Ito, Yuhei; Takaiwa, Takuya; Fujii, Hiroyuki; Hashimoto, Toru; Nakajima, Hiroshi; Amemura-Maekawa, Junko

2017-11-22

Legionella species are important causative pathogens for severe community-acquired pneumonia (CAP). Most cases of Legionella pneumonia are due to Legionella pneumophila serogroup 1, and CAP due to L. pneumophila serogroup 9 is rare. A fourth case of CAP due to L. pneumophila serogroup 9 has been reported, and initial treatment using single-dose oral azithromycin appeared useful. Azithromycin or fluoroquinolone injection is usually recommended for the treatment of Legionella pneumonia, and no previous reports have shown the effectiveness of single-dose oral azithromycin. This case report is therefore valuable from the perspective of possible treatment for mild to moderate Legionella pneumonia using single-dose oral azithromycin.

Preclinical Study of Single-Dose Moxidectin, a New Oral Treatment for Scabies: Efficacy, Safety, and Pharmacokinetics Compared to Two-Dose Ivermectin in a Porcine Model.

PubMed

Bernigaud, Charlotte; Fang, Fang; Fischer, Katja; Lespine, Anne; Aho, Ludwig Serge; Dreau, Dominique; Kelly, Andrew; Sutra, Jean-François; Moreau, Francis; Lilin, Thomas; Botterel, Françoise; Guillot, Jacques; Chosidow, Olivier

2016-10-01

Scabies is one of the commonest dermatological conditions globally; however it is a largely underexplored and truly neglected infectious disease. Foremost, improvement in the management of this public health burden is imperative. Current treatments with topical agents and/or oral ivermectin (IVM) are insufficient and drug resistance is emerging. Moxidectin (MOX), with more advantageous pharmacological profiles may be a promising alternative. Using a porcine scabies model, 12 pigs were randomly assigned to receive orally either MOX (0.3 mg/kg once), IVM (0.2 mg/kg twice) or no treatment. We evaluated treatment efficacies by assessing mite count, clinical lesions, pruritus and ELISA-determined anti-S. scabiei IgG antibodies reductions. Plasma and skin pharmacokinetic profiles were determined. At day 14 post-treatment, all four MOX-treated but only two IVM-treated pigs were mite-free. MOX efficacy was 100% and remained unchanged until study-end (D47), compared to 62% (range 26-100%) for IVM, with one IVM-treated pig remaining infected until D47. Clinical scabies lesions, pruritus and anti-S. scabiei IgG antibodies had completely disappeared in all MOX-treated but only 75% of IVM-treated pigs. MOX persisted ~9 times longer than IVM in plasma and skin, thereby covering the mite's entire life cycle and enabling long-lasting efficacy. Our data demonstrate that oral single-dose MOX was more effective than two consecutive IVM-doses, supporting MOX as potential therapeutic approach for scabies.

Modulation of Distinct Asthmatic Phenotypes in Mice by Dose-Dependent Inhalation of Microbial Products

PubMed Central

Whitehead, Gregory S.; Thomas, Seddon Y.

2013-01-01

Background: Humans with asthma display considerable heterogeneity with regard to T helper (Th) 2–associated eosinophilic and Th17-associated neutrophilic inflammation, but the impact of the environment on these different forms of asthma is poorly understood. Objective: We studied the nature and longevity of asthma-like responses triggered by inhalation of allergen together with environmentally relevant doses of inhaled lipopolysaccharide (LPS). Methods: Ovalbumin (OVA) was instilled into the airways of mice together with a wide range of LPS doses. Following a single OVA challenge, or multiple challenges, animals were assessed for pulmonary cytokine production, airway inflammation, and airway hyperresponsiveness (AHR). Results: Mice instilled with OVA together with very low doses (≤ 10–3 μg) of LPS displayed modest amounts of Th2 cytokines, with associated airway eosinophilia and AHR after a single challenge, and these responses were sustained after multiple OVA challenges. When the higher but still environmentally relevant dose of 10–1 μg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia. After multiple OVA challenges, however, the 10–1 μg LPS animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells with high levels of inducible co-stimulatory molecule (ICOS). As a result, asthma-like features in these mice were shorter-lived than in mice sensitized using lower doses of LPS. Conclusions: The nature and longevity of Th2, Th17, and Treg immune responses to inhaled allergen are dependent on the quantity of LPS inhaled at the time of allergic sensitization. These findings might account in part for the heterogeneity of inflammatory infiltrates seen in lungs of asthmatics. Citation: Whitehead GS, Thomas SY, Cook DN. 2014. Modulation of distinct asthmatic phenotypes in mice by dose-dependent inhalation of microbial products. Environ Health Perspect 122:34–42; http://dx.doi.org/10.1289/ehp.1307280 PMID:24168764

WE-D-BRA-04: Online 3D EPID-Based Dose Verification for Optimum Patient Safety

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spreeuw, H; Rozendaal, R; Olaciregui-Ruiz, I

2015-06-15

Purpose: To develop an online 3D dose verification tool based on EPID transit dosimetry to ensure optimum patient safety in radiotherapy treatments. Methods: A new software package was developed which processes EPID portal images online using a back-projection algorithm for the 3D dose reconstruction. The package processes portal images faster than the acquisition rate of the portal imager (∼ 2.5 fps). After a portal image is acquired, the software seeks for “hot spots” in the reconstructed 3D dose distribution. A hot spot is in this study defined as a 4 cm{sup 3} cube where the average cumulative reconstructed dose exceedsmore » the average total planned dose by at least 20% and 50 cGy. If a hot spot is detected, an alert is generated resulting in a linac halt. The software has been tested by irradiating an Alderson phantom after introducing various types of serious delivery errors. Results: In our first experiment the Alderson phantom was irradiated with two arcs from a 6 MV VMAT H&N treatment having a large leaf position error or a large monitor unit error. For both arcs and both errors the linac was halted before dose delivery was completed. When no error was introduced, the linac was not halted. The complete processing of a single portal frame, including hot spot detection, takes about 220 ms on a dual hexacore Intel Xeon 25 X5650 CPU at 2.66 GHz. Conclusion: A prototype online 3D dose verification tool using portal imaging has been developed and successfully tested for various kinds of gross delivery errors. The detection of hot spots was proven to be effective for the timely detection of these errors. Current work is focused on hot spot detection criteria for various treatment sites and the introduction of a clinical pilot program with online verification of hypo-fractionated (lung) treatments.« less

Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- and Multiple-Dose Study.

PubMed

Agarwal, Suresh K; Hu, Beibei; Chien, David; Wong, Shekman L; Salem, Ahmed Hamed

2016-11-01

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single-dose and multiple-dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax C max and AUC ∞ by 106% (90%CI, 73%-145%) and 78% (90%CI, 50%-111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax C max and AUC ∞ by 42% (90%CI, 31%-52%) and 71% (90%CI, 66%-76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P-glycoprotein (P-gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax C max and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P-gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax. © 2016, The American College of Clinical Pharmacology.

Evaluation of LiF:Mg,Ti (TLD-100) for Intraoperative Electron Radiation Therapy Quality Assurance

PubMed Central

Liuzzi, Raffaele; Savino, Federica; D’Avino, Vittoria; Pugliese, Mariagabriella; Cella, Laura

2015-01-01

Background Purpose of the present work was to investigate thermoluminescent dosimeters (TLDs) response to intraoperative electron radiation therapy (IOERT) beams. In an IOERT treatment, a large single radiation dose is delivered with a high dose-per-pulse electron beam (2–12 cGy/pulse) during surgery. To verify and to record the delivered dose, in vivo dosimetry is a mandatory procedure for quality assurance. The TLDs feature many advantages such as a small detector size and close tissue equivalence that make them attractive for IOERT as in vivo dosimeters. Methods LiF:Mg,Ti dosimeters (TLD-100) were irradiated with different IOERT electron beam energies (5, 7 and 9 MeV) and with a 6 MV conventional photon beam. For each energy, the TLDs were irradiated in the dose range of 0–10 Gy in step of 2Gy. Regression analysis was performed to establish the response variation of thermoluminescent signals with dose and energy. Results The TLD-100 dose-response curves were obtained. In the dose range of 0–10 Gy, the calibration curve was confirmed to be linear for the conventional photon beam. In the same dose region, the quadratic model performs better than the linear model when high dose-per-pulse electron beams were used (F test; p<0.05). Conclusions This study demonstrates that the TLD dose response, for doses ≤10Gy, has a parabolic behavior in high dose-per-pulse electron beams. TLD-100 can be useful detectors for IOERT patient dosimetry if a proper calibration is provided. PMID:26427065

Evaluation of LiF:Mg,Ti (TLD-100) for Intraoperative Electron Radiation Therapy Quality Assurance.

PubMed

Liuzzi, Raffaele; Savino, Federica; D'Avino, Vittoria; Pugliese, Mariagabriella; Cella, Laura

2015-01-01

Purpose of the present work was to investigate thermoluminescent dosimeters (TLDs) response to intraoperative electron radiation therapy (IOERT) beams. In an IOERT treatment, a large single radiation dose is delivered with a high dose-per-pulse electron beam (2-12 cGy/pulse) during surgery. To verify and to record the delivered dose, in vivo dosimetry is a mandatory procedure for quality assurance. The TLDs feature many advantages such as a small detector size and close tissue equivalence that make them attractive for IOERT as in vivo dosimeters. LiF:Mg,Ti dosimeters (TLD-100) were irradiated with different IOERT electron beam energies (5, 7 and 9 MeV) and with a 6 MV conventional photon beam. For each energy, the TLDs were irradiated in the dose range of 0-10 Gy in step of 2 Gy. Regression analysis was performed to establish the response variation of thermoluminescent signals with dose and energy. The TLD-100 dose-response curves were obtained. In the dose range of 0-10 Gy, the calibration curve was confirmed to be linear for the conventional photon beam. In the same dose region, the quadratic model performs better than the linear model when high dose-per-pulse electron beams were used (F test; p<0.05). This study demonstrates that the TLD dose response, for doses ≤10 Gy, has a parabolic behavior in high dose-per-pulse electron beams. TLD-100 can be useful detectors for IOERT patient dosimetry if a proper calibration is provided.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Unkelbach, J; Perko, Z; Wolfgang, J

Purpose: Stereotactic body radiotherapy (SBRT) has become an established treatment option for liver cancer. For patients with large tumors, the prescription dose is often limited by constraints on the mean liver dose, leading to tumor recurrence. In this work, we demonstrate that spatiotemporal fractionation schemes, ie delivering distinct dose distributions in different fractions, may allow for a 10% increase in biologically effective dose (BED) in the tumor compared to current practice where each fraction delivers the same dose distribution. Methods: We consider rotation therapy delivered with x-ray beams. Treatment plan optimization is performed using objective functions evaluated for the cumulativemore » BED delivered at the end of treatment. This allows for simultaneously optimizing multiple distinct treatment plans for different fractions. Results: The treatment that optimally exploits fractionation effects is designed such that each fraction delivers a similar dose bath to the uninvolved liver while delivering high single fraction doses to complementary parts of the target volume. Thereby, partial hypofractionation in the tumor is achieved along with near uniform fractionation in the surrounding liver - leading to an improvement in the therapeutic ratio. The benefit of such spatiotemporal fractionation schemes depends on tumor geometry and location as well as the number of fractions. For 5-fraction treatments (allowing for 5 distinct dose distributions) an improvement in the order of 10% is observed. Conclusion: Delivering distinct dose distributions in different fractions, purely motivated by fractionation effects rather than geometric changes, may improve the therapeutic ratio. For treatment sites where the prescriptions dose is limited by mean dose constraints in the surrounding organ, such as liver cancer, this approach may facilitate biological dose escalation and improved cure rates.« less

Safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole sodium injections after single and multiple intravenous doses in healthy Chinese subjects.

PubMed

Jiao, Hui-Wen; Sun, Lu-Ning; Li, Yue-Qi; Yu, Lei; Zhang, Hong-Wen; Wang, Mei-Feng; Yu, Li-Yuan; Yuan, Zi-Qing-Yun; Xie, Li-Jun; Chen, Juan; Meng, Ling; Zhang, Xue-Hui; Wang, Yong-Qing

2018-03-01

The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole (PPZ) sodium injections following single and multiple intravenous doses in healthy Chinese subjects. The dosage groups were set as followed: 20 mg of single and multiple intravenous administration of S-(-)-PPZ, 40 mg of single and multiple intravenous administration of S-(-)-PPZ or pantoprazole, and 80 mg of single dosage group of S-(-)-PPZ. Subjects were sampled for pharmacokinetic analysis and were monitored for 24-h intragastric pH prior to and 48-h intragastric pH after administration for the pharmacodynamic study. The pharmacokinetic and pharmacodynamic parameters were compared between S-(-)-PPZ and PPZ. Safety was evaluated on the basis of adverse events, vital signs, laboratory tests, and physical examination. All adverse events were mild and of limited duration. Maximum plasma concentration and area under the concentration-time curve for S-(-)-PPZ were dose proportional over the range of 20-80 mg following a single intravenous administration. Elimination rate constant and half-life observed statistical difference from a single dose to multiple doses in 40 mg of S-(-)-PPZ groups. After administration of a single dose, the mean 24-h intragastric pH value was observed higher in 80-mg group than in 40- and 20-mg groups. Slightly increase of intragastric pH was found after a single dose of 40 mg S-(-)-PPZ than 40 mg PPZ; however, the differences were not statistically significant. Twice daily of 40 mg S-(-)-PPZ sodium injections is effective in achieving satisfying acid inhibition. Compared with plasma R-(+)-PPZ levels, most subjects presented more potent and prolonged suppression of gastric acid of S-(-)-PPZ, while a few subjects showed faster metabolic rate of S-(-)-PPZ in vivo.

On the interplay effects with proton scanning beams in stage III lung cancer

PubMed Central

Li, Yupeng; Kardar, Laleh; Li, Xiaoqiang; Li, Heng; Cao, Wenhua; Chang, Joe Y.; Liao, Li; Zhu, Ronald X.; Sahoo, Narayan; Gillin, Michael; Liao, Zhongxing; Komaki, Ritsuko; Cox, James D.; Lim, Gino; Zhang, Xiaodong

2014-01-01

Purpose: To assess the dosimetric impact of interplay between spot-scanning proton beam and respiratory motion in intensity-modulated proton therapy (IMPT) for stage III lung cancer. Methods: Eleven patients were sampled from 112 patients with stage III nonsmall cell lung cancer to well represent the distribution of 112 patients in terms of target size and motion. Clinical target volumes (CTVs) and planning target volumes (PTVs) were defined according to the authors' clinical protocol. Uniform and realistic breathing patterns were considered along with regular- and hypofractionation scenarios. The dose contributed by a spot was fully calculated on the computed tomography (CT) images corresponding to the respiratory phase that the spot is delivered, and then accumulated to the reference phase of the 4DCT to generate the dynamic dose that provides an estimation of what might be delivered under the influence of interplay effect. The dynamic dose distributions at different numbers of fractions were compared with the corresponding 4D composite dose which is the equally weighted average of the doses, respectively, computed on respiratory phases of a 4DCT image set. Results: Under regular fractionation, the average and maximum differences in CTV coverage between the 4D composite and dynamic doses after delivery of all 35 fractions were no more than 0.2% and 0.9%, respectively. The maximum differences between the two dose distributions for the maximum dose to the spinal cord, heart V40, esophagus V55, and lung V20 were 1.2 Gy, 0.1%, 0.8%, and 0.4%, respectively. Although relatively large differences in single fraction, correlated with small CTVs relative to motions, were observed, the authors' biological response calculations suggested that this interfractional dose variation may have limited biological impact. Assuming a hypofractionation scenario, the differences between the 4D composite and dynamic doses were well confined even for single fraction. Conclusions: Despite the presence of interplay effect, the delivered dose may be reliably estimated using the 4D composite dose. In general the interplay effect may not be a primary concern with IMPT for lung cancers for the authors' institution. The described interplay analysis tool may be used to provide additional confidence in treatment delivery. PMID:24506612

Single- and multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel agent for the treatment of premature ejaculation.

PubMed

Modi, Nishit B; Dresser, Mark J; Simon, Mary; Lin, Denise; Desai, Dhaval; Gupta, Suneel

2006-03-01

Dapoxetine is a serotonin transporter inhibitor currently in development for the treatment of premature ejaculation. This randomized, 2-sequence, 2-treatment crossover study assessed the single- and multiple-dose pharmacokinetics of dapoxetine following once-daily administration of dapoxetine 30 mg and 60 mg to healthy male volunteers. Dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations reached approximately 1 hour after dosing; plasma concentrations after single doses of dapoxetine decreased rapidly to approximately 5% of peak concentrations by 24 hours. Elimination was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours. Dapoxetine showed time-invariant pharmacokinetics and dose proportionality between doses, and its pharmacokinetics was unaffected by multiple dosing. The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing. There were no serious adverse events; the most commonly reported adverse events were diarrhea, dizziness, and nausea.

Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction.

PubMed

Guo, Yiru; Wysoczynski, Marcin; Nong, Yibing; Tomlin, Alex; Zhu, Xiaoping; Gumpert, Anna M; Nasr, Marjan; Muthusamy, Senthikumar; Li, Hong; Book, Michael; Khan, Abdur; Hong, Kyung U; Li, Qianhong; Bolli, Roberto

2017-03-01

We have recently demonstrated that repeated administrations of c-kit POS cardiac progenitor cells (CPCs) have cumulative beneficial effects in rats with old myocardial infarction (MI), resulting in markedly greater improvement in left ventricular (LV) function compared with a single administration. To determine whether this paradigm applies to other species and cell types, mice with a 3-week-old MI received one or three doses of cardiac mesenchymal cells (CMCs), a novel cell type that we have recently described. CMCs or vehicle were infused percutaneously into the LV cavity, 14 days apart. Compared with vehicle-treated mice, the single-dose group exhibited improved LV ejection fraction (EF) after the 1st infusion (consisting of CMCs) but not after the 2nd and 3rd (vehicle). In contrast, in the multiple-dose group, LV EF improved after each CMC infusion, so that at the end of the study, LV EF averaged 35.5 ± 0.7% vs. 32.7 ± 0.6% in the single-dose group (P < 0.05). The multiple-dose group also exhibited less collagen in the non-infarcted region vs. the single-dose group. Engraftment and differentiation of CMCs were negligible in both groups, indicating paracrine effects. These results demonstrate that, in mice with ischemic cardiomyopathy, the beneficial effects of three doses of CMCs are significantly greater than those of one dose, supporting the concept that multiple treatments are necessary to properly evaluate the full therapeutic potential of cell therapy. Thus, the repeated-treatment paradigm is not limited to c-kit POS CPCs or to rats, but applies to other cell types and species. The generalizability of this concept dramatically augments its significance.

Pharmacodynamics and pharmacokinetics of single doses of subcutaneous pegylated human G-CSF mutant (Ro 25-8315) in healthy volunteers: comparison with single and multiple daily doses of filgrastim.

PubMed

van Der Auwera, P; Platzer, E; Xu, Z X; Schulz, R; Feugeas, O; Capdeville, R; Edwards, D J

2001-04-01

Ro 25-8315 is produced by conjugation of rhG-CSF mutant with polyethylene glycol (PEG). The purpose of this study was to examine the pharmacodynamics and pharmacokinetics of Ro 25-8315 in comparison with Filgrastim (rhG-CSF). Subjects received single subcutaneous doses of Ro 25-8315 ranging from 10 to 150 microg/kg using a double-blind, randomized, placebo-controlled design. Filgrastim was administered as a single dose (5 or 10 microg/kg) and, following a 14-day washout period, daily for 7 days. Ro 25-8315 increased absolute neutrophil count (ANC) by 6- to 8-fold and CD34+ cell count more than 30-fold at the highest doses tested. Single doses (60-150 microg/kg) of Ro 25-8315 and multiple doses of Filgrastim had similar effects on ANC and CD34+, although Ro 25-8315 had a greater effect on CFU-GM. The pharmacokinetics of Ro 25-8315 were dose-dependent, with peak concentrations and area under the serum concentration-time curve (AUC) increasing 100-fold over the range of doses studied. Time to reach peak concentration (T(max)) and half-life of Ro 25-8315 averaged 20-30 hr at all doses, approximately three times longer than with Filgrastim. Adverse events were not serious and occurred with similar frequency with both products. Pegylation of rhG-CSF mutant results in more desirable pharmacokinetic properties and a longer duration of action with effective increases in ANC and measures of peripheral blood progenitor cell mobilization for at least 1 week. Copyright 2001 Wiley-Liss, Inc.

[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (1)--Single oral and intravenous dose toxicity studies in rats].

PubMed

Yahara, I; Furukawa, H; Sato, K; Nishimura, K; Harihara, A; Yabuuchi, K; Miyauchi, H; Kii, Y; Muraoka, Y; Kitamura, T; Kato, I

2001-05-01

A single oral dose toxicity study of Cefmatilen hydrochloride hydrate (S-1090) and a single intravenous dose toxicity study of its sodium salt (S-1090-Na) were conducted in rats. One dose level of 2000 mg potency/kg was set in both studies. Single oral dose toxicity study of S-1090 No deaths occurred. Diarrhea occurred on the dosing day and slightly soft feces lasted until 6 days after administration. These changes were considered to result from changes of intestinal flora induced by the antibiotic activity of S-1090. Reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet) were also observed until the next day after administration. Body weights increased favorably, and no S-1090-related pathological changes were observed. The oral lethal dose of S-1090 was estimated to be more than 2000 mg potency/kg. Single intravenous dose toxicity study of S-1090-Na No deaths occurred. The rats showed characteristic clinical signs such as hypoactivity, abnormal gait and hypopnea immediately after dosing, and some rats showed prone position or paleness of eyeballs and ear auricles in due course. These signs disappeared by 4 hr after administration. Slightly soft feces and reddish-brown feces were observed much the same as in the orally-treated rats. Body weights increased favorably. In the pathological examinations, slight cecal enlargement and increased basophilia, dilatation and calcification of the renal tubules in the kidney were observed. The intravenous lethal dose of S-1090-Na was estimated to be more than 2000 mg potency/kg.

Functional recovery upon human dental pulp stem cell transplantation in a diabetic neuropathy rat model.

PubMed

Datta, Indrani; Bhadri, Naini; Shahani, Pradnya; Majumdar, Debanjana; Sowmithra, Sowmithra; Razdan, Rema; Bhonde, Ramesh

2017-10-01

Diabetic neuropathy (DN) is among the most debilitating complications of diabetes. Here, we investigated the effects of human dental pulp stem cell (DPSC) transplantation in Streptozotocin (STZ)-induced neuropathic rats. Six weeks after STZ injection, DPSCs were transplanted through two routes, intravenous (IV) or intramuscular (IM), in single or two repeat doses. Two weeks after transplantation, a significant improvement in hyperalgesia, grip-strength, motor coordination and nerve conduction velocity was observed in comparison with controls. A rapid improvement in neuropathic symptoms was observed for a single dose of DPSC IV; however, repeat dose of DPSC IV did not bring about added improvement. A single dose of DPSC IM showed steady improvement, and further recovery continued upon repeat IM administration. DPSC single dose IV showed greater improvement than DPSC single dose IM, but IM transplantation brought about better improvement in body weight. A marked reduction in tumor necrosis factor (TNF) α and C-reactive protein (CRP) levels was observed in the blood plasma for all treated groups, as compared with controls. With respect to inflammatory cytokines, repeat dose of DPSC IM showed further improvement, suggesting that a repeat dose is required to maintain the improved inflammatory state. Gene expression of inflammatory markers in liver confirmed amelioration in inflammation. Arachidonic acid level was unaffected by IV DPSC transplantation but showed noticeable increase through IM administration of a repeat dose. These results suggest that DPSC transplantation through both routes and dosage was beneficial for the retrieval of neuropathic parameters of DN; transplantation via the IM route with repeat dose was the most effective. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

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

PubMed

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.

A RANDOMIZED TREATMENT TRIAL: SINGLE VERSUS 7 DAY DOSE OF METRONIDAZOLE FOR THE TREATMENT OF TRICHOMONAS VAGINALIS AMONG HIV-INFECTED WOMEN

PubMed Central

Kissinger, Patricia; Mena, Leandro; Levison, Judy; Clark, Rebecca A.; Gatski, Megan; Henderson, Harold; Schmidt, Norine; Rosenthal, Susan; Myers, Leann; Martin, David H.

2010-01-01

Objective To determine if the metronidazole (MTZ) 2 gm single dose (recommended) is as effective as the 7 day 500 mg BID dose (alternative) for treatment of Trichomonas vaginalis (TV) among HIV+ women. Methods Phase IV randomized clinical trial; HIV+ women with culture confirmed TV were randomized to treatment arm: MTZ 2 gm single dose or MTZ 500 mg BID 7 day dose. All women were given 2 gm MTZ doses to deliver to their sex partners. Women were re-cultured for TV at a test-of-cure (TOC) visit occurring 6-12 days after treatment completion. TV-negative women at TOC were again re-cultured at a 3 month visit. Repeat TV infection rates were compared between arms. Results 270 HIV+/TV+ women were enrolled (mean age = 40 years, ± 9.4; 92.2% African-American). Treatment arms were similar with respect to age, race, CD4 count, viral load, ART status, site, and loss-to-follow up. Women in the 7 day arm had: lower repeat TV infection rates at TOC [8.5% (11/130) versus 16.8% (21/125) (R.R. 0.50, 95% CI=0.25, 1.00; P<0.05)], and at 3 months [11.0% (8/73) versus 24.1% (19/79) (R.R. 0.46, 95% CI=0.21, 0.98; P=0.03)] compared to the single dose arm. Conclusions The 7 day MTZ dose was more effective than the single dose for the treatment of TV among HIV+ women. PMID:21423852

Controlled Administration of Penicillamine Reduces Radiation Exposure in Critical Organs during 64Cu-ATSM Internal Radiotherapy: A Novel Strategy for Liver Protection

PubMed Central

Yoshii, Yukie; Matsumoto, Hiroki; Yoshimoto, Mitsuyoshi; Furukawa, Takako; Morokoshi, Yukie; Sogawa, Chizuru; Zhang, Ming-Rong; Wakizaka, Hidekatsu; Yoshii, Hiroshi; Fujibayashi, Yasuhisa; Saga, Tsuneo

2014-01-01

Purpose 64Cu-diacetyl-bis (N 4-methylthiosemicarbazone) (64Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with 64Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during 64Cu-ATSM IRT. Methods Biodistribution was evaluated in HT-29 tumor-bearing mice injected with 64Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between 64Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after 64Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic 64Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses. Results Penicillamine reduced 64Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after 64Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic 64Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine. Conclusions We developed a novel strategy to reduce radiation exposure in critical organs during 64Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other 64Cu-labeled compounds. PMID:24466309

Methodological improvements in quantifying cognitive change in clinical trials: an example with single-dose administration of donepezil.

PubMed

Pietrzak, R H; Maruff, P; Snyder, P J

2009-03-01

Change in cognitive function in response to a pharmacologic challenge can be observed with greater sensitivity by employing cognitive tests with optimal psychometric properties and a statistical approach that more accurately accounts for individual variability in performance. To demonstrate this approach we examined the cognitive effects of a single acute dose administration of an acetylcholinesterase inhibitor, donepezil, in healthy older adults and in older adults with mild Alzheimer's disease (AD). Placebo-controlled crossover study with three separate testing days: baseline, placebo, and donepezil, with assessments at baseline, and 1-, 2-, 3-, 6-, and 8-hrs post-dosing on each day. Early phase I clinical trial. 15 healthy older adults; 14 older adults with mild Alzheimer's disease. Single acute dose of 5mg donepezil. Performance on the Groton Maze Learning Test (GMLT), a computerized neuropsychological measure of spatial working memory and error monitoring. A single acute dose of donepezil improved GMLT performance in healthy older adults (effect size: 0.83 at 6 hrs post-dosing) and older adults with mild AD (effect size: 0.58 at 3 hrs post-dosing). The GMLT detected cognitive improvement following a single, acute dose administration of donepezil in healthy older adults and older adults with mild AD. The choice of cognitive tests designed for repeated administration, as well as an analytic approach that emphasizes individual-level change in cognitive function, provides a sensitive approach to detecting central nervous system drug penetration and activity of cognitive-enhancing agents.

Estimation and comparison of effective dose (E) in standard chest CT by organ dose measurements and dose-length-product methods and assessment of the influence of CT tube potential (energy dependency) on effective dose in a dual-source CT.

PubMed

Paul, Jijo; Banckwitz, Rosemarie; Krauss, Bernhard; Vogl, Thomas J; Maentele, Werner; Bauer, Ralf W

2012-04-01

To determine effective dose (E) during standard chest CT using an organ dose-based and a dose-length-product-based (DLP) approach for four different scan protocols including high-pitch and dual-energy in a dual-source CT scanner of the second generation. Organ doses were measured with thermo luminescence dosimeters (TLD) in an anthropomorphic male adult phantom. Further, DLP-based dose estimates were performed by using the standard 0.014mSv/mGycm conversion coefficient k. Examinations were performed on a dual-source CT system (Somatom Definition Flash, Siemens). Four scan protocols were investigated: (1) single-source 120kV, (2) single-source 100kV, (3) high-pitch 120kV, and (4) dual-energy with 100/Sn140kV with equivalent CTDIvol and no automated tube current modulation. E was then determined following recommendations of ICRP publication 103 and 60 and specific k values were derived. DLP-based estimates differed by 4.5-16.56% and 5.2-15.8% relatively to ICRP 60 and 103, respectively. The derived k factors calculated from TLD measurements were 0.0148, 0.015, 0.0166, and 0.0148 for protocol 1, 2, 3 and 4, respectively. Effective dose estimations by ICRP 103 and 60 for single-energy and dual-energy protocols show a difference of less than 0.04mSv. Estimates of E based on DLP work equally well for single-energy, high-pitch and dual-energy CT examinations. The tube potential definitely affects effective dose in a substantial way. Effective dose estimations by ICRP 103 and 60 for both single-energy and dual-energy examinations differ not more than 0.04mSv. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Steady-state plasma concentration profile of transdermal rotigotine: an integrated analysis of three, open-label, randomized, phase I multiple dose studies.

PubMed

Elshoff, Jan-Peer; Braun, Marina; Andreas, Jens-Otto; Middle, Michelle; Cawello, Willi

2012-04-01

The dopamine agonist rotigotine is formulated in a transdermal delivery system (patch) for once-daily application. It has been reported as efficacious in the treatment of idiopathic Parkinson's disease (PD) and restless legs syndrome. This article summarizes the results of 3 clinical studies conducted to characterize the 24-hour pharmacokinetic profile of rotigotine in steady state and the effect of different patch application sites on this profile. In addition, the relative bioavailability of a single, large patch versus 2 smaller patches was assessed. One Phase I study (SP871) assessed the steady-state pharmacokinetic properties at different application sites at a rotigotine maintenance dose of 3 mg/24 hours in healthy participants. Due to tolerability issues, the steady-state pharmacokinetic properties of rotigotine at higher doses (8 mg/24 hours) was assessed in 2 Phase I studies (SP630, SP651) in early-stage PD patients. Relative rotigotine bioavailability from a 40 cm(2) patch versus 2 × 20 cm(2) patches (SP651) and from a 15 cm(2) patch versus 1 × 5 cm(2) + 1 × 10 cm(2) patches (SP871) was also evaluated. Rotigotine concentrations in plasma were analyzed using a validated LC-MS/MS method. The pharmacokinetic variables were calculated using standard noncompartmental analysis. Release of rotigotine to the skin was 31% to 62% of total drug content in the patch. Variability of rotigotine exposure was low within participants (15%) compared with the variability observed between participants (54%). Rotigotine exposure increased proportionally in the therapeutic dose range of 2 mg/24 hours to 8 mg/24 hours. Plasma concentrations at steady state were stable over the 24-hour patch-on period. Delivery via a single, large patch compared with a combination of smaller patches did not appear to influence exposure to rotigotine. Bioavailability showed some variability depending on patch application site (hip, shoulder, abdomen, flank, thigh, upper arm); the respective mean ratios for AUC ranged between 0.87 (abdomen vs flank) and 1.46 (shoulder vs thigh). Continuous rotigotine delivery via a once-daily transdermal patch generated stable mean steady-state 24-hour plasma concentrations in healthy participants as well as patients with early-stage PD. Doses were achieved either by application of 1 large patch or a combination of smaller patches, resulting in the same total surface area. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Retrospective analysis of factors that affect the success of single-dose methotrexate treatment in ectopic pregnancy

PubMed Central

Var, Altan; Özyurt, Ramazan; Şık, Bulat Aytek; Kumbasar, Serkan; Sever, Erman; Deveci, Mustafa; Çöt, Özgür; Salman, Süleyman; Güzel, Yılmaz

2015-01-01

Objective: Detection of factors that affect the success of single-dose methotrexate treatment in ectopic pregnancy. Materials and Methods: We investigated 99 patients who had been treated with single-dose methotrexate for ectopic pregnancy in our clinic between January 2009 and June 2014. Demographic, clinical, and laboratory results of possible factors that affect treatment success were retrospectively analyzed. Successfully and unsuccessfully treated patients were compared based on their pre-treatment results. Results: The success rate of single-dose methotrexate treatment was found to be 70.7%. No significant difference was found between succesfully and unsuccessfully treated patients before treatment in terms of factors such as gestational weeks, mass size, presence of yolk sac, and presence of free fluid (p=0.224, p=0.201, p=0.200, p=0.200). Serum β-hCG values in patients whose treatment was unsuccessful was found to be higher compared with the successfully treated group (mean β-hCG value of unsuccessful group: 4412±3501 mIU/mL; mean β-hCG value of successful group: 1079±942 mIU/mL; p<0.001). Conclusion: Single-dose methotrexate treatment is an effective and reliable method in the treatment of ectopic pregnancy. Elevation of serum β-hCG value stands as the main prognostic factor that affects the success of single-dose methotrexate treatment. PMID:28913072

Efficacy and Safety of a Single-Pill Fixed-Dose Combination of Azilsartan and Amlodipine.

PubMed

Motozato, Kota; Miura, Shin-Ichiro; Shiga, Yuhei; Kusumoto, Takaaki; Saku, Keijiro

2016-12-01

Guidelines for the management of hypertension recommend the use of drugs with different mechanisms of action in antihypertensive regimens that include single-pill fixed-dose combinations of medications. There is some controversy regarding which single-pill fixed-dose combinations of angiotensin II type 1 receptor blockers (ARBs) and calcium channel blockers (CCBs) are effective at reducing blood pressure (BP). Forty hypertensive patients who were receiving a single-pill fixed-dose combination of valsartan 80 mg/day and amlodipine 5 mg/day or irbesartan 100 mg/day and amlodipine 5 mg/day were enrolled. They were randomly divided into two treatment groups, a group that changed to a single-pill fixed-dose combination of azilsartan 20 mg/day and amlodipine 5 mg/day (changeover group) and a group that continued to receive valsartan 80 mg/day and amlodipine 5 mg/day or irbesartan 100 mg/day and amlodipine 5 mg/day (control group), and treated for 16 weeks. There were no significant differences in systolic blood pressure (SBP), diastolic blood pressure (DBP) or pulse rate (PR) at 16 weeks between the control and changeover groups. In addition, there were no significant changes in biochemical parameters throughout the study period in both groups. The ability of a single-pill fixed-dose combination of azilsartan and amlodipine to reduce BP may be comparable to that of a combination of valsartan and amlodipine or irbesartan and amlodipine.

Performance evaluation of an improved optical computed tomography polymer gel dosimeter system for 3D dose verification of static and dynamic phantom deliveries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lopatiuk-Tirpak, O.; Langen, K. M.; Meeks, S. L.

2008-09-15

The performance of a next-generation optical computed tomography scanner (OCTOPUS-5X) is characterized in the context of three-dimensional gel dosimetry. Large-volume (2.2 L), muscle-equivalent, radiation-sensitive polymer gel dosimeters (BANG-3) were used. Improvements in scanner design leading to shorter acquisition times are discussed. The spatial resolution, detectable absorbance range, and reproducibility are assessed. An efficient method for calibrating gel dosimeters using the depth-dose relationship is applied, with photon- and electron-based deliveries yielding equivalent results. A procedure involving a preirradiation scan was used to reduce the edge artifacts in reconstructed images, thereby increasing the useful cross-sectional area of the dosimeter by nearly amore » factor of 2. Dose distributions derived from optical density measurements using the calibration coefficient show good agreement with the treatment planning system simulations and radiographic film measurements. The feasibility of use for motion (four-dimensional) dosimetry is demonstrated on an example comparing dose distributions from static and dynamic delivery of a single-field photon plan. The capability to visualize three-dimensional dose distributions is also illustrated.« less

Evidence for a cost of immunity when the crustacean Daphnia magna is exposed to the bacterial pathogen Pasteuria ramosa.

PubMed

Little, Tom J; Killick, Stuart C

2007-11-01

The deployment of the immune system has the obvious potential to ameliorate infection outcomes, but immune responses can also harm hosts by either damaging host tissues or monopolizing resources, leading to enhanced mortality. To gain insight into such a 'cost of immunity' when the crustacean Daphnia magna is challenged with the bacterium Pasteuria ramosa, we measured survivorship among hosts that resisted infection following exposure to various strains and doses of the parasite. In the first of two experiments, these exposures were: single exposures with relatively non-aggressive strains, double exposures with non-aggressive strains, and exposure to aggressive strains. Mortality increased across this gradient of exposure. In a second experiment, we varied the dose of the most aggressive P. ramosa strain and found that resisting infection when a large dose was applied resulted in greater mortality than when a medium or low dose was applied. Assuming that resistance is accomplished with an immune response, and that more aggressive parasites and/or larger doses of parasites are more immunostimulatory, these data are compatible with a cost of immunity. Indeed, in terms of survival, resisting parasites can be more harmful than infection.

Immunogenicity and safety of a live attenuated shingles (herpes zoster) vaccine (Zostavax®) in individuals aged ≥ 70 years: a randomized study of a single dose vs. two different two-dose schedules.

PubMed

Vesikari, Timo; Hardt, Roland; Rümke, Hans C; Icardi, Giancarlo; Montero, Jordi; Thomas, Stéphane; Sadorge, Christine; Fiquet, Anne

2013-04-01

Disease protection provided by herpes zoster (HZ) vaccination tends to reduce as age increases. This study was designed to ascertain whether a second dose of the HZ vaccine, Zostavax(®), would increase varicella zoster virus (VZV)-specific immune response among individuals aged ≥ 70 y. Individuals aged ≥ 70 y were randomized to receive HZ vaccine in one of three schedules: a single dose (0.65 mL), two doses at 0 and 1 mo, or two doses at 0 and 3 mo. VZV antibody titers were measured at baseline, 4 weeks after each vaccine dose, and 12 mo after the last dose. In total, 759 participants (mean age 76.1 y) were randomized to receive vaccination. Antibody responses were similar after a single dose or two doses of HZ vaccine [post-dose 2/post-dose 1 geometric mean titer (GMT) ratios for the 1-mo or 3-mo schedules were 1.11, 95% confidence interval (CI) 1.02-1.22 and 0.78, 95% CI 0.73-0.85], respectively). The 12-mo post-dose 2/12-mo post-dose 1 GMT ratio was similar for the 1-mo schedule and for the 3-mo schedule (1.06, 95% CI 0.96-1.17 and 1.08, 95% CI 0.98-1.19, respectively). Similar immune responses were observed in participants aged 70-79 y and those aged ≥ 80 y. HZ vaccine was generally well tolerated, with no evidence of increased adverse event incidence after the second dose with either schedule. Compared with a single-dose regimen, two-dose vaccination did not increase VZV antibody responses among individuals aged ≥ 70 y. Antibody persistence after 12 mo was similar with all three schedules.

Radiation-Induced Growth Retardation and Microstructural and Metabolite Abnormalities in the Hippocampus

PubMed Central

Zawaski, Janice A.; Sahnoune, Iman

2016-01-01

Cranial radiotherapy (CRT) increases survival in pediatric brain-tumor patients but can cause deleterious effects. This study evaluates the acute and long-term impact of CRT delivered during childhood/adolescence on the brain and body using a rodent model. Rats received CRT, either 4 Gy fractions × 5 d (fractionated) or a cumulative dose of 20 Gy (single dose) at 28 d of age. Animals were euthanized 1 d, 5 d, or 3.5 mo after CRT. The 3.5 mo group was imaged prior to euthanasia. At 3.5 mo, we observed significant growth retardation in irradiated animals, versus controls, and the effects of single dose on brain and body weights were more severe than fractionated. Acutely single dose significantly reduced body weight but increased brain weight, whereas fractionation significantly reduced brain but not body weights, versus controls. CRT suppressed cell proliferation in the hippocampal subgranular zone acutely. Fractional anisotropy (FA) in the fimbria was significantly lower in the single dose versus controls. Hippocampal metabolite levels were significantly altered in the single dose animals, reflecting a heightened state of inflammation that was absent in the fractionated. Our findings indicate that despite the differences in severity between the doses they both demonstrated an effect on cell proliferation and growth retardation, important factors in pediatric CRT. PMID:27242931

Radiation-Induced Growth Retardation and Microstructural and Metabolite Abnormalities in the Hippocampus.

PubMed

Rodgers, Shaefali P; Zawaski, Janice A; Sahnoune, Iman; Leasure, J Leigh; Gaber, M Waleed

2016-01-01

Cranial radiotherapy (CRT) increases survival in pediatric brain-tumor patients but can cause deleterious effects. This study evaluates the acute and long-term impact of CRT delivered during childhood/adolescence on the brain and body using a rodent model. Rats received CRT, either 4 Gy fractions × 5 d (fractionated) or a cumulative dose of 20 Gy (single dose) at 28 d of age. Animals were euthanized 1 d, 5 d, or 3.5 mo after CRT. The 3.5 mo group was imaged prior to euthanasia. At 3.5 mo, we observed significant growth retardation in irradiated animals, versus controls, and the effects of single dose on brain and body weights were more severe than fractionated. Acutely single dose significantly reduced body weight but increased brain weight, whereas fractionation significantly reduced brain but not body weights, versus controls. CRT suppressed cell proliferation in the hippocampal subgranular zone acutely. Fractional anisotropy (FA) in the fimbria was significantly lower in the single dose versus controls. Hippocampal metabolite levels were significantly altered in the single dose animals, reflecting a heightened state of inflammation that was absent in the fractionated. Our findings indicate that despite the differences in severity between the doses they both demonstrated an effect on cell proliferation and growth retardation, important factors in pediatric CRT.

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

PubMed

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.

Effects of single doses of rabeprazole 20 mg and esomeprazole 40 mg on 24-h intragastric pH in healthy subjects.

PubMed

Warrington, Steve; Baisley, Kathy; Dunn, Kate; Boyce, Malcolm; Morocutti, Anna

2006-09-01

To compare antisecretory effects of single doses of rabeprazole and esomeprazole. Open, randomised, 2-way crossover, clinical pharmacology study. 24 healthy subjects (10 men; mean age 26.2 y) received a single dose of rabeprazole 20 mg or esomeprazole 40 mg, with a 14-day 'washout'. Intragastric pH was recorded continuously from 24 h before to 24 h after dosing. Mean intragastric pH was higher after esomeprazole than rabeprazole during 0-5 h after dosing (P=0.0001); the reverse was true from 14-24 h (P=0.0002). Mean % time pH>3 and >4 was greater after esomeprazole than rabeprazole during 0-14 h (P=0.041 and 0.044), but the reverse was true during 14-24 h (P=0.0005 and 0.001). In the 0-24 h interval as a whole, there was no difference between treatments in mean pH or % time pH>3 or >4. Single-dose rabeprazole 20 mg was as effective as esomeprazole 40 mg in increasing intragastric pH and maintaining pH>3 and >4, despite the 2-fold difference in dose.

Single dose parenteral hyposensitization to poison ivy urushiol in guinea pigs.

PubMed

Walker, L A; Watson, E S; elSohly, M A

1995-08-01

Studies were carried out in guinea pigs to evaluate the potential for single dose hyposensitization to poison ivy urushiol dermatitis. Sensitization was induced by topical application of 1 mg of poison ivy urushiol to the back of the neck. In the first series of studies, three different analogs of poison ivy urushiol were studied: 1) a mixture of pentadecyl and heptadecyl catechols (PDC/HDC), the saturated side chain analog of the natural urushiol mixture; 2) a mixture of the diacetate esters of PDC and HDC (PDC/HDC Ac), the esterified form of the saturated sidechain analogs; 3) 2-n-pentadecyl hydroquinone diacetate (HQ Ac). Each of these compounds was administered as 5 mg of the free catechol i.m. each week for three weeks. A vehicle group received only corn oil injections. Reactivity to poison ivy urushiol (PIU) challenge was evaluated in skin tests at 1 and 5 weeks post-treatment. PDC/HDC Ac induced a marked reduction in both the incidence and the severity of lesions induced by PIU at both 1 and at 5 weeks post-treatment. Other analogs were ineffective at 5 weeks post-treatment, and were less effective than PDC/HDC Ac at 1 week post-treatment. In a second series of experiments, the efficacy of PDC/HDC Ac was evaluated in both single and multiple dose regiments. One treatment group received 5 mg of PDC/HDC Ac intramuscularly each week for 4 weeks, while another treatment group received a single dose of 20 mg PDC/HDC Ac i.m. Corresponding vehicle control groups were also included. At 1 week post-treatment in the single dose group, the PDC/HDC Ac was only modestly effective, with some reduction of severity of lesions at the higher challenge doses of PIU. However, at 4 and 7 weeks post-treatment, both the incidence and the severity of the lesions at all challenge doses were reduced. In the multiple dose group, the incidence and severity of lesions are reduced at 1 week and 4 weeks post-treatment (4 weeks and 7 weeks after the initial dose) but were not significantly different from the single dose group. These findings indicate that the diacetate ester of PDC/HDC is an effective hyposensitizer to poison ivy urushiol, and that this hyposensitization can be reasonably accomplished in a single dose treatment regimen.

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers

PubMed Central

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-01-01

Aim The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Methods Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. Results ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Conclusions Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. PMID:23016924

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.

PubMed

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-05-01

The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. © 2012 Abbott Laboratories. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Bayesian dose-response analysis for epidemiological studies with complex uncertainty in dose estimation.

PubMed

Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian E; Simon, Steven L

2016-02-10

Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure. Copyright © 2015 John Wiley & Sons, Ltd.

High-dose total-body irradiation and autologous marrow reconstitution in dogs: dose-rate-related acute toxicity and fractionation-dependent long-term survival

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deeg, H.J.; Storb, R.; Weiden, P.L.

1981-11-01

Beagle dogs treated by total-body irradiation (TBI) were given autologous marrow grafts in order to avoid death from marrow toxicity. Acute and delayed non-marrow toxicities of high single-dose (27 dogs) and fractionated TBI (20 dogs) delivered at 0.05 or 0.1 Gy/min were compared. Fractionated TBI was given in increments of 2 Gy every 6 hr for three increments per day. Acute toxicity and early mortality (<1 month) at identical total irradiation doses were comparable for dogs given fractionated or single-dose TBI. With single-dose TBI, 14, 16, and 18 Gy, respectively, given at 0.05 Gy/min, 0/5, 5/5, and 2/2 dogs diedmore » from acute toxicity; with 10, 12, and 14 Gy, respectively, given at 0.1 Gy/min, 1/5, 4/5, and 5/5 dogs died acutely. With fractionated TBI, 14 and 16 Gy, respectively, given at 0.1 Gy/min, 1/5, 4/5, and 2/2 dogs died auctely. Early deaths were due to radiation enteritis with or without associated septicemia (29 dogs; less than or equal to Day 10). Three dogs given 10 Gy of TBI at 0.1 Gy/min died from bacterial pneumonia; one (Day 18) had been given fractionated and two (Days 14, 22) single-dose TBI. Fifteen dogs survived beyond 1 month; eight of these had single-dose TBI (10-14 Gy) and all died within 7 months of irradiation from a syndrome consisting of hepatic damage, pancreatic fibrosis, malnutrition, wasting, and anemia. Seven of the 15 had fractionated TBI, and only one (14 Gy) died on Day 33 from hepatic failure, whereas 6 (10-14 Gy) are alive and well 250 to 500 days after irradiation. In conclusion, fractionated TBI did not offer advantages over single-dose TBI with regard to acute toxicity and early mortality; rather, these were dependent upon the total dose of TBI. The total acutely tolerated dose was dependent upon the exposure rate; however, only dogs given fractionated TBI became healthy long-term survivors.« less

Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33 secreted from impaired vessels in the skin compared to fractionated irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Eun-Jung, E-mail: forejs2@yuhs.ac; Kim, Jun Won, E-mail: JUNWON@yuhs.ac; Yoo, Hyun, E-mail: gochunghee@yuhs.ac

We have revealed in a porcine skin injury model that eosinophil recruitment was dose-dependently enhanced by a single high-dose irradiation. In this study, we investigated the underlying mechanism of eosinophil-associated skin fibrosis and the effect of high-dose-per-fraction radiation. The dorsal skin of a mini-pig was divided into two sections containing 4-cm{sup 2} fields that were irradiated with 30 Gy in a single fraction or 5 fractions and biopsied regularly over 14 weeks. Eosinophil-related Th2 cytokines such as interleukin (IL)-4, IL-5, and C–C motif chemokine-11 (CCL11/eotaxin) were evaluated by quantitative real-time PCR. RNA-sequencing using 30 Gy-irradiated mouse skin and functional assays in amore » co-culture system of THP-1 and irradiated-human umbilical vein endothelial cells (HUVECs) were performed to investigate the mechanism of eosinophil-mediated radiation fibrosis. Single high-dose-per-fraction irradiation caused pronounced eosinophil accumulation, increased profibrotic factors collagen and transforming growth factor-β, enhanced production of eosinophil-related cytokines including IL-4, IL-5, CCL11, IL-13, and IL-33, and reduced vessels compared with 5-fraction irradiation. IL-33 notably increased in pig and mouse skin vessels after single high-dose irradiation of 30 Gy, as well as in irradiated HUVECs following 12 Gy. Blocking IL-33 suppressed the migration ability of THP-1 cells and cytokine secretion in a co-culture system of THP-1 cells and irradiated HUVECs. Hence, high-dose-per-fraction irradiation appears to enhance eosinophil-mediated fibrotic responses, and IL-33 may be a key molecule operating in eosinophil-mediated fibrosis in high-dose-per fraction irradiated skin. - Highlights: • Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33. • Vascular endothelial cells damaged by high-dose radiation secrete IL-33. • Blocking IL-33 suppressed migration of inflammatory cells and cytokine secretion. • IL-33 is a key in eosinophil-mediated fibrosis in high-dose-per-fraction radiation.« less

HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat

PubMed Central

Archin, Nancy M.; Bateson, Rosalie; Tripathy, Manoj K.; Crooks, Amanda M.; Yang, Kuo-Hsiung; Dahl, Noelle P.; Kearney, Mary F.; Anderson, Elizabeth M.; Coffin, John M.; Strain, Matthew C.; Richman, Douglas D.; Robertson, Kevin R.; Kashuba, Angela D.; Bosch, Ronald J.; Hazuda, Daria J.; Kuruc, Joann D.; Eron, Joseph J.; Margolis, David M.

2014-01-01

Background. A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4+ T cells of treated, aviremic human immunodeficiency virus (HIV)–positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge. Methods. Five participants in whom resting CD4+ T-cell–associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4+ T cells were assayed. Results. VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged. Conclusions. Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥24 hours. The optimal schedule for VOR administration is still to be defined. PMID:24620025

Pigmentation after single and multiple UV-exposures depending on UV-spectrum.

PubMed

Ravnbak, M H; Wulf, H C

2007-04-01

Minimal pigmentation dose (MMD) after a single UV-exposure is well investigated. Whereas only few studies have established MMD after multiple UV-exposures and mainly in fair-skinned persons. The purpose of this study was to establish MMD 1 week after, respectively, one and five UV-exposures in volunteers with a large variation in constitutive pigmentation. A total of 52 volunteers (skin Types II-V) had skin pigmentation quantified by reflectance spectroscopy. They were UV-exposed on the back for 1 and 5 days using a Solar Simulator, narrowband UVB, broadband UVA and UVA1. For all sources a higher dose was needed the more pigmented the skin, except for UVA1. After one UV-exposure, we found a significant positive linear correlation between UV-dose to one MMD, skin type and pre-exposure skin pigmentation. After five UV-exposures the positive linear correlation between UV-dose and MMD and skin type was only significant for narrow band UVB, pre-exposure skin pigmentation was significant also for Solar Simulator. For UVA and particularly UVA1 the MMD was independent of pre-exposure pigmentation. The number of SED to MMD is therefore almost the same for very fair-skinned and dark-skinned persons. Pre-exposure pigmentation was clearly more predictive of MMD than skin type. 50% of MMD equals a pigmentation increase of 1%. The shorter the wavelengths the higher the SED to produce MMD. Solar was the least melanogenic and UVA1 the most melanogenic. For the UVB-sources a higher dose was needed the more pigmented the skin. For UVA the MMD was independent of pre-exposure pigmentation.

Safety and pharmacokinetics of Bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers.

PubMed

Martin, David E; Blum, Robert; Wilton, John; Doto, Judy; Galbraith, Hal; Burgess, Gina L; Smith, Philip C; Ballow, Charles

2007-09-01

Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV) maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (n = 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (n = 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters. BVM was well absorbed after oral administration, with peak plasma concentrations being achieved 1 to 3 h after dosing. The half-life was 60 to 80 h. The exposure assessed by determination of the peak concentration and the area under the concentration-time curve was dose proportional. Single oral doses of BVM were well tolerated: there were no dose-limiting toxicities, and no serious adverse events were reported. These findings suggest that that BVM offers a favorable pharmacokinetic profile, with predictable pharmacokinetics following the oral administration of single doses. The long half-life of BVM may facilitate once-daily dosing.

Diagnostic medical imaging radiation exposure and risk of development of solid and hematologic malignancy.

PubMed

Fabricant, Peter D; Berkes, Marschall B; Dy, Christopher J; Bogner, Eric A

2012-05-01

Limiting patients' exposure to ionizing radiation during diagnostic imaging is of concern to patients and clinicians. Large single-dose exposures and cumulative exposures to ionizing radiation have been associated with solid tumors and hematologic malignancy. Although these associations have been a driving force in minimizing patients' exposure, significant risks are found when diagnoses are missed and subsequent treatment is withheld. Therefore, based on epidemiologic data obtained after nuclear and occupational exposures, dose exposure limits have been estimated. A recent collaborative effort between the US Food and Drug Administration and the American College of Radiology has provided information and tools that patients and imaging professionals can use to avoid unnecessary ionizing radiation scans and ensure use of the lowest feasible radiation dose necessary for studies. Further collaboration, research, and development should focus on producing technological advances that minimize individual study exposures and duplicate studies. This article outlines the research used to govern safe radiation doses, defines recent initiatives in decreasing radiation exposure, and provides orthopedic surgeons with techniques that may help decrease radiation exposure in their daily practice. Copyright 2012, SLACK Incorporated.

The blocking action of choline 2:6-xylyl ether bromide on adrenergic nerves

PubMed Central

Exley, K. A.

1957-01-01

Choline 2:6-xylyl ether bromide (TM 10), given systemically to cats in doses of 5 to 15 mg./kg., abolishes the effects of adrenergic nerve stimulation whilst leaving the reactions of the effector organs to adrenaline unimpaired. The effects of a single dose may take up to one hour to become fully established and last for more than twenty-four hours. Apart from transitory ganglionic blockade, cholinergic autonomic nerves are unaffected even by large doses of TM 10. Doses of TM 10 which produce effective blockade do not impair conduction along adrenergic nerve trunks; the drug must, therefore, act at, or close to, the nerve terminals. TM 10 prevents the output of noradrenaline from the spleen on stimulating the splenic nerves; but, in acute experiments, it does not influence the liberation of pressor amines from the stimulated suprarenals. Examination of some ethers related to TM 10 revealed no correlation between TM 10-like adrenergic blocking activity and local anaesthetic activity. The action of TM 10 on adrenergic nerves does not, therefore, seem to be accounted for by axonal block. ImagesFIG. 8 PMID:13460234

Experimental Design for Multi-drug Combination Studies Using Signaling Networks

PubMed Central

Huang, Hengzhen; Fang, Hong-Bin; Tan, Ming T.

2017-01-01

Summary Combinations of multiple drugs are an important approach to maximize the chance for therapeutic success by inhibiting multiple pathways/targets. Analytic methods for studying drug combinations have received increasing attention because major advances in biomedical research have made available large number of potential agents for testing. The preclinical experiment on multi-drug combinations plays a key role in (especially cancer) drug development because of the complex nature of the disease, the need to reduce development time and costs. Despite recent progresses in statistical methods for assessing drug interaction, there is an acute lack of methods for designing experiments on multi-drug combinations. The number of combinations grows exponentially with the number of drugs and dose-levels and it quickly precludes laboratory testing. Utilizing experimental dose-response data of single drugs and a few combinations along with pathway/network information to obtain an estimate of the functional structure of the dose-response relationship in silico, we propose an optimal design that allows exploration of the dose-effect surface with the smallest possible sample size in this paper. The simulation studies show our proposed methods perform well. PMID:28960231

Nutrition Composition and Single, 14-Day and 13-Week Repeated Oral Dose Toxicity Studies of the Leaves and Stems of Rubus coreanus Miquel.

PubMed

Om, Ae-Son; Song, Yu-Na; Noh, GeonMin; Kim, HaengRan; Choe, JeongSook

2016-01-08

The leaves and stems of the plant Rubus coreanus Miquel (RCMLS) are rich in vitamins, minerals and phytochemicals which have antioxidant, anti-hemolytic, anti-inflammatory, anti-fatigue and anti-cancer effects. However, RCMLS is not included in the Korean Food Standards Codex due to the lack of safety assurance concerning RCMLS. We evaluated single and repeated oral dose toxicity of RCMLS in Sprague-Dawley rats. RCMLS did not induce any significant toxicological changes in both male and female rats at a single doses of 2500 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects in clinical signs, body weight, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at doses of 625, 1250, and 2500 mg/kg/day. The LD50 and LOAEL of RCMLS might be over 2500 mg/kg body weight/day and no target organs were identified. Therefore, this study revealed that single and repeated oral doses of RCMLS are safe.

Pharmacokinetics of isotretinoin and its major blood metabolite following a single oral dose to man.

PubMed

Colburn, W A; Vane, F M; Shorter, H J

1983-01-01

A pharmacokinetic profile of isotretinoin and its major dermatologically active blood metabolite, 4-oxo-isotretinoin, was developed following a single 80 mg oral suspension dose of isotretinoin to 15 normal male subjects. Blood samples were assayed for isotretinoin and 4-oxo-isotretinoin using a newly developed reverse-phase HPLC method. Following rapid absorption from the suspension formulation, isotretinoin is distributed and eliminated with harmonic mean half-lives of 1.3 and 17.4 h, respectively. Maximum concentrations of isotretinoin in blood were observed at 1 to 4 h after dosing. Maximum concentrations of the major blood metabolite of isotretinoin, 4-oxo-isotretinoin, are approximately one-half those of isotretinoin and occur at 6 to 16 h after isotretinoin dosing. The ratio of areas under the curve for metabolite and parent drug following the single dose suggests that average steady-state ratios of metabolite to parent drug during a dosing interval will be approximately 2.5. Both isotretinoin and its metabolite can be adequately described using a single linear pharmacokinetic model.

Single multivalent vaccination boosted by trickle larval infection confers protection against experimental lymphatic filariasis

PubMed Central

Joseph, SK; Ramaswamy, K

2013-01-01

The multivalent vaccine BmHAT, consisting of the Brugia malayi infective larval (L3) antigens heat shock protein12.6 (HSP12.6), abundant larval transcript-2 (ALT-2) and tetraspanin large extra cellular loop (TSP-LEL), was shown to be protective in rodent models from our laboratory. We hypothesize that since these antigens were identified using protective antibodies from immune endemic normal individuals, the multivalent vaccine can be augmented by natural L3 infections providing protection to the vaccinated host. This hypothesis was tested using single dose of DNA and Protein or Protein alone of the BmHAT vaccination in gerbils followed by live trickle L3 infection as booster dose. Vaccine-induced protection in gerbils was determined by worm establishment, micropore chamber assay and by antibody dependant cell cytotoxicity (ADCC) assay. Results were compared with the traditional prime-boost vaccination regimen. Gerbils vaccinated with BmHAT and boosted with L3 trickle infection were protected 51% (BmHAT DNA-Protein) and 48% (BmHAT Protein) respectively. BmHAT vaccination plus L3 trickle booster generated significant titer of antigen-specific IgG antibodies comparable to the traditional prime boost vaccination approach. BmHAT vaccination plus L3 trickle booster also generated antigen-specific cells in the spleen of vaccinated animals and these cells secreted predominantly IFN-γ and IL-4 in response to the vaccine antigens. These studies thus show that single dose of BmHAT multivalent vaccination followed by L3 trickle booster infection can confer significant protection against lymphatic filariasis. PMID:23735679

Economic and microbiologic evaluation of single-dose vial extension for hazardous drugs.

PubMed

Rowe, Erinn C; Savage, Scott W; Rutala, William A; Weber, David J; Gergen-Teague, Maria; Eckel, Stephen F

2012-07-01

The update of US Pharmacopeia Chapter <797> in 2008 included guidelines stating that single-dose vials (SDVs) opened and maintained in an International Organization for Standardization Class 5 environment can be used for up to 6 hours after initial puncture. A study was conducted to evaluate the cost of discarding vials after 6 hours and to further test sterility of vials beyond this time point, subsequently defined as the beyond-use date (BUD). Financial determination of SDV waste included 2 months of retrospective review of all doses prescribed. Additionally, actual waste log data were collected. Active and control vials (prepared using sterilized trypticase soy broth) were recovered, instead of discarded, at the defined 6-hour BUD. The institution-specific waste of 19 selected SDV medications discarded at 6 hours was calculated at $766,000 annually, and tracking waste logs for these same medications was recorded at $770,000 annually. Microbiologic testing of vial extension beyond 6 hours showed that 11 (1.86%) of 592 samples had one colony-forming unit on one of two plates. Positive plates were negative at subsequent time points, and all positives were single isolates most likely introduced during the plating process. The cost of discarding vials at 6 hours was significant for hazardous medications in a large academic medical center. On the basis of microbiologic data, vial BUD extension demonstrated a contamination frequency of 1.86%, which likely represented exogenous contamination; vial BUD extension for the tested drugs showed no growth at subsequent time points and could provide an annual cost savings of more than $600,000.

The Impact on Space Radiation Requirements and Effects on ASIMS

NASA Technical Reports Server (NTRS)

Barnes, C.; Johnston, A.; Swift, G.

1995-01-01

The evolution of highly miniaturized electronic and mechanical systems will be accompanied by new problems and issues regarding the radiation response of these systems in the space environment. In this paper we discuss some of the more prominent radiation problems brought about by miniaturization. For example, autonomous micro-spacecraft will require large amounts of high density memory, most likely in the form of stacked, multichip modules of DRAM's, that must tolerate the radiation environment. However, advanced DRAM's (16 to 256 Mbit) are quite susceptible to radiation, particularly single event effects, and even exhibit new radiation phenomena that were not a problem for older, less dense memory chips. Another important trend in micro-spacecraft electronics is toward the use of low-voltage microelectronic systems that consume less power. However, the reduction in operating voltage also caries with it an increased susceptibility to radiation. In the case of application specific integrated microcircuits (ASIM's), advanced devices of this type, such as high density field programmable gate arrays (FPGA's) exhibit new single event effects (SEE), such as single particle reprogramming of anti-fuse links. New advanced bipolar circuits have been shown recently to degrade more rapidly in the low dose rate space environment than in the typical laboratory total dose radiation test used to qualify such devices. Thus total dose testing of these parts is no longer an appropriately conservative measure to be used for hardness assurance. We also note that the functionality of micromechanical Si-based devices may be altered due to the radiation-induced deposition of charge in the oxide passivation layers.

Compendium of Single Event Effects, Total Ionizing Dose, and Displacement Damage for Candidate Spacecraft Electronics for NASA

NASA Technical Reports Server (NTRS)

LaBel, Kenneth A.; OBryan, Martha V.; Chen, Dakai; Campola, Michael J.; Casey, Megan C.; Pellish, Jonathan A.; Lauenstein, Jean-Marie; Wilcox, Edward P.; Topper, Alyson D.; Ladbury, Raymond L.;

Brentuximab vedotin in refractory CD30+ lymphomas: a bridge to allogeneic transplantation in approximately one quarter of patients treated on a Named Patient Programme at a single UK center

PubMed Central

Gibb, Adam; Jones, Craig; Bloor, Adrian; Kulkarni, Samar; Illidge, Tim; Linton, Kim; Radford, John

2013-01-01

The CD30-targeted agent brentuximab vedotin has shown impressive activity in relapsed/refractory Hodgkin lymphoma and anaplastic large cell lymphoma in phase II studies. We have treated 24 patients with relapsed/refratory disease enrolled onto a Named Patient Programme during 2010-11 at a single UK center. Overall response rate across all histologies was 67% (Hodgkin 72%; anaplastic large cell 60%), complete response rate 25% (Hodgkin 17%; anaplastic large cell 60%), median progression-free survival 5.1 months, and toxicity mild to moderate in the majority of cases. Six patients proceeded to allogeneic transplantation and one patient awaits this procedure. These results are similar to phase II data and show that brentuximab vedotin provides a bridge to allogeneic transplantation in approximately one quarter of patients refractory to conventional salvage therapies. Best response was seen after four doses, so consideration of allogeneic transplantation should be made early and scheduled following the first assessment indicating response. PMID:23065511

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs

PubMed Central

Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-01-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day. PMID:25874036

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs.

PubMed

Nam, Chunja; Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-03-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

Benefits of online in vivo dosimetry for single-fraction total body irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eaton, David J., E-mail: davideaton@nhs.net; Warry, Alison J.; Trimble, Rachel E.

Use of a patient test dose before single-fraction total body irradiation (TBI) allows review of in vivo dosimetry and modification of the main treatment setup. However, use of computed tomography (CT) planning and online in vivo dosimetry may reduce the need for this additional step. Patients were treated using a supine CT-planned extended source-to-surface distance (SSD) technique with lead compensators and bolus. In vivo dosimetry was performed using thermoluminescent dosimeters (TLDs) and diodes at 10 representative anatomical locations, for both a 0.1-Gy test dose and the treatment dose. In total, 28 patients were treated between April 2007 and July 2013,more » with changes made in 10 cases (36%) following test dose results. Overall, 98.1% of measured in vivo treatment doses were within 10% of the prescribed dose, compared with 97.0% of test dose readings. Changes made following the test dose could have been applied during the single-fraction treatment itself, assuming that the dose was delivered in subportions and online in vivo dosimetry was available for all clinically important anatomical sites. This alleviates the need for a test dose, saving considerable time and resources.« less

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

PubMed

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 healthy volunteers. The absolute bioavailability of BBUP was 46% to 51% across a 16-fold dose range, with dose-proportional increases in systemic exposure. Apparent steady-state conditions occurred within 3 days of dosing. These pharmacokinetic results suggest that therapeutic buprenorphine plasma concentrations can be obtained with BBUP across a wide dose range in a shorter time than other (eg, transdermal) dosage forms. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Technical Note: System for evaluating local hypothermia as a radioprotector of the rectum in a small animal model.

PubMed

Hrycushko, Brian A; Bing, Chenchen; Futch, Cecil; Wodzak, Michelle; Stojadinovic, Strahinja; Medin, Paul M; Chopra, Rajiv

2017-08-01

The protective effects of induced or even accidental hypothermia on the human body are widespread with several medical uses currently under active research. In vitro experiments using human cell lines have shown hypothermia provides a radioprotective effect that becomes more pronounced at large, single-fraction doses common to stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS) treatments. This work describes the development of a system to evaluate local hypothermia for a radioprotective effect of the rat rectum during a large dose of radiation relevant to prostate SBRT. This includes the evaluation of a 3D-printed small animal rectal cooling device and the integration with a small animal irradiator. A 3-cm long, dual-lumen rectal temperature control apparatus (RTCA) was designed in SOLIDWORKS CAD for 3D printing. The RTCA was capable of recirculating flow in a device small enough for insertion into the rat rectum, with a metal support rod for strength as well as visibility during radiation treatment planning. The outer walls of the RTCA comprised of thin heat shrink plastic, achieving efficient heat transfer into adjacent tissues. Following leak-proof testing, fiber optic temperature probes were used to evaluate the temperature over time when placed adjacent to the cooling device within the rat rectum. MRI thermometry characterized the relative temperature distribution in concentric ROIs surrounding the probe. Integration with an image-guided small animal irradiator and associated treatment planning system included evaluation for imaging artifacts and effect of brass tubing on dose calculation. The rectal temperature adjacent to the cooling device decreased from body temperature to 15°C within 10-20 min from device insertion and was maintained at 15 ± 3°C during active cooling for the evaluated time of one hour. MR thermometry revealed a steep temperature gradient with increasing distance from the cooling device with the desired temperature range maintained within the surrounding few millimeters. A 3D-printed rectal cooling device was fabricated for the purpose of inducing local hypothermia in the rat rectum. The RTCA was simply integrated with an image-guided small animal irradiator and Monte Carlo-based treatment planning system to facilitate an in vivo investigation of the radioprotective effect of hypothermia for late rectal toxicity following a single large dose of radiation. © 2017 American Association of Physicists in Medicine.

Current practice of antibiotic prophylaxis for surgical fixation of closed long bone fractures: a survey of 297 members of the Orthopaedic Trauma Association.

PubMed

Gans, Itai; Jain, Amit; Sirisreetreerux, Norachart; Haut, Elliott R; Hasenboehler, Erik A

2017-01-01

The risk of postoperative surgical site infection after long bone fracture fixation can be decreased with appropriate antibiotic use. However, there is no agreement on the superiority of a single- or multiple-dose perioperative regimen of antibiotic prophylaxis. The purpose of this study is to determine the following: 1) What are the current practice patterns of orthopaedic trauma surgeons in using perioperative antibiotics for closed long bone fractures? 2) What is the current knowledge of published antibiotic prophylaxis guidelines among orthopaedic trauma surgeons? 3) Are orthopaedic surgeons willing to change their current practices? A questionnaire was distributed via email between September and December 2015 to 955 Orthopaedic Trauma Association members, of whom 297 (31%) responded. Most surgeons (96%) use cefazolin as first-line infection prophylaxis. Fifty-nine percent used a multiple-dose antibiotic regimen, 39% used a single-dose regimen, and 2% varied this decision according to patient factors. Thirty-six percent said they were unfamiliar with Centers for Disease Control and Prevention (CDC) antibiotic prophylaxis guidelines; only 30% were able to select the correct CDC recommendation from a multiple-choice list. However, 44% of surgeons said they followed CDC recommendations. Fifty-six percent answered that a single-dose antibiotic prophylaxis regimen was not inferior to a multiple-dose regimen. If a level-I study comparing a single preoperative dose versus multiple perioperative antibiotic dosing regimen for treatment of closed long bone fractures were published, most respondents (64%) said they would fully follow these guidelines, and 22% said they would partially change their practice to follow these guidelines. There is heterogeneity in the use of single- versus multiple-dose antibiotic prophylaxis for surgical repair of closed long bone fractures. Many surgeons were unsure of current evidence-based recommendations regarding perioperative antibiotic use. Most respondents indicated they would be receptive to high-level evidence regarding the single- versus multiple-dose perioperative prophylactic antibiotics for the treatment of closed long bone fractures.

SU-E-J-53: Dosimetric Evaluation at Volumetric Modulated Arc Therapy for Treatment of Prostate Cancer Using Single Or Double Arcs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silva, D; Salmon, H; Pavan, G

2014-06-01

Purpose: Evaluate and compare retrospective prostate treatment plan using Volumetric Modulated Arc Therapy (RapidArc™ - Varian) technique with single or double arcs at COI Group. Methods: Ten patients with present prostate and seminal vesicle neoplasia were replanned as a target treatment volume and a prescribed dose of 78 Gy. A baseline planning, using single arc, was developed for each case reaching for the best result on PTV, in order to minimize the dose on organs at risk (OAR). Maintaining the same optimization objectives used on baseline plan, two copies for optimizing single and double arcs, have been developed. The plansmore » were performed with 10 MV photon beam energy on Eclipse software, version 11.0, making use of Trilogy linear accelerator with Millenium HD120 multileaf collimator. Comparisons on PTV have been performed, such as: maximum, minimum and mean dose, gradient dose, as well as the quantity of monitor units, treatment time and homogeneity and conformity index. OARs constrains dose have been evaluated, comparing both optimizations. Results: Regarding PTV coverage, the difference of the minimum, maximum and mean dose were 1.28%, 0.7% and 0.2% respectively higher for single arc. When analyzed the index of homogeneity found a difference of 0.99% higher when compared with double arcs. However homogeneity index was 0.97% lower on average by using single arc. The doses on the OARs, in both cases, were in compliance to the recommended limits RTOG 0415. With the use of single arc, the quantity of monitor units was 10,1% lower, as well as the Beam-On time, 41,78%, when comparing double arcs, respectively. Conclusion: Concerning the optimization of patients with present prostate and seminal vesicle neoplasia, the use of single arc reaches similar objectives, when compared to double arcs, in order to decrease the treatment time and the quantity of monitor units.« less

Bioequivalence of fixed-dose combination RIN®-150 to each reference drug in loose combination.

PubMed

Wang, H F; Wang, R; O'Gorman, M; Crownover, P; Damle, B

2015-03-01

RIN(®)-150 is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg) and isoniazid (INH, 75 mg) developed for the treatment of tuberculosis. This study was conducted at a single center: the Pfizer Clinical Research Unit in Singapore. To demonstrate bioequivalence of each drug component between RIN-150 and individual products in a loose combination. This was a randomized, open-label, single-dose, two-way crossover study. Subjects received single doses of RIN-150 or two individual reference products under fasting conditions in a crossover fashion, with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC). Of 28 subjects enrolled, 26 completed the study. The adjusted geometric mean ratios of Cmax and AUClast between the FDC and single-drug references and 90% confidence intervals were respectively 91.63% (90%CI 83.13-101.01) and 95.45% (90%CI 92.07-98.94) for RMP, and 107.58% (90%CI 96.07-120.47) and 103.45% (90%CI 99.33-107.75) for INH. Both formulations were generally well tolerated in this study. The RIN-150 FDC tablet formulation is bioequivalent to the two single-drug references for RMP and INH at equivalent doses.

A new single crystal diamond dosimeter for small beam: comparison with different commercial active detectors.

PubMed

Marsolat, F; Tromson, D; Tranchant, N; Pomorski, M; Le Roy, M; Donois, M; Moignau, F; Ostrowsky, A; De Carlan, L; Bassinet, C; Huet, C; Derreumaux, S; Chea, M; Cristina, K; Boisserie, G; Bergonzo, P

2013-11-07

Recent developments of new therapy techniques using small photon beams, such as stereotactic radiotherapy, require suitable detectors to determine the delivered dose with a high accuracy. The dosimeter has to be as close as possible to tissue equivalence and to exhibit a small detection volume compared to the size of the irradiation field, because of the lack of lateral electronic equilibrium in small beam. Characteristics of single crystal diamond (tissue equivalent material Z = 6, high density) make it an ideal candidate to fulfil most of small beam dosimetry requirements. A commercially available Element Six electronic grade synthetic diamond was used to develop a single crystal diamond dosimeter (SCDDo) with a small detection volume (0.165 mm(3)). Long term stability was studied by irradiating the SCDDo in a (60)Co beam over 14 h. A good stability (deviation less than ± 0.1%) was observed. Repeatability, dose linearity, dose rate dependence and energy dependence were studied in a 10 × 10 cm(2) beam produced by a Varian Clinac 2100 C linear accelerator. SCDDo lateral dose profile, depth dose curve and output factor (OF) measurements were performed for small photon beams with a micro multileaf collimator m3 (BrainLab) attached to the linac. This study is focused on the comparison of SCDDo measurements to those obtained with different commercially available active detectors: an unshielded silicon diode (PTW 60017), a shielded silicon diode (Sun Nuclear EDGE), a PinPoint ionization chamber (PTW 31014) and two natural diamond detectors (PTW 60003). SCDDo presents an excellent spatial resolution for dose profile measurements, due to its small detection volume. Low energy dependence (variation of 1.2% between 6 and 18 MV photon beam) and low dose rate dependence of the SCDDo (variation of 1% between 0.53 and 2.64 Gy min(-1)) are obtained, explaining the good agreement between the SCDDo and the efficient unshielded diode (PTW 60017) in depth dose curve measurements. For field sizes ranging from 0.6 × 0.6 to 10 × 10 cm(2), OFs obtained with the SCDDo are between the OFs measured with the PinPoint ionization chamber and the Sun Nuclear EDGE diode that are known to respectively underestimate and overestimate OF values in small beam, due to the large detection volume of the chamber and the non-water equivalence of both detectors.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects.

PubMed

Li, Xiaojiao; Liu, Chang; Wu, Min; Zhang, Hong; Sun, Yanfu; Cheng, Longmei; Chen, Hong; Liu, Chengjiao; Yang, Lizhi; Zhang, Qi; Cao, Yuchen; Gu, Jingkai; Ding, Yanhua

2016-08-01

Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.

In Vivo Imaging Reveals Significant Tumor Vascular Dysfunction and Increased Tumor Hypoxia-Inducible Factor-1α Expression Induced by High Single-Dose Irradiation in a Pancreatic Tumor Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maeda, Azusa; Department of Medical Biophysics, University of Toronto, Toronto, Ontario; Chen, Yonghong

Purpose: To investigate the effect of high-dose irradiation on pancreatic tumor vasculature and microenvironment using in vivo imaging techniques. Methods and Materials: A BxPC3 pancreatic tumor xenograft was established in a dorsal skinfold window chamber model and a subcutaneous hind leg model. Tumors were irradiated with a single dose of 4, 12, or 24 Gy. The dorsal skinfold window chamber model was used to assess tumor response, vascular function and permeability, platelet and leukocyte adhesion to the vascular endothelium, and tumor hypoxia for up to 14 days after 24-Gy irradiation. The hind leg model was used to monitor tumor size, hypoxia, and vascularitymore » for up to 65 days after 24-Gy irradiation. Tumors were assessed histologically to validate in vivo observations. Results: In vivo fluorescence imaging revealed temporary vascular dysfunction in tumors irradiated with a single dose of 4 to 24 Gy, but most significantly with a single dose of 24 Gy. Vascular functional recovery was observed by 14 days after irradiation in a dose-dependent manner. Furthermore, irradiation with 24 Gy caused platelet and leukocyte adhesion to the vascular endothelium within hours to days after irradiation. Vascular permeability was significantly higher in irradiated tumors compared with nonirradiated controls 14 days after irradiation. This observation corresponded with increased expression of hypoxia-inducible factor-1α in irradiated tumors. In the hind leg model, irradiation with a single dose of 24 Gy led to tumor growth delay, followed by tumor regrowth. Conclusions: Irradiation of the BxPC3 tumors with a single dose of 24 Gy caused transient vascular dysfunction and increased expression of hypoxia-inducible factor-1α. Such biological changes may impact tumor response to high single-dose and hypofractionated irradiation, and further investigations are needed to better understand the clinical outcomes of stereotactic body radiation therapy.« less

Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

NASA Astrophysics Data System (ADS)

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

2014-02-01

Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

High-precision dosimetry for radiotherapy using the optically stimulated luminescence technique and thin Al2O3:C dosimeters.

PubMed

Yukihara, E G; Yoshimura, E M; Lindstrom, T D; Ahmad, S; Taylor, K K; Mardirossian, G

2005-12-07

The potential of using the optically stimulated luminescence (OSL) technique with aluminium oxide (Al(2)O(3):C) dosimeters for a precise and accurate estimation of absorbed doses delivered by high-energy photon beams was investigated. This study demonstrates the high reproducibility of the OSL measurements and presents a preliminary determination of the depth-dose curve in water for a 6 MV photon beam from a linear accelerator. The uncertainty of a single OSL measurement, estimated from the variance of a large sample of dosimeters irradiated with the same dose, was 0.7%. In the depth-dose curve obtained using the OSL technique, the difference between the measured and expected doses was < or =0.7% for depths between 1.5 and 10 cm, and 1.1% for a depth of 15 cm. The readout procedure includes a normalization of the response of the dosimeter with respect to a reference dose in order to eliminate variations in the dosimeter mass, dosimeter sensitivity, and the reader's sensitivity. This may be relevant for quality assurance programmes, since it simplifies the requirements in terms of personnel training to achieve the precision and accuracy necessary for radiotherapy applications. We concluded that the OSL technique has the potential to be reliably incorporated in quality assurance programmes and dose verification.

Sibutramine-induced anorexia: potent, dose-dependent and behaviourally-selective profile in male rats.

PubMed

Tallett, A J; Blundell, J E; Rodgers, R J

2009-03-17

The serotonin and noradrenaline reuptake inhibitor sibutramine has been licensed as an anti-obesity treatment for more than a decade. However, while inhibitory effects on food intake and weight gain are well documented, surprisingly little published detail exists regarding its influence on feeding and related behaviours. The present study was therefore designed to assess the effects of acute sibutramine treatment on food intake, the behavioural satiety sequence (BSS) and post-treatment weight gain. Subjects were 10 non-deprived adult male Lister hooded rats, tested with 0.5-3.0 mg/kg sibutramine hydrochloride during 1-h DVD-recorded test sessions with palatable mash. Our results show that sibutramine dose-dependently reduced food intake, an effect significant at all doses tested. Ethological analysis revealed very few behavioural effects, except for a dose-dependent reduction in time spent feeding and an increase in the frequency of resting. Behavioural specificity was further supported by time-bin analysis which confirmed both the structural integrity and dose-dependent acceleration of the BSS. Single dosing with sibutramine (3.0 mg/kg) also suppressed daily weight gain over the 24-72 h period post-dosing. Current data support the conclusion that the acute anorectic and weight loss efficacy of sibutramine in adult male rats is not secondary to behavioural disruption but, instead, is due largely to an acceleration in behavioural satiety.

Estimating systemic exposure to ethinyl estradiol from an oral contraceptive.

PubMed

Westhoff, Carolyn L; Pike, Malcolm C; Tang, Rosalind; DiNapoli, Marianne N; Sull, Monica; Cremers, Serge

2015-05-01

This study was conducted to compare single-dose pharmacokinetics of ethinyl estradiol in an oral contraceptive with steady-state values and to assess whether any simpler measures could provide an adequate proxy of the "gold standard" 24-hour steady-state area under the curve (AUC) value. Identification of a simple, less expensive measure of systemic ethinyl estradiol exposure would be useful for larger studies that are designed to assess the relationship between an individual's ethinyl estradiol exposure and side-effects. We collected 13 samples over 24 hours for pharmacokinetic analysis on days 1 and 21 of the first cycle of a monophasic oral contraceptive that contained 30 μg ethinyl estradiol and 150 μg levonorgestrel in 17 nonobese healthy white women. We also conducted an abbreviated single-dose 9-sample pharmacokinetic analysis after a month washout. Ethinyl estradiol was measured by liquid chromatography-tandem mass spectrometry. We compared results of a full 13-sample steady-state pharmacokinetic analysis with results that had been calculated with the use of fewer samples (9 or 5) and after the single doses. We calculated Pearson correlation coefficients to evaluate the relationships between these estimates of systemic ethinyl estradiol exposure. The AUC, maximum, and 24-hour values were similar after the 2 single oral contraceptive doses (AUC; r=0.92). The steady-state 13-sample 24-hour AUC value was correlated highly with the average 9-sample AUC value after the 2 single doses (r=0.81; P=.0002). This correlation remained the same if the number of single-dose samples was reduced to 4, taken at time 1, 2.5, 4, and 24 hours. The 24-hour value at steady-state was correlated highly with the 24-hour steady-state AUC value (r=0.92; P<.0001). The average of the 24-hour values after the 2 single doses was also correlated quite highly with the steady-state AUC value (r=0.72; P=.0026). Limited blood sampling, including results from 2 single doses, gave highly correlated estimates of an oral contraceptive user's steady-state ethinyl estradiol exposure. Copyright © 2015 Elsevier Inc. All rights reserved.

Printable organometallic perovskite enables large-area, low-dose X-ray imaging

NASA Astrophysics Data System (ADS)

Kim, Yong Churl; Kim, Kwang Hee; Son, Dae-Yong; Jeong, Dong-Nyuk; Seo, Ja-Young; Choi, Yeong Suk; Han, In Taek; Lee, Sang Yoon; Park, Nam-Gyu

2017-10-01

Medical X-ray imaging procedures require digital flat detectors operating at low doses to reduce radiation health risks. Solution-processed organic-inorganic hybrid perovskites have characteristics that make them good candidates for the photoconductive layer of such sensitive detectors. However, such detectors have not yet been built on thin-film transistor arrays because it has been difficult to prepare thick perovskite films (more than a few hundred micrometres) over large areas (a detector is typically 50 centimetres by 50 centimetres). We report here an all-solution-based (in contrast to conventional vacuum processing) synthetic route to producing printable polycrystalline perovskites with sharply faceted large grains having morphologies and optoelectronic properties comparable to those of single crystals. High sensitivities of up to 11 microcoulombs per air KERMA of milligray per square centimetre (μC mGyair-1 cm-2) are achieved under irradiation with a 100-kilovolt bremsstrahlung source, which are at least one order of magnitude higher than the sensitivities achieved with currently used amorphous selenium or thallium-doped cesium iodide detectors. We demonstrate X-ray imaging in a conventional thin-film transistor substrate by embedding an 830-micrometre-thick perovskite film and an additional two interlayers of polymer/perovskite composites to provide conformal interfaces between perovskite films and electrodes that control dark currents and temporal charge carrier transportation. Such an all-solution-based perovskite detector could enable low-dose X-ray imaging, and could also be used in photoconductive devices for radiation imaging, sensing and energy harvesting.

Printable organometallic perovskite enables large-area, low-dose X-ray imaging.

PubMed

Kim, Yong Churl; Kim, Kwang Hee; Son, Dae-Yong; Jeong, Dong-Nyuk; Seo, Ja-Young; Choi, Yeong Suk; Han, In Taek; Lee, Sang Yoon; Park, Nam-Gyu

2017-10-04

Medical X-ray imaging procedures require digital flat detectors operating at low doses to reduce radiation health risks. Solution-processed organic-inorganic hybrid perovskites have characteristics that make them good candidates for the photoconductive layer of such sensitive detectors. However, such detectors have not yet been built on thin-film transistor arrays because it has been difficult to prepare thick perovskite films (more than a few hundred micrometres) over large areas (a detector is typically 50 centimetres by 50 centimetres). We report here an all-solution-based (in contrast to conventional vacuum processing) synthetic route to producing printable polycrystalline perovskites with sharply faceted large grains having morphologies and optoelectronic properties comparable to those of single crystals. High sensitivities of up to 11 microcoulombs per air KERMA of milligray per square centimetre (μC mGy air -1 cm -2 ) are achieved under irradiation with a 100-kilovolt bremsstrahlung source, which are at least one order of magnitude higher than the sensitivities achieved with currently used amorphous selenium or thallium-doped cesium iodide detectors. We demonstrate X-ray imaging in a conventional thin-film transistor substrate by embedding an 830-micrometre-thick perovskite film and an additional two interlayers of polymer/perovskite composites to provide conformal interfaces between perovskite films and electrodes that control dark currents and temporal charge carrier transportation. Such an all-solution-based perovskite detector could enable low-dose X-ray imaging, and could also be used in photoconductive devices for radiation imaging, sensing and energy harvesting.

Results of a Markov model analysis to assess the cost-effectiveness of a single tablet of fixed-dose amlodipine and atorvastatin for the primary prevention of cardiovascular disease in Korea.

PubMed

Liew, Danny; Park, Hye-Jin; Ko, Su-Kyoung

2009-10-01

In Korea, the treatment of hypertension and dyslipidemia constitutes an important strategy for the prevention of cardiovascular disease (CVD). This study sought to investigate the cost-effectiveness (from the Korean health care system perspective) of prescribing a proprietary formulation single-tablet fixed-dose combination of amlodipine and atorvastatin (at weighted mean doses of 5 mg and 10.25 mg, respectively) to all eligible patients aged > or = 45 years for the primary prevention of CVD (ie, coronary heart disease and ischemic stroke) in Korea, compared with currently observed patterns of blood-pressure and lipid-lowering medication prescription and use. A Markov model was developed with 4 health states: alive without CVD, alive with CVD, dead from CVD, and dead from non-CVD causes. The model population comprised 244 Koreans aged >/=45 years from the 2005 Korean National Health and Nutrition Examination Survey (KNHNES) without a history of myocardial infarction (MI) or stroke who met current criteria for both blood-pressure and lipid-lowering treatment. From a 2008 baseline, follow-up was simulated for 40 years. Cardiovascular risk was estimated for each subject individually using a multivariate, Asian population-specific equation, and updated with ongoing cycles. Decision analysis compared the effects of prescribing the fixed-dose combination to all subjects versus currently observed patterns of treatment. Data regarding the blood-pressure and lipid-lowering efficacies of combination therapy were drawn from the Respond trial. Costs of the fixed-dose combination tablet and CVD were sourced from pharmaceutical pricing lists and Korean Health Insurance Review and Assessment Services estimates, respectively. Utility values for CVD were obtained from a large Korean utility study. In the model, of the 244 treatment-eligible subjects, 126 (51.6%) and 13 (5.3%) were taking blood-pressure and lipid-lowering therapy, respectively. Use of single-tablet fixed-dose combination amlodipine and atorvastatin by all subjects was associated with estimated incremental cost-effectiveness ratios of 7,773,063 Korean won (KRW) per quality-adjusted life-year gained and 10,378,230 KRW per overall life-year gained (1300 KRW approximately US $1). Sensitivity and uncertainty analyses indicated these results to be robust. In this model, based on data from the 2005 KNHNES, hypertension and dyslipidemia were undertreated among Koreans aged > or = 45 years without a history of MI or stroke. The administration of single-tablet fixed-dose combination amlodipine and atorvastatin to all such individuals was likely to represent a cost-effective means of preventing first-onset CVD (ie, coronary heart disease and ischemic stroke) in this subgroup, compared with current patterns of treatment.

Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects.

PubMed

Krösser, S; Tillner, J; Fluck, M; Ungethüm, W; Wolna, P; Kovar, A

2007-05-01

Sarizotan is a 5-HTIA receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. Two single-dose (5 -25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 -2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 - 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 -25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.

9 CFR 113.3 - Sampling of biological products.

Code of Federal Regulations, 2013 CFR

2013-01-01

... bacterial vaccines; (iii) Two samples of Coccidiosis Vaccine; (iv) Eighteen samples of Rabies Vaccine...) Twenty-two single-dose or 14 multiple-dose samples of Rabies Vaccine, Killed Virus; (viii) Sixteen single...

9 CFR 113.3 - Sampling of biological products.

Code of Federal Regulations, 2014 CFR

2014-01-01

... bacterial vaccines; (iii) Two samples of Coccidiosis Vaccine; (iv) Eighteen samples of Rabies Vaccine...) Twenty-two single-dose or 14 multiple-dose samples of Rabies Vaccine, Killed Virus; (viii) Sixteen single...

9 CFR 113.3 - Sampling of biological products.

Code of Federal Regulations, 2012 CFR

2012-01-01

... bacterial vaccines; (iii) Two samples of Coccidiosis Vaccine; (iv) Eighteen samples of Rabies Vaccine...) Twenty-two single-dose or 14 multiple-dose samples of Rabies Vaccine, Killed Virus; (viii) Sixteen single...

Optimization-based image reconstruction from sparse-view data in offset-detector CBCT

NASA Astrophysics Data System (ADS)

Bian, Junguo; Wang, Jiong; Han, Xiao; Sidky, Emil Y.; Shao, Lingxiong; Pan, Xiaochuan

2013-01-01

The field of view (FOV) of a cone-beam computed tomography (CBCT) unit in a single-photon emission computed tomography (SPECT)/CBCT system can be increased by offsetting the CBCT detector. Analytic-based algorithms have been developed for image reconstruction from data collected at a large number of densely sampled views in offset-detector CBCT. However, the radiation dose involved in a large number of projections can be of a health concern to the imaged subject. CBCT-imaging dose can be reduced by lowering the number of projections. As analytic-based algorithms are unlikely to reconstruct accurate images from sparse-view data, we investigate and characterize in the work optimization-based algorithms, including an adaptive steepest descent-weighted projection onto convex sets (ASD-WPOCS) algorithms, for image reconstruction from sparse-view data collected in offset-detector CBCT. Using simulated data and real data collected from a physical pelvis phantom and patient, we verify and characterize properties of the algorithms under study. Results of our study suggest that optimization-based algorithms such as ASD-WPOCS may be developed for yielding images of potential utility from a number of projections substantially smaller than those used currently in clinical SPECT/CBCT imaging, thus leading to a dose reduction in CBCT imaging.

A new fully human recombinant FSH (follitropin epsilon): two phase I randomized placebo and comparator-controlled pharmacokinetic and pharmacodynamic trials.

PubMed

Abd-Elaziz, Khalid; Duijkers, Ingrid; Stöckl, Lars; Dietrich, Bruno; Klipping, Christine; Eckert, Kelvin; Goletz, Steffen

2017-08-01

What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters. Recombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule. Both studies were randomized, placebo- and comparator-controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing. In the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or 150 IU once daily [QD], or 150 IU every other day [QAD], 10 subjects each) and 27 subjects received 150 IU Gonal-f, 150 IU Bravelle, or placebo for 7 days (11/10/6 subjects). Blood samples for measuring PK as well as PD parameters were collected systematically before, during and after dosing. Adverse events (AEs) and other relevant safety parameters were recorded. Data were summarized using descriptive statistics. The single- and multiple-dose PK parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) increased in a linear fashion with increasing dose levels of follitropin epsilon. Follitropin epsilon showed PK characteristics comparable to the comparators indicating that well established treatment schemes could be applied. There was a dose-response effect of single and multiple doses of follitropin epsilon on follicular growth, which was shown for the biomarker inhibin B as well as for the mean number and size of follicles. Multiple doses of 75 IU follitropin epsilon given daily, as well as 150 IU follitropin epsilon every second day, showed a follicle growth comparable with 150 IU Gonal-f given daily, while in case of daily administration of 150 IU Bravelle only weak follicle stimulation was observed. Multiple doses of 150 IU follitropin epsilon induced a much higher follicle growth compared to the same dose of Gonal-f. All single and multiple follitropin epsilon doses tested were safe and well tolerated, and overall there were no relevant differences between follitropin epsilon and the comparators in terms of safety. The average number of AEs increased with increasing dose levels. No clinically relevant abnormalities were reported for any of the other safety parameters assessed. No follitropin epsilon anti-drug antibodies were observed. The studies were conducted as a single-blind design. Hormone levels or other parameters assessed in serum are generally not considered as being subject to bias. Other assessments directly performed by the investigators, such as transvaginal ultrasound assessments, may have been subject to personal bias. No prospective calculations of statistical power had been made, as is common practice for first in human and early phase I studies in healthy volunteers. These early development studies showed that follitropin epsilon exhibits comparable PK characteristics, as well as inducing stronger PD effects in terms of follicle growth and serum inhibin B, than the comparators. Follitropin epsilon induced a dose-dependent increase in follicular growth. The results warrant further studies with this new fully human recombinant FSH. The studies were sponsored by GLYCOTOPE GmbH, Berlin, Germany. K.A-E. is an employee of QPS-Netherlands, B.V., which received funding for the studies from Glycotope GmbH; I.D. and C.K. are employees of Dinox B.V., which received funding for the studies from Glycotope GmbH; L.S. and S.G. are employees and shareholders of Glycotope GmbH; B.D. and K.E. are employees of Glycotope GmbH. www.clinicaltrials.gov: NCT01354886 (single-dose); NCT01477073 (multiple-dose). The single-dose trial was registered on 11 May 2011 while the multiple-dose trial was registered on 09 November 2011. First subject was enroled in the single-dose trial in 27 April 2011 and in the multiple-dose trial in 02 October 2011. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Comparison of image quality and radiation dose between split-filter dual-energy images and single-energy images in single-source abdominal CT.

PubMed

Euler, André; Obmann, Markus M; Szucs-Farkas, Zsolt; Mileto, Achille; Zaehringer, Caroline; Falkowski, Anna L; Winkel, David J; Marin, Daniele; Stieltjes, Bram; Krauss, Bernhard; Schindera, Sebastian T

2018-02-19

To compare image quality and radiation dose of abdominal split-filter dual-energy CT (SF-DECT) combined with monoenergetic imaging to single-energy CT (SECT) with automatic tube voltage selection (ATVS). Two-hundred single-source abdominal CT scans were performed as SECT with ATVS (n = 100) and SF-DECT (n = 100). SF-DECT scans were reconstructed and subdivided into composed images (SF-CI) and monoenergetic images at 55 keV (SF-MI). Objective and subjective image quality were compared among single-energy images (SEI), SF-CI and SF-MI. CNR and FOM were separately calculated for the liver (e.g. CNR liv ) and the portal vein (CNR pv ). Radiation dose was compared using size-specific dose estimate (SSDE). Results of the three groups were compared using non-parametric tests. Image noise of SF-CI was 18% lower compared to SEI and 48% lower compared to SF-MI (p < 0.001). Composed images yielded higher CNR liv over single-energy images (23.4 vs. 20.9; p < 0.001), whereas CNR pv was significantly lower (3.5 vs. 5.2; p < 0.001). Monoenergetic images overcame this inferiority in CNR pv and achieved similar results compared to single-energy images (5.1 vs. 5.2; p > 0.628). Subjective sharpness was equal between single-energy and monoenergetic images and diagnostic confidence was equal between single-energy and composed images. FOM liv was highest for SF-CI. FOM pv was equal for SEI and SF-MI (p = 0.78). SSDE was significant lower for SF-DECT compared to SECT (p < 0.022). The combined use of split-filter dual-energy CT images provides comparable objective and subjective image quality at lower radiation dose compared to single-energy CT with ATVS. • Split-filter dual-energy results in 18% lower noise compared to single-energy with ATVS. • Split-filter dual-energy results in 11% lower SSDE compared to single-energy with ATVS. • Spectral shaping of split-filter dual-energy leads to an increased dose-efficiency.

Dose-finding design for multi-drug combinations

PubMed Central

Wages, Nolan A; Conaway, Mark R; O'Quigley, John

2012-01-01

Background Most of the current designs used for Phase I dose finding trials in oncology will either involve only a single cytotoxic agent or will impose some implicit ordering among the doses. The goal of the studies is to estimate the maximum tolerated dose (MTD), the highest dose that can be administered with an acceptable level of toxicity. A key working assumption of these methods is the monotonicity of the dose–toxicity curve. Purpose Here we consider situations in which the monotonicity assumption may fail. These studies are becoming increasingly common in practice, most notably, in phase I trials that involve combinations of agents. Our focus is on studies where there exist pairs of treatment combinations for which the ordering of the probabilities of a dose-limiting toxicity cannot be known a priori. Methods We describe a new dose-finding design which can be used for multiple-drug trials and can be applied to this kind of problem. Our methods proceed by laying out all possible orderings of toxicity probabilities that are consistent with the known orderings among treatment combinations and allowing the continual reassessment method (CRM) to provide efficient estimates of the MTD within these orders. The design can be seen to simplify to the CRM when the full ordering is known. Results We study the properties of the design via simulations that provide comparisons to the Bayesian approach to partial orders (POCRM) of Wages, Conaway, and O'Quigley. The POCRM was shown to perform well when compared to other suggested methods for partial orders. Therefore, we comapre our approach to it in order to assess the performance of the new design. Limitations A limitation concerns the number of possible orders. There are dose-finding studies with combinations of agents that can lead to a large number of possible orders. In this case, it may not be feasible to work with all possible orders. Conclusions The proposed design demonstrates the ability to effectively estimate MTD combinations in partially ordered dosefinding studies. Because it relaxes the monotonicity assumption, it can be considered a multivariate generalization of the CRM. Hence, it can serve as a link between single and multiple-agent dosefinding trials. PMID:21652689

Oral and Inactivated Poliovirus Vaccines in the Newborn: A review

PubMed Central

Mateen, Farrah J.; Shinohara, Russell T.; Sutter, Roland W.

2015-01-01

Background Oral poliovirus vaccine (OPV) remains the vaccine-of-choice for routine immunization and supplemental immunization activities (SIAs) to eradicate poliomyelitis globally. Recent data from India suggested lowerthanexpected immunogenicity of an OPV birth dose, prompting a review of the immunogenicity of OPV or inactivated poliovirus vaccine (IPV) when administered at birth. Methods We evaluated the seroconversion and reported adverse events among infants given a single birth dose (given ≤7 days of life) of OPV or IPV through a systematic review of published articles and conference abstracts from 1959-2011 in any language found on PubMed, Google Scholar, or reference lists of selected articles. Results 25 articles from 13 countries published between1959 and 2011 documented seroconversion rates in newborns following an OPV dose given within the first seven days of life. There were 10 studies that measured seroconversion rates between 4 and 8 weeks of a single birth dose of TOPV, using an umbilical cord blood draw at the time of birth to establish baseline antibody levels. The percentage of newborns who seroconverted at 8 weeks range 6-42% for poliovirus type 1, 2-63% for type 2, and 1-35% for type 3). For mOPV type 1, seroconversion ranged from 10-76%; mOPV type 3, the range was 12-58%; and for the one study reporting bOPV, it was 20% for type 1 and 7% for type 3. There were four studies of IPV in newborns with a seroconversion rate of 8-100% for serotype 1, 15-100% for serotype 2, and 15-94% for serotype 3, measured at 4-6 weeks of life. No serious adverse events related to newborn OPV or IPV dosing were reported, including no cases of acute flaccid paralysis. Conclusions There is great variability of the immunogenicity of a birth dose of OPV for reasons largely unknown. Our review confirms the utility of a birth dose of OPV, particularly in countries where early induction of polio immunity is imperative. IPV has higher seroconversion rates in newborns and may be a superior choice in countries which can afford IPV, but there have been studies of an IPV dose for newborns. PMID:22728224

Pharmacologic Treatment Reduces Pressure Times Time Dose and Relative Duration of Intracranial Hypertension.

PubMed

Colton, Katharine; Yang, S; Hu, P F; Chen, H H; Bonds, B; Stansbury, L G; Scalea, T M; Stein, D M

2016-05-01

Past work has shown the importance of the "pressure times time dose" (PTD) of intracranial hypertension (intracranial pressure [ICP] > 19 mm Hg) in predicting outcome after severe traumatic brain injury. We used automated data collection to measure the effect of common medications on the duration and dose of intracranial hypertension. Patients >17 years old, admitted and requiring ICP monitoring between 2008 and 2010 at a single, large urban tertiary care facility, were retrospectively enrolled. Timing and dose of ICP-directed therapy were recorded from paper and electronic medical records. The ICP data were collected automatically at 6-second intervals and averaged over 5 minutes. The percentage of time of intracranial hypertension (PTI) and PTD (mm Hg h) were calculated. A total of 98 patients with 664 treatment instances were identified. Baseline PTD ranged from 27 (before administration of propofol and fentanyl) to 150 mm Hg h (before mannitol). A "small" dose of hypertonic saline (HTS; ≤250 mL 3%) reduced PTD by 38% in the first hour and 37% in the second hour and reduced the time with ICP >19 by 38% and 39% after 1 and 2 hours, respectively. A "large" dose of HTS reduced PTD by 40% in the first hour and 63% in the second (PTI reduction of 36% and 50%, respectively). An increased dose of propofol or fentanyl infusion failed to decrease PTD but reduced PTI between 14% (propofol alone) and 30% (combined increase in propofol and fentanyl, after 2 hours). Barbiturates failed to decrease PTD but decreased PTI by 30% up to 2 hours after administration. All reductions reported are significantly changed from baseline, P < .05. Baseline PTD values before drug administration reflects varied patient criticality, with much higher values seen before the use of mannitol or barbiturates. Treatment with HTS reduced PTD and PTI burden significantly more than escalation of sedation or pain management, and this effect remained significant at 2 hours after administration. © The Author(s) 2014.

Brachytherapy dosimetry of 125I and 103Pd sources using an updated cross section library for the MCNP Monte Carlo transport code.

PubMed

Bohm, Tim D; DeLuca, Paul M; DeWerd, Larry A

2003-04-01

Permanent implantation of low energy (20-40 keV) photon emitting radioactive seeds to treat prostate cancer is an important treatment option for patients. In order to produce accurate implant brachytherapy treatment plans, the dosimetry of a single source must be well characterized. Monte Carlo based transport calculations can be used for source characterization, but must have up to date cross section libraries to produce accurate dosimetry results. This work benchmarks the MCNP code and its photon cross section library for low energy photon brachytherapy applications. In particular, we calculate the emitted photon spectrum, air kerma, depth dose in water, and radial dose function for both 125I and 103Pd based seeds and compare to other published results. Our results show that MCNP's cross section library differs from recent data primarily in the photoelectric cross section for low energies and low atomic number materials. In water, differences as large as 10% in the photoelectric cross section and 6% in the total cross section occur at 125I and 103Pd photon energies. This leads to differences in the dose rate constant of 3% and 5%, and differences as large as 18% and 20% in the radial dose function for the 125I and 103Pd based seeds, respectively. Using a partially updated photon library, calculations of the dose rate constant and radial dose function agree with other published results. Further, the use of the updated photon library allows us to verify air kerma and depth dose in water calculations performed using MCNP's perturbation feature to simulate updated cross sections. We conclude that in order to most effectively use MCNP for low energy photon brachytherapy applications, we must update its cross section library. Following this update, the MCNP code system will be a very effective tool for low energy photon brachytherapy dosimetry applications.

Investigation of intracranial peripheral dose arising from the treatment of large lesions with Leksell GammaKnife Perfexion.

PubMed

Ruschin, Mark; Nordström, Håkan; Kjäll, Per; Cho, Young-Bin; Jaffray, David

2009-06-01

This investigation involves quantifying the extent of intracranial peripheral dose arising from simulated targets situated in the skull-base or upper-spine region using the Leksell GammaKnife Perfexion treatment unit. For each of three spherical target volumes--denoted as Vs (4 cm3), VM (18 cm3), and VL (60 cm3)--three treatment plans were manually generated, one for each of the three collimator sizes--4, 8, and 16 mm. Each of the plans was delivered to a spherical dosimetry phantom with an insert containing EBT Gafchromic film. The total dose at 70 mm from the targets' edges, %D(70 mm), was measured as a function of elevation angle and expressed as a percentage of the prescription dose. The film insert was placed centered in the median sagittal plane (Leksell X = 100) and %D(70 mm) was measured for the angular range from 0 degree (superior/along Z axis) to 90 degrees (anterior/along Y axis). For a given collimator i, the irradiation time ti to treat a spherical target of volume V using the 50% isodose line was observed to follow a power-law relationship of the form ti = Ai(V/ Vi)n where Ai was the maximum dose divided by collimator dose rate and Vi was the volume encompassed by the 50% isodose line for a single shot. The mean value of n was 0.61 (range: 0.61-0.62). Along the superior (Z) direction (angle=0 degree) and up to angles of around 30 degrees, the %D(70 mm) was always highest for the 4 mm plans, followed by the 8 mm, followed by the 16 mm. In this angular range, the maximum measured %D(70 mm) was 1.7% of the prescription dose. The intracranial peripheral dose along the superior direction (combined scatter and leakage dose) resulting from irradiation of upper-spine or base-of-skull lesions is measured to be less than 2% of the prescription dose, even for very large (60 cm3) targets. The results of this study indicate that, for a given target volume, treatment plans consisting of only 4 mm shots yield larger peripheral dose in the superior direction than 8 mm shot only plans, which in turn yield larger peripheral dose than 16 mm shot only plans.

WE-AB-BRB-08: Progress Towards a 2D OSL Dosimetry System Using Al2O3:C Films

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahmed, M F; Yukihara, E; Schnell, E

Purpose: To develop a 2D dosimetry system based on the optically stimulated luminescence (OSL) of Al{sub 2}O{sub 3}:C films for medical applications. Methods: A 2D laser scanning OSL reader was built for readout of newly developed Al2O3:C films (Landauer Inc.). An image reconstruction algorithm was developed to correct for inherent effects introduced by reader design and detector properties. The system was tested using irradiations with photon and carbon ion beams. A calibration was obtained using a 6 MV photon beam from clinical accelerator and the dose measurement precision was tested using a range of doses and different dose distributions (flatmore » field and wedge field). The dynamic range and performance of the system in the presence of large dose gradients was also tested using 430 MeV/u {sup 12}C single and multiple pencil beams. All irradiations were performed with Gafchromic EBT3 film for comparison. Results: Preliminary results demonstrate a near-linear OSL dose response to photon fields and the ability to measure dose in dose distributions such as flat field and wedge field. Tests using {sup 12}C pencil beam demonstrate ability to measure doses over four orders of magnitude. The dose profiles measured by the OSL film generally agreed well with that measured by the EBT3 film. The OSL image signal-to-noise ratio obtained in the current conditions require further improvement. On the other hand, EBT3 films had large uncertainties in the low dose region due to film-to-film or intra-film variation in the background. Conclusion: A 2D OSL dosimetry system was developed and initial tests have demonstrated a wide dynamic range as well as good agreement between the delivered and measured doses. The low background, wide dynamic range and wide range of linearity in dose response observed for the Al{sub 2}O{sub 3}:C OSL film can be beneficial for dosimetry in radiation therapy applications, especially for small field dosimetry. This work has been funded by Landauer Inc. Dr. Eduardo G. Yukihara also would like to thank the Alexander von Humboldt Foundation for his support at the DKFZ.« less

Fosfomycin trometamol: a review of its use as a single-dose oral treatment for patients with acute lower urinary tract infections and pregnant women with asymptomatic bacteriuria.

PubMed

Keating, Gillian M

2013-11-01

Fosfomycin trometamol (fosfomycin tromethamine) [Monuril(®), Monurol(®), Monural(®)] is approved in numerous countries worldwide, mainly for the treatment of uncomplicated urinary tract infections (UTIs). Fosfomycin has good in vitro activity against common uropathogens, such as Escherichia coli (including extended-spectrum β-lactamase-producing E. coli), Proteus mirabilis, Klebsiella pneumoniae and Staphylococcus saprophyticus, and the susceptibility of uropathogens to fosfomycin has remained relatively stable over time. A single oral dose of fosfomycin trometamol 3 g (the approved dosage) achieves high concentrations in urine. Results of recent randomized trials indicate that single-dose fosfomycin trometamol had similar clinical and/or bacteriological efficacy to 3- to 7-day regimens of ciprofloxacin, norfloxacin, cotrimoxazole or nitrofurantoin in women with uncomplicated lower UTIs. In addition, single-dose fosfomycin trometamol had similar bacteriological efficacy to a 5-day course of cefuroxime axetil or a 7-day course of amoxicillin/clavulanic acid in pregnant women with asymptomatic bacteriuria, and similar clinical and/or bacteriological efficacy to a 5-day course of cefuroxime axetil or amoxicillin/clavulanic acid or a 3-day course of ceftibuten in pregnant women with a lower UTI. Single-dose fosfomycin trometamol was generally well tolerated, with gastrointestinal adverse events (e.g. diarrhoea, nausea) reported most commonly. In conclusion, single-dose fosfomycin trometamol is an important option for the first-line empirical treatment of uncomplicated lower UTIs.

Vaxchora: A Single-Dose Oral Cholera Vaccine.

PubMed

Cabrera, Adriana; Lepage, Jayne E; Sullivan, Karyn M; Seed, Sheila M

2017-07-01

To review trials evaluating the efficacy and safety of Vaxchora, a reformulated, single-dose, oral, lyophilized Vibrio cholerae CVD 103-HgR vaccine for the prevention of travel-related cholera caused by V cholerae serogroup O1. A literature search was conducted using MEDLINE (1946 to January week 3, 2017) and EMBASE (1996 to 2017 week 3). Keywords included oral cholera vaccine, single-dose, Vaxchora, and CVD 103-HgR. Limits included human, clinical trials published in English since 2010. ClinicalTrials.gov was used as a source for unpublished data. Additional data sources were obtained through bibliographic review of selected articles. Studies that addressed the safety and efficacy of Vaxchora, the reformulated, single-dose oral CVD 103-HgR cholera vaccine, were selected for analysis. Approval of Vaxchora, was based on efficacy of the vaccine in human trials demonstrating 90.3% protection among those challenged with V cholerae 10 days after vaccination and in immunogenicity studies with 90% systemic vibriocidal antibody conversion at 6 months after a single-dose of vaccine. Tolerability was acceptable, with the most common adverse effects reported to be fatigue, headache, and abdominal pain. Vaxchora is the only FDA-approved, single-dose oral vaccine for the prevention of cholera caused by V cholerae serogroup O1 in adult travelers from the United States going to cholera-affected areas. Safety and efficacy has not been established in children, immunocompromised persons, and pregnant or breastfeeding women or those living in cholera-endemic areas.

Efficacy and Safety of a Single-Pill Fixed-Dose Combination of Azilsartan and Amlodipine

PubMed Central

Motozato, Kota; Miura, Shin-ichiro; Shiga, Yuhei; Kusumoto, Takaaki; Saku, Keijiro

2016-01-01

Background Guidelines for the management of hypertension recommend the use of drugs with different mechanisms of action in antihypertensive regimens that include single-pill fixed-dose combinations of medications. There is some controversy regarding which single-pill fixed-dose combinations of angiotensin II type 1 receptor blockers (ARBs) and calcium channel blockers (CCBs) are effective at reducing blood pressure (BP). Methods Forty hypertensive patients who were receiving a single-pill fixed-dose combination of valsartan 80 mg/day and amlodipine 5 mg/day or irbesartan 100 mg/day and amlodipine 5 mg/day were enrolled. They were randomly divided into two treatment groups, a group that changed to a single-pill fixed-dose combination of azilsartan 20 mg/day and amlodipine 5 mg/day (changeover group) and a group that continued to receive valsartan 80 mg/day and amlodipine 5 mg/day or irbesartan 100 mg/day and amlodipine 5 mg/day (control group), and treated for 16 weeks. Results There were no significant differences in systolic blood pressure (SBP), diastolic blood pressure (DBP) or pulse rate (PR) at 16 weeks between the control and changeover groups. In addition, there were no significant changes in biochemical parameters throughout the study period in both groups. Conclusion The ability of a single-pill fixed-dose combination of azilsartan and amlodipine to reduce BP may be comparable to that of a combination of valsartan and amlodipine or irbesartan and amlodipine. PMID:27829955

Environmental standards for ionizing radiation: theoretical basis for dose-response curves.

PubMed Central

Upton, A C

1983-01-01

The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell. PMID:6653536

Eye doses to staff in a nuclear medicine department.

PubMed

Summers, Elizabeth C; Brown, Janis L E; Bownes, Peter J; Anderson, Shona E

2012-05-01

Occupational radiation doses to the Nuclear Medicine Department staff at Mount Vernon Hospital are routinely measured using optically stimulated luminescence dosemeters for whole-body effective dose and ring thermoluminescence dosemeters (TLDs) for finger dose. In 2002, a project was carried out using LiF:Mg,Cu,P Chinese TLDs to measure the dose to the lens of the eye received by staff during normal working procedures. Separate pairs of TLDs were worn by staff on their forehead between their eyes while dispensing and releasing in the radiopharmacy, injecting, and when administering I-131 capsules to patients. The dose received was calculated using calibration data from identical TLDs irradiated with Tc-99m, I-131, and the Ir-192 source of a Gammamed High Dose Rate (HDR) treatment unit. Data were collected over a 5-month period and the mean dose to the eye was calculated for each procedure. Using a typical yearly workload, the annual dose to the eye for a single member of staff was calculated and found to be 4.5 mSv. The occupational eye dose limit was, at the time, 150 mSv; therefore, staff were well below the level (3/10th of this limit) that would have required them to be classified. However, there have been large increases in radiopharmacy production and I-131 therapies administered at Mount Vernon in subsequent years. It is therefore expected that the eye dose received by staff will have increased to be significantly higher than 4.5 mSv and will in fact be greater than 6 mSv, which is 3/10th of the proposed new dose limit and would require these staff to become classified workers.

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

PubMed

Gonçalves, Daniela; Alves, Gilberto; Fortuna, Ana; Soares-da-Silva, Patrício; Falcão, Amílcar

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 90mg/kg) or multiple (30mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24h 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≤2h) 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 (30-90mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58-4.50h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen. Copyright © 2017 Elsevier Inc. All rights reserved.

Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies.

PubMed

Cirik, Derya Akdag; Kinay, Tugba; Keskin, Ugur; Ozden, Eda; Altay, Metin; Gelisen, Orhan

2016-04-01

To compare the success of the single-dose methotrexate regimen and the requirement for a second or third dose of methotrexate between women with their first ectopic pregnancy (EP) and those with previous EP. In a retrospective cohort study, data were analyzed from women treated for EP by single-dose methotrexate at a Turkish tertiary referral center between January 2010 and December 2013. Data were compared between women with at least one previous EP and those with their first EP. The success rate of the protocol in the first and previous EP groups was similar: 93.0% (320/344) and 87.3% (48/55), respectively. History of previous EP was not a predictor of treatment failure. However, the requirement for additional methotrexate doses was significantly higher in the previous EP group (16/48 [33.4%]) than in the first EP group (55/320 [17.2%]; P=0.03). Multivariate analysis showed that history of tubal surgery (P=0.006) and initial levels of the β-subunit of human chorionic gonadotropin (P=0.001) were significant predictors of treatment failure. Although the single-dose regimen had similar success rates in the previous EP and first EP groups, additional doses of methotrexate were more frequently required in the previous EP group. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Online 3D EPID-based dose verification: Proof of concept

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spreeuw, Hanno; Rozendaal, Roel, E-mail: r.rozenda

Purpose: Delivery errors during radiotherapy may lead to medical harm and reduced life expectancy for patients. Such serious incidents can be avoided by performing dose verification online, i.e., while the patient is being irradiated, creating the possibility of halting the linac in case of a large overdosage or underdosage. The offline EPID-based 3D in vivo dosimetry system clinically employed at our institute is in principle suited for online treatment verification, provided the system is able to complete 3D dose reconstruction and verification within 420 ms, the present acquisition time of a single EPID frame. It is the aim of thismore » study to show that our EPID-based dosimetry system can be made fast enough to achieve online 3D in vivo dose verification. Methods: The current dose verification system was sped up in two ways. First, a new software package was developed to perform all computations that are not dependent on portal image acquisition separately, thus removing the need for doing these calculations in real time. Second, the 3D dose reconstruction algorithm was sped up via a new, multithreaded implementation. Dose verification was implemented by comparing planned with reconstructed 3D dose distributions delivered to two regions in a patient: the target volume and the nontarget volume receiving at least 10 cGy. In both volumes, the mean dose is compared, while in the nontarget volume, the near-maximum dose (D2) is compared as well. The real-time dosimetry system was tested by irradiating an anthropomorphic phantom with three VMAT plans: a 6 MV head-and-neck treatment plan, a 10 MV rectum treatment plan, and a 10 MV prostate treatment plan. In all plans, two types of serious delivery errors were introduced. The functionality of automatically halting the linac was also implemented and tested. Results: The precomputation time per treatment was ∼180 s/treatment arc, depending on gantry angle resolution. The complete processing of a single portal frame, including dose verification, took 266 ± 11 ms on a dual octocore Intel Xeon E5-2630 CPU running at 2.40 GHz. The introduced delivery errors were detected after 5–10 s irradiation time. Conclusions: A prototype online 3D dose verification tool using portal imaging has been developed and successfully tested for two different kinds of gross delivery errors. Thus, online 3D dose verification has been technologically achieved.« less

Single-dose lubiprostone along with split-dose PEG solution without dietary restrictions for bowel cleansing prior to colonoscopy: a randomized, double-blind, placebo-controlled trial.

PubMed

Stengel, Joel Z; Jones, David P

2008-09-01

Proper colonic cleansing prior to colonoscopy is paramount to ensuring complete mucosal visualization and polyp identification. In a double-blind fashion, we compared single-dose lubiprostone (24 microg) versus placebo pretreatment prior to a split-dose polyethylene glycol electrolyte (PEG-E) bowel preparation without dietary restriction to determine the efficacy, safety, and patient tolerability. Two hundred patients referred for outpatient colorectal cancer screening were randomized to receive a single-dose of unlabeled lubiprostone (24 microg) or placebo prior to a split-dose PEG-E bowel preparation without dietary restriction. The patients were surveyed prior to the colonoscopy on the tolerability of the bowel preparation, and any adverse events were recorded. The cleanliness of the colon was graded by the endoscopist during the procedure utilizing the Ottawa bowel preparation scale. One hundred ninety-one patients completed the study (95%). Split-dose PEG-E with lubiprostone pretreatment was found to be more effective at bowel cleansing in each segment of the colon when compared with split-dose PEG-E with placebo (P < 0.001). Patients enrolled in the lubiprostone treatment arm rated the overall experience as more tolerable (P 0.003) and complained of less abdominal bloating (P 0.049). No differences were observed between the groups for treatment-emergent side effects or adverse events (P > 0.05). Single-dose lubiprostone prior to split-dose PEG-E without dietary restriction significantly improves colonic mucosa visualization during colonoscopy and is well tolerated by patients.

Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects.

PubMed

Akahori, Mizuki; Ayalasomayajula, Surya; Langenickel, Thomas; Pal, Parasar; Zhou, Wei; Sunkara, Gangadhar

2017-06-01

LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failure patients with reduced ejection fraction and approved in the US, Europe, and many other countries. This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receiving LCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.

Duration of treatment for asymptomatic bacteriuria during pregnancy.

PubMed

Villar, J; Lydon-Rochelle, M T; Gülmezoglu, A M; Roganti, A

2000-01-01

A Cochrane systematic review has shown that drug treatment of asymptomatic bacteriuria in pregnant women substantially decreases the risk of pyelonephritis and reduces the risk of preterm delivery. However, it is not clear whether single dose therapy is as effective as longer conventional antibiotic treatment. The objective of this review was to assess the effects of different durations of treatment for asymptomatic bacteriuria in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register and the reference lists of articles. Randomised and quasi-randomised trials comparing antimicrobial therapeutic regimens that differed in duration (particularly comparing single dose with longer duration regimens) in pregnant women diagnosed with asymptomatic bacteriuria. Trial quality was assessed and data were extracted independently by the reviewers. Eight studies involving over 400 women were included. All were comparisons of single dose treatment with four to seven day treatments. The trials were generally of poor quality. No difference in 'no-cure' rate was detected between single dose and short course (4-7 day) treatment for asymptomatic bacteriuria in pregnant women (relative risk 1.13, 95% confidence interval 0.82 to 1.54) as well as in the recurrent asymptomtic bacteriuria (relative risk 1.08, 95% confidence interval 0.70 to 1.66). However these results showed significant heterogeneity. No differences were detected for preterm births and pyelonephritis although sample size of trials was small. Longer duration treatment was associated with an increase in reports of adverse effects (relative risk 0.53, 95% confidence interval 0.31 to 0.91). There is not enough evidence to evaluate whether single dose or longer duration doses are more effective in treating asymptomatic bacteriuria in pregnant women. Because single dose has lower cost and increases compliance, this comparison should be explored in a properly sized randomized controlled trial.

Estimation of background radiation doses for the Peninsular Malaysia's population by ESR dosimetry of tooth enamel.

PubMed

Rodzi, Mohd; Zhumadilov, Kassym; Ohtaki, Megu; Ivannikov, Alexander; Bhattacharjee, Deborshi; Fukumura, Akifumi; Hoshi, Masaharu

2011-08-01

Background radiation dose is used in dosimetry for estimating occupational doses of radiation workers or determining radiation dose of an individual following accidental exposure. In the present study, the absorbed dose and the background radiation level are determined using the electron spin resonance (ESR) method on tooth samples. The effect of using different tooth surfaces and teeth exposed with single medical X-rays on the absorbed dose are also evaluated. A total of 48 molars of position 6-8 were collected from 13 district hospitals in Peninsular Malaysia. Thirty-six teeth had not been exposed to any excessive radiation, and 12 teeth had been directly exposed to a single X-ray dose during medical treatment prior to extraction. There was no significant effect of tooth surfaces and exposure with single X-rays on the measured absorbed dose of an individual. The mean measured absorbed dose of the population is 34 ± 6.2 mGy, with an average tooth enamel age of 39 years. From the slope of a regression line, the estimated annual background dose for Peninsular Malaysia is 0.6 ± 0.3 mGy y(-1). This value is slightly lower than the yearly background dose for Malaysia, and the radiation background dose is established by ESR tooth measurements on samples from India and Russia.

Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.

PubMed

Scherz, Michael W; Brossard, Patrick; D'Ambrosio, Daniele; Ipek, Murat; Dingemanse, Jasper

2015-06-01

Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval. © 2015, The American College of Clinical Pharmacology.

Segmenting data sets for RIP.

PubMed

de Sanctis, Daniele; Nanao, Max H

2012-09-01

Specific radiation damage can be used for the phasing of macromolecular crystal structures. In practice, however, the optimization of the X-ray dose used to `burn' the crystal to induce specific damage can be difficult. Here, a method is presented in which a single large data set that has not been optimized in any way for radiation-damage-induced phasing (RIP) is segmented into multiple sub-data sets, which can then be used for RIP. The efficacy of this method is demonstrated using two model systems and two test systems. A method to improve the success of this type of phasing experiment by varying the composition of the two sub-data sets with respect to their separation by image number, and hence by absorbed dose, as well as their individual completeness is illustrated.

Clinical evaluation of rosoxacin for the treatment of chancroid.

PubMed Central

Haase, D A; Ndinya-Achola, J O; Nash, R A; D'Costa, L J; Hazlett, D; Lubwama, S; Nsanze, H; Ronald, A R

1986-01-01

One hundred seven men with Haemophilus ducreyi-positive chancroid were assigned to receive 300 mg of rosoxacin as a single dose or 150 mg twice daily for 3 days. Ulcers and buboes were followed clinically and bacteriologically for 1 month. Of 40 evaluable males on the 3-day regimen, 38 (95%) were cured, while only 14 of 23 (61%) males on the single-dose regimen were cured; this regimen was discontinued. There was one ulcer relapse at day 21 in both groups; the one relapse in the single-dose group had a persistent culture-positive bubo. Eight of nine (89%) buboes followed to the endpoint on the 3-day rosoxacin regimen were cured, versus three of six (50%) on the single-dose regimen. Adverse effects were mainly related to the central nervous system but were minor and did not require intervention. None of the treatment failures was due to organisms resistant to rosoxacin, and failure of the single-dose regimen presumably was related to duration of tissue levels rather than to drug resistance. Administration of 150 mg of rosoxacin twice daily for 3 days is an effective regimen for the therapy of chancroid and is a reasonable alternative to other short-course regimens. PMID:3489439

Single-dose radiation therapy for prevention of heterotopic ossification after total hip arthroplasty

DOE Office of Scientific and Technical Information (OSTI.GOV)

Healy, W.L.; Lo, T.C.; Covall, D.J.

1990-12-01

Single-dose radiation therapy was prospectively evaluated for its efficacy in prevention of heterotopic ossification in patients at high risk after total hip arthroplasty. Thirty-one patients (34 hips) were treated between 1981 and 1988. Risk factors for inclusion in the protocol included prior evidence of heterotopic ossification, ankylosing spondylitis, and diffuse idiopathic skeletal hyperostosis. Patients with hypertrophic osteoarthritis or traumatic arthritis with osteophytes were not included. Operations on 34 hips included 19 primary total and 11 revision total hip arthroplasties and 4 excisions of heterotopic ossification. All patients received radiotherapy to the hip after operation with a single dose of 700more » centigray. Radiotherapy is recommended on the first postoperative day. After this single-dose radiation treatment, no patient had clinically significant heterotopic ossification. Recurrent disease developed in two hips (6%), as seen on radiography (grades 2 and 3). This series documents a 100% clinical success rate and a 94% radiographic success rate in preventing heterotopic ossification in patients at high risk after total hip arthroplasty. Single-dose radiotherapy is as effective as other radiation protocols in preventing heterotopic ossification after total hip arthroplasty. It is less expensive and easier to administer than multidose radiotherapy.« less

First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors.

PubMed

Hidalgo, Manuel; Martinez-Garcia, Maria; Le Tourneau, Christophe; Massard, Christophe; Garralda, Elena; Boni, Valentina; Taus, Alvaro; Albanell, Joan; Sablin, Marie-Paule; Alt, Marie; Bahleda, Ratislav; Varga, Andrea; Boetsch, Christophe; Franjkovic, Izolda; Heil, Florian; Lahr, Angelika; Lechner, Katharina; Morel, Anthony; Nayak, Tapan; Rossomanno, Simona; Smart, Kevin; Stubenrauch, Kay; Krieter, Oliver

2018-04-01

Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating biweekly (3-30 mg/kg) or weekly (10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in K TRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation. Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536-45. ©2017 AACR . ©2017 American Association for Cancer Research.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sudhyadhom, A; McGuinness, C; Descovich, M

Purpose: To develop a methodology for validation of a Monte-Carlo dose calculation model for robotic small field SRS/SBRT deliveries. Methods: In a robotic treatment planning system, a Monte-Carlo model was iteratively optimized to match with beam data. A two-part analysis was developed to verify this model. 1) The Monte-Carlo model was validated in a simulated water phantom versus a Ray-Tracing calculation on a single beam collimator-by-collimator calculation. 2) The Monte-Carlo model was validated to be accurate in the most challenging situation, lung, by acquiring in-phantom measurements. A plan was created and delivered in a CIRS lung phantom with film insert.more » Separately, plans were delivered in an in-house created lung phantom with a PinPoint chamber insert within a lung simulating material. For medium to large collimator sizes, a single beam was delivered to the phantom. For small size collimators (10, 12.5, and 15mm), a robotically delivered plan was created to generate a uniform dose field of irradiation over a 2×2cm{sup 2} area. Results: Dose differences in simulated water between Ray-Tracing and Monte-Carlo were all within 1% at dmax and deeper. Maximum dose differences occurred prior to dmax but were all within 3%. Film measurements in a lung phantom show high correspondence of over 95% gamma at the 2%/2mm level for Monte-Carlo. Ion chamber measurements for collimator sizes of 12.5mm and above were within 3% of Monte-Carlo calculated values. Uniform irradiation involving the 10mm collimator resulted in a dose difference of ∼8% for both Monte-Carlo and Ray-Tracing indicating that there may be limitations with the dose calculation. Conclusion: We have developed a methodology to validate a Monte-Carlo model by verifying that it matches in water and, separately, that it corresponds well in lung simulating materials. The Monte-Carlo model and algorithm tested may have more limited accuracy for 10mm fields and smaller.« less

Pharmacokinetic Properties and Tolerability of Cycloserine Following Oral Administration in Healthy Chinese Volunteers: A Randomized, Open-Label, Single- and Multiple-Dose 3-Way Crossover Study.

PubMed

Zhou, Huili; Wu, Guolan; Hu, Xingjiang; Zhu, Meixiang; Zhai, You; Liu, Jian; Shentu, Jianzhong; Wu, Lihua

2015-06-01

A new generic formulation of cycloserine has been developed in China but the pharmacokinetic properties of cycloserine in the Chinese population have not been reported. The aim of our study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of cycloserine capsules in healthy Chinese volunteers. This open-label, single- and multiple-dose 3-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of cycloserine (250, 500, or 1000 mg) in separate trial periods, with a 1-week washout between periods. Those allocated to the 250-mg dose continued into the multiple-dose phase, in which they received 250 mg BID for 5 consecutive days. During the single-dose phase, blood samples were collected at regular intervals from 0 to 72 hours after drug administration and the concentrations of cycloserine were determined using LC-MS/MS. During the multiple-dose phase, blood samples were obtained before drug administration on Days 4, 5, and 6 to determine the Cmin at steady state. On Day 6, blood samples were also collected from 0 to 72 hours after drug administration. Pharmacokinetic parameters were estimated using noncompartmental methods. Tolerability was determined using clinical evaluation and monitoring of adverse events. The study enrolled 12 healthy Chinese volunteers (6 men: mean [SD] age = 23.0 [2.6] years, weight = 60.2 [6.2] kg, height = 170.0 [3.0] cm, and body mass index = 20.7 [1.7]; 6 women: mean [SD] age = 25.3 [1.4] years, weight = 51.5 [3.3] kg, height = 160.0 [4.0] cm, and body mass index = 20.1 [0.9]). After administration of a single dose, cycloserine was rapidly absorbed, reaching peak plasma concentrations approximately 0.84 hours after oral administration, and t½ in plasma was about 13.0 hours. The geometric mean (SD) Cmax value increased in proportion to cycloserine dose, from 19.42 (5.89) to 84.76 (21.74) mg/L, and the geometric mean (SD) AUC0-72h value increased from 264.16 (133.37) to 1153.87 (522.16) mg·h/L in the range of a 250- to 1000-mg dose. After administration of multiple doses of cycloserine 250 mg BID, the mean (SD) t½ was 13.56 (4.38) hours, the apparent total clearance of the drug from plasma after oral administration was 1.02 (0.42) L/h, and the apparent volume of distribution was 18.22 (5.25) L, which were comparable with those after single dosing. The accumulation index was 2.19 (0.51), and the fluctuation was 1.05 (0.35). Results of the t tests of Cmax and AUC found no significant differences between the male and female groups. No serious adverse events were reported, and there were no discontinuations due to adverse events. The pharmacokinetic properties of cycloserine were linear at doses from 250 mg to 1000 mg. After multiple doses, the pharmacokinetic properties of cycloserine were consistent with those after single doses. At the doses studied, cycloserine appears to be well tolerated in these healthy volunteers. Chinese Clinical Trials registration: ChiCTR-TTRCC-13003982. Copyright © 2015. Published by Elsevier Inc.

Single-dose pharmacokinetic properties of esomeprazole in children aged 1 - 11 years with endoscopically proven GERD: a randomized, open-label study.

PubMed

Youssef, Nader N; Tron, Eduardo; Tolia, Vasundhara; Hamer-Maansson, Jennifer E; Lundborg, Per; Illueca, Marta

2014-11-01

To assess the overall exposure after a single dose of esomeprazole in children with gastroesophageal reflux disease (GERD). Oral esomeprazole administered as an intact capsule with 30 - 180 mL of water, or as an opened capsule mixed with as much as 1 tablespoon of applesauce followed by 30 - 180 mL of water. In this randomized, open-label study of children aged 1 - 11 years with endoscopically proven GERD, patients weighing 8 - < 20 kg were randomized to a single 5- or 10-mg oral dose of esomeprazole, and patients weighing >= 20 kg were randomized to a single 10- or 20-mg oral dose of esomeprazole. Esomeprazole exposure (AUC(0-∞)), AUC from zero to last measurable concentration (AUC(0-t)), maximum plasma concentration (C(max)), time to C(max) (t(max)), terminal-phase half-life, apparent oral clearance, and apparent volume of distribution were determined. 28 patients were randomized to receive esomeprazole: 14 patients weighing 8 to < 20 kg received esomeprazole 5 mg (n = 7) or 10 mg (n = 7), and 14 patients weighing ≥20 kg received esomeprazole 10 mg (n = 6) or 20 mg (n = 8). Children weighing 8 - < 20 kg had a 1.8-fold higher exposure with the 10-mg vs. 5-mg dose (AUC(0-∞), 1.32 vs. 0.73 μmol·h/L, respectively); children weighing ≥ 20 kg had a 4.4-fold higher exposure with the 20-mg vs. 10-mg dose (AUC(0-∞), 3.06 vs. 0.69 μmol·h/L). C(max) was 2.2-fold higher for the 10-mg vs. 5-mg dose (8 to < 20 kg) and 2.4-fold higher for the 20-mg vs.10-mg dose (>= 20 kg). The pharmacokinetics of single-dose esomeprazole were dose-dependent in children weighing >= 20 kg but not in children weighing 8 to < 20 kg.

Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects.

PubMed

Shin, Dongseong; Lee, SeungHwan; Yi, Sojeong; Yoon, Seo Hyun; Cho, Joo-Youn; Bahng, Mi Young; Jang, In-Jin; Yu, Kyung-Sang

2017-01-01

DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects. A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated. After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2-3 h and was eliminated with terminal elimination half-life of 17.9-28.7 h. The mean renal clearance was 3.7-5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20-80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized C max and AUC 0- t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported. In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20-80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less.

Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen.

PubMed

Smith, S D; Bolwell, B J; Rybicki, L A; Brown, S; Dean, R; Kalaycio, M; Sobecks, R; Andresen, S; Hsi, E D; Pohlman, B; Sweetenham, J W

2007-08-01

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin's lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan-Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed.

Impact of Dietary Antioxidants on Sport Performance: A Review.

PubMed

Braakhuis, Andrea J; Hopkins, Will G

2015-07-01

Many athletes supplement with antioxidants in the belief this will reduce muscle damage, immune dysfunction and fatigue, and will thus improve performance, while some evidence suggests it impairs training adaptations. Here we review the effect of a range of dietary antioxidants and their effects on sport performance, including vitamin E, quercetin, resveratrol, beetroot juice, other food-derived polyphenols, spirulina and N-acetylcysteine (NAC). Older studies suggest vitamin E improves performance at altitude, with possible harmful effects on sea-level performance. Acute intake of vitamin E is worthy of further consideration, if plasma levels can be elevated sufficiently. Quercetin has a small beneficial effect for exercise of longer duration (>100 min), but it is unclear whether this benefits athletes. Resveratrol benefits trained rodents; more research is needed in athletes. Meta-analysis of beetroot juice studies has revealed that the nitrate component of beetroot juice had a substantial but unclear effect on performance when averaged across athletes, non-athletes and modes of exercise (single dose 1.4 ± 2.0%, double dose 0.5 ± 1.9%). The effect of addition of polyphenols and other components to beetroot juice was trivial but unclear (single dose 0.4 ± 3.2%, double dose -0.5 ± 3.3%). Other food-derived polyphenols indicate a range of performance outcomes from a large improvement to moderate impairment. Limited evidence suggests spirulina enhances endurance performance. Intravenous NAC improved endurance cycling performance and reduced muscle fatigue. On the basis of vitamin E and NAC studies, acute intake of antioxidants is likely to be beneficial. However, chronic intakes of most antioxidants have a harmful effect on performance.

Preclinical Study of Single-Dose Moxidectin, a New Oral Treatment for Scabies: Efficacy, Safety, and Pharmacokinetics Compared to Two-Dose Ivermectin in a Porcine Model

PubMed Central

Bernigaud, Charlotte; Aho, Ludwig Serge; Dreau, Dominique; Kelly, Andrew; Sutra, Jean-François; Moreau, Francis; Lilin, Thomas; Botterel, Françoise; Guillot, Jacques; Chosidow, Olivier

2016-01-01

Background Scabies is one of the commonest dermatological conditions globally; however it is a largely underexplored and truly neglected infectious disease. Foremost, improvement in the management of this public health burden is imperative. Current treatments with topical agents and/or oral ivermectin (IVM) are insufficient and drug resistance is emerging. Moxidectin (MOX), with more advantageous pharmacological profiles may be a promising alternative. Methodology/Principal Findings Using a porcine scabies model, 12 pigs were randomly assigned to receive orally either MOX (0.3 mg/kg once), IVM (0.2 mg/kg twice) or no treatment. We evaluated treatment efficacies by assessing mite count, clinical lesions, pruritus and ELISA-determined anti-S. scabiei IgG antibodies reductions. Plasma and skin pharmacokinetic profiles were determined. At day 14 post-treatment, all four MOX-treated but only two IVM-treated pigs were mite-free. MOX efficacy was 100% and remained unchanged until study-end (D47), compared to 62% (range 26–100%) for IVM, with one IVM-treated pig remaining infected until D47. Clinical scabies lesions, pruritus and anti-S. scabiei IgG antibodies had completely disappeared in all MOX-treated but only 75% of IVM-treated pigs. MOX persisted ~9 times longer than IVM in plasma and skin, thereby covering the mite’s entire life cycle and enabling long-lasting efficacy. Conclusions/Significance Our data demonstrate that oral single-dose MOX was more effective than two consecutive IVM-doses, supporting MOX as potential therapeutic approach for scabies. PMID:27732588

The difference of scoring dose to water or tissues in Monte Carlo dose calculations for low energy brachytherapy photon sources.

PubMed

Landry, Guillaume; Reniers, Brigitte; Pignol, Jean-Philippe; Beaulieu, Luc; Verhaegen, Frank

2011-03-01

The goal of this work is to compare D(m,m) (radiation transported in medium; dose scored in medium) and D(w,m) (radiation transported in medium; dose scored in water) obtained from Monte Carlo (MC) simulations for a subset of human tissues of interest in low energy photon brachytherapy. Using low dose rate seeds and an electronic brachytherapy source (EBS), the authors quantify the large cavity theory conversion factors required. The authors also assess whether ap plying large cavity theory utilizing the sources' initial photon spectra and average photon energy induces errors related to spatial spectral variations. First, ideal spherical geometries were investigated, followed by clinical brachytherapy LDR seed implants for breast and prostate cancer patients. Two types of dose calculations are performed with the GEANT4 MC code. (1) For several human tissues, dose profiles are obtained in spherical geometries centered on four types of low energy brachytherapy sources: 125I, 103Pd, and 131Cs seeds, as well as an EBS operating at 50 kV. Ratios of D(w,m) over D(m,m) are evaluated in the 0-6 cm range. In addition to mean tissue composition, compositions corresponding to one standard deviation from the mean are also studied. (2) Four clinical breast (using 103Pd) and prostate (using 125I) brachytherapy seed implants are considered. MC dose calculations are performed based on postimplant CT scans using prostate and breast tissue compositions. PTV D90 values are compared for D(w,m) and D(m,m). (1) Differences (D(w,m)/D(m,m)-1) of -3% to 70% are observed for the investigated tissues. For a given tissue, D(w,m)/D(m,m) is similar for all sources within 4% and does not vary more than 2% with distance due to very moderate spectral shifts. Variations of tissue composition about the assumed mean composition influence the conversion factors up to 38%. (2) The ratio of D90(w,m) over D90(m,m) for clinical implants matches D(w,m)/D(m,m) at 1 cm from the single point sources, Given the small variation with distance, using conversion factors based on the emitted photon spectrum (or its mean energy) of a given source introduces minimal error. The large differences observed between scoring schemes underline the need for guidelines on choice of media for dose reporting. Providing such guidelines is beyond the scope of this work.

SU-F-T-441: Dose Calculation Accuracy in CT Images Reconstructed with Artifact Reduction Algorithm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ng, C; Chan, S; Lee, F

Purpose: Accuracy of radiotherapy dose calculation in patients with surgical implants is complicated by two factors. First is the accuracy of CT number, second is the dose calculation accuracy. We compared measured dose with dose calculated on CT images reconstructed with FBP and an artifact reduction algorithm (OMAR, Philips) for a phantom with high density inserts. Dose calculation were done with Varian AAA and AcurosXB. Methods: A phantom was constructed with solid water in which 2 titanium or stainless steel rods could be inserted. The phantom was scanned with the Philips Brillance Big Bore CT. Image reconstruction was done withmore » FBP and OMAR. Two 6 MV single field photon plans were constructed for each phantom. Radiochromic films were placed at different locations to measure the dose deposited. One plan has normal incidence on the titanium/steel rods. In the second plan, the beam is at almost glancing incidence on the metal rods. Measurements were then compared with dose calculated with AAA and AcurosXB. Results: The use of OMAR images slightly improved the dose calculation accuracy. The agreement between measured and calculated dose was best with AXB and image reconstructed with OMAR. Dose calculated on titanium phantom has better agreement with measurement. Large discrepancies were seen at points directly above and below the high density inserts. Both AAA and AXB underestimated the dose directly above the metal surface, while overestimated the dose below the metal surface. Doses measured downstream of metal were all within 3% of calculated values. Conclusion: When doing treatment planning for patients with metal implants, care must be taken to acquire correct CT images to improve dose calculation accuracy. Moreover, great discrepancies in measured and calculated dose were observed at metal/tissue interface. Care must be taken in estimating the dose in critical structures that come into contact with metals.« less

Single-dose replication-defective VSV-based Nipah virus vaccines provide protection from lethal challenge in Syrian hamsters.

PubMed

Lo, Michael K; Bird, Brian H; Chattopadhyay, Anasuya; Drew, Clifton P; Martin, Brock E; Coleman, Joann D; Rose, John K; Nichol, Stuart T; Spiropoulou, Christina F

2014-01-01

Nipah virus (NiV) continues to cause outbreaks of fatal human encephalitis due to spillover from its bat reservoir. We determined that a single dose of replication-defective vesicular stomatitis virus (VSV)-based vaccine vectors expressing either the NiV fusion (F) or attachment (G) glycoproteins protected hamsters from over 1000 times LD50 NiV challenge. This highly effective single-dose protection coupled with an enhanced safety profile makes these candidates ideal for potential use in livestock and humans. Published by Elsevier B.V.

Failure rate of single dose methotrexate in managment of ectopic pregnancy.

PubMed

Sendy, Feras; AlShehri, Eman; AlAjmi, Amani; Bamanie, Elham; Appani, Surekha; Shams, Taghreed

2015-01-01

Background. One of the treatment modalities for ectopic pregnancy is methotrexate. The purpose of this study is to identify the failure rate of methotrexate in treating patients with ectopic pregnancy as well as the risk factors leading to treatment failure. Methods. A retrospective chart review of 225 patients who received methotrexate as a primary management option for ectopic pregnancy. Failure of single dose of methotrexate was defined as drop of BHCG level less than or equal to 14% in the seventh day after administration of methotrexate. Results. 225 patients had methotrexate. Most of the patients (151 (67%)) received methotrexate based on the following formula: f 50 mg X body surface area. Single dose of methotrexate was successful in 72% (162/225) of the patients. 28% (63/225) were labeled as failure of single dose of methotrexate because of suboptimal drop in BhCG. 63% (40/63) of failure received a second dose of methotrexate, and 37% (23/63) underwent surgical treatment. Among patient who received initial dose of methotrexate, 71% had moderate or severe pain, and 58% had ectopic mass size of more than 4 cm on ultrasound. Conclusion. Liberal use of medical treatment of ectopic pregnancy results in 71% success rate.

Toward the development of a one-dose classical swine fever subunit vaccine: antigen titration, immunity onset, and duration of immunity

PubMed Central

Madera, Rachel F.; Wang, Lihua; Gong, Wenjie; Burakova, Yulia; Buist, Sterling; Nietfeld, Jerome; Henningson, Jamie; Cino-Ozuna, Ada G.; Tu, Changchun

2018-01-01

Highly contagious classical swine fever (CSF) remains a major trade and health problem in the pig industry, resulting in large economic losses worldwide. In CSF-endemic countries, attenuated CSF virus (CSFV) vaccines have been routinely used to control the disease. However, eradication of CSFV in a geographical area would require permanent reduction to zero presence of the virus. It is therefore of paramount importance to develop a safe, potent, and non-infectious CSF vaccine. We have previously reported on a cost-effective CSF E2 subunit vaccine, KNB-E2, which can protect against CSF symptoms in a single dose containing 75 µg of recombinant CSFV glycoprotein E2. In this study, we report on a series of animal studies undertaken to elucidate further the efficacy of KNB-E2. We found that pigs vaccinated with a single KNB-E2 dose containing 25 µg of recombinant CSFV glycoprotein E2 were protected from clinical symptoms of CSF. In addition, KNB-E2-mediated reduction of CSF symptoms was observed at two weeks post-vaccination and the vaccinated pigs continued to exhibit reduced CSF clinical signs when virus challenged at two months and four months post-vaccination. These results suggest that KNB-E2 effectively reduces CSF clinical signs, indicating the potential of this vaccine for safely minimizing CSF-related losses. PMID:29510474

Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia

NASA Astrophysics Data System (ADS)

Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G.; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S. H.; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

2015-06-01

Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies.

Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia

PubMed Central

Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G.; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S. H.; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

2015-01-01

Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies. PMID:26119831

Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia.

PubMed

Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S H; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

2015-06-29

Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies.

Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study.

PubMed

Morain, P; Robin, J L; De Nanteuil, G; Jochemsen, R; Heidet, V; Guez, D

2000-10-01

The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers. This was a double-blind, randomized, placebo-controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection. PEP activity in plasma was dose-dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5-2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half-life (t(1/2)) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose. S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once-daily dosing without any serious adverse events.

Immunogenicity Following One, Two, or Three Doses of the 7-valent Pneumococcal Conjugate Vaccine

PubMed Central

Russell, FM; Balloch, A; Tang, MLK; Carapetis, JR; Licciardi, P; Nelson, J; Jenney, AWJ; Tikoduadua, L; Waqatakirewa, L; Pryor, J; Byrnes, GB; Cheung, YB; Mulholland, EK

2009-01-01

The aim was to identify an appropriate infant pneumococcal vaccination strategy for resource poor countries. Fijian infants received 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV) in early infancy. Following 3 PCV doses, geometric mean concentration (GMC) to all 7 serotypes were ≥ 1.0μg/mL, and >85% of children achieved antibody levels ≥0.35μg/mL at 18 weeks. Following 2 doses, GMC were lower for 6B, 14, and 23F, but higher for 19F compared with 3 doses. Following a single dose, significant responses were seen for all serotypes post primary series compared with the unvaccinated. By 12 months, differences between 2 and 3 doses persisted for serotype 14 only. Although GMC following 3 doses are higher than after 2 doses, the differences were small. A single dose may offer some protection for most serotypes. PMID:19616498

Single-Dose and Multiple-Dose Pharmacokinetics of Nicotine 6 mg Gum.

PubMed

Hansson, Anna; Rasmussen, Thomas; Kraiczi, Holger

2017-04-01

Under-dosing is a recognized problem with current nicotine replacement therapy (NRT). Therefore, a new 6mg nicotine gum has been developed. To compare the nicotine uptake from the 6mg gum versus currently available NRT products, two pharmacokinetic studies were performed. In one randomized crossover study, 44 healthy adult smokers received single doses of 6, 4, and 2mg nicotine gum, and 4mg nicotine lozenge on separate occasions. In a separate randomized crossover multiple-dose study over 11 hours, 50 healthy adult smokers received one 6mg gum every hour and 90 minutes, respectively, one 4mg gum every hour, and one 4mg lozenge every hour. In both studies, blood samples were collected over 12 hours to determine single-dose and multiple-dose pharmacokinetic variables. In the single-dose study, the amount of nicotine released from the 2, 4, and 6mg gums (1.44, 3.36, and 4.94mg) as well as the resulting maximum concentration and area under the curve (5.9, 10.1, and 13.8ng/mL, and 17.1, 30.7, 46.2ng/mL × h, respectively) increased with dose. The maximum concentration and area under the curve of the 6mg gum were 44% and 30% greater, respectively, than those for 4mg lozenge. Upon hourly administration, the steady-state average plasma nicotine concentration with 6mg gum (37.4ng/mL) was significantly higher than those for 4mg lozenge (28.3ng/mL) and 4mg gum (27.1ng/mL). Nicotine delivery via the 6mg gum results in higher plasma nicotine concentrations after a single dose and at steady state than with currently available oral NRT. Under-dosing is a recognized problem with current NRT. Therefore, a new 6mg nicotine gum has been developed. Our studies show that upon single-dose and multiple-dose administration, the 6mg gum releases and delivers more nicotine to the systemic circulation than 2mg gum, 4mg gum, and 4mg lozenge. Thus, each 6mg nicotine gum provides a higher degree of nicotine substitution and/or lasts for a longer period of time than currently available nicotine gums and lozenges. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Single and multidose ocular kinetics and stability analysis of extemporaneous formulation of topical voriconazole in humans.

PubMed

Senthilkumari, Srinivasan; Lalitha, Prajna; Prajna, Namperumalsamy Venkatesh; Haripriya, Aravind; Nirmal, Jeyabalan; Gupta, Pankaj; Velpandian, Thirumurthy

2010-11-01

The purpose of the present study was to evaluate the kinetics of single and multiple doses of topical, non-preserved voriconazole (VZ) in human eyes. For single dose kinetics, 119 patients undergoing cataract surgery were divided into group I and group II and each group received a single drop (30 µl) of either 1% or 0.1% VZ formulation. Aqueous humor was collected at designated time intervals. For multidose kinetics, a single drop of 1% VZ was instilled 5 times either hourly or every 2 hr. The aqueous humor was tested for VZ at the 5th hr and 9th hr, respectively, after initial instillation. The stability and efficacy of the reconstituted VZ formulations were also evaluated after 30 days. Single dose ocular kinetics of 1% VZ resulted in a maximum mean aqueous concentration of 3.333 ± 1.61 µg/ml in 30 min whereas 0.1% showed a maximum mean aqueous concentration of 0.817 ±.36 µg/ml. In the multidose kinetic study, hourly and bi-hourly dosing resulted in mean aqueous concentrations of 7.47 ± 2.14 µg/ml and 4.69 ± 2.7 µg/ml, respectively. The reconstituted VZ formulations were stable at all studied temperatures, and their efficacy was maintained throughout the study period. The present study showed that the achieved mean concentration of VZ in both single dose and multi dose kinetic studies satisfactorily met the MIC(90) for almost all causative fungal organisms. The frequency of instillation may be designed for an "every 2 hr regimen" to maintain a therapeutic concentration for successful therapy.

Single dose filgastrim in cytotoxic-induced neutropaenia in children.

PubMed

Abdallah, F K

2008-01-01

To document the impact of fixed dose weight adjusted filgastrim (G-CSF) in cytotoxic-induced neutropaenia. A descriptive cross-sectional study. Paediatric Oncology Unit at Kenyatta National Hospital, Nairobi, Kenya. All paediatric oncology patients who had developed cytotoxic-induced neutropaenia. The following were documented for every tissue proven case of malignancy; age, sex, type of malignancy, treatment regimen and schedule, initial blood count at the time of neutropaenia; subsequent blood counts daily for five days from day one of single dose filgastrim, and the calculated neutrophil incremental count. Initially eight patients with solid tumours previously treated with filgastrim revealed that cytotoxic induced neutropaenia could be ameliorated by a single dose of filgastrim. Subsequently, the study listed thirty patients. This cohort consisted of; 37% rhabdomyosarcoma, 30% Burkitts, 27% acute lymphoblastic leukaemia and 6% Hodgkin's lymphoma. Increased neutrophil count after 48 hours was documented in 26 (87%) patients, with absolute neutrophil counts range of 0.5 to 31.5 x 10(9)/L. This response was significantly influenced by gender (p>0.0001), malignancy type and chemotherapy regimen (p>0.001). The study shows that chemotherapy induced neutropaenia can be alleviated by a single dose of filgastrim without adverse effects on lymphoblastic leukaemia. This study suggests that a single dose of filgastrim should be first tried in cytotoxic induced neutropaenia in the paediatric age group.

A calibration method for patient specific IMRT QA using a single therapy verification film

PubMed Central

Shukla, Arvind Kumar; Oinam, Arun S.; Kumar, Sanjeev; Sandhu, I.S.; Sharma, S.C.

2013-01-01

Aim The aim of the present study is to develop and verify the single film calibration procedure used in intensity-modulated radiation therapy (IMRT) quality assurance. Background Radiographic films have been regularly used in routine commissioning of treatment modalities and verification of treatment planning system (TPS). The radiation dosimetery based on radiographic films has ability to give absolute two-dimension dose distribution and prefer for the IMRT quality assurance. However, the single therapy verification film gives a quick and significant reliable method for IMRT verification. Materials and methods A single extended dose rate (EDR 2) film was used to generate the sensitometric curve of film optical density and radiation dose. EDR 2 film was exposed with nine 6 cm × 6 cm fields of 6 MV photon beam obtained from a medical linear accelerator at 5-cm depth in solid water phantom. The nine regions of single film were exposed with radiation doses raging from 10 to 362 cGy. The actual dose measurements inside the field regions were performed using 0.6 cm3 ionization chamber. The exposed film was processed after irradiation using a VIDAR film scanner and the value of optical density was noted for each region. Ten IMRT plans of head and neck carcinoma were used for verification using a dynamic IMRT technique, and evaluated using the gamma index method with TPS calculated dose distribution. Results Sensitometric curve has been generated using a single film exposed at nine field region to check quantitative dose verifications of IMRT treatments. The radiation scattered factor was observed to decrease exponentially with the increase in the distance from the centre of each field region. The IMRT plans based on calibration curve were verified using the gamma index method and found to be within acceptable criteria. Conclusion The single film method proved to be superior to the traditional calibration method and produce fast daily film calibration for highly accurate IMRT verification. PMID:24416558

Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy.

PubMed

Moore, R A; McQuay, H J; Tomaszewski, J; Raba, G; Tutunaru, D; Lietuviete, N; Galad, J; Hagymasy, L; Melka, D; Kotarski, J; Rechberger, T; Fülesdi, B; Nizzardo, A; Guerrero-Bayón, C; Cuadripani, S; Pizà-Vallespir, B; Bertolotti, M

2016-01-22

Dexketoprofen trometamol plus tramadol hydrochloride is a new oral combination of two analgesics, which have different mechanisms of action for the treatment of moderate to severe acute pain. Randomised, double-blind, parallel, placebo and active-controlled, single and multiple-dose study to evaluate the analgesic efficacy and safety of dexketoprofen/tramadol 25 mg/75 mg in comparison with the single agents (dexketoprofen 25 mg and tramadol 100 mg) in moderate to severe acute pain after abdominal hysterectomy. Patients received seven consecutive doses of study drug within a 3-day period, each dose separated by an 8-hour interval. A placebo arm was included during the single-dose phase to validate the pain model. Efficacy assessments included pain intensity, pain relief, patient global evaluation and use of rescue medication. The primary endpoint was the mean sum of pain intensity differences over the first 8 h (SPID8). The efficacy analysis included 606 patients, with a mean age of 48 years (range 25-73). The study results confirmed the superiority of the combination over the single agents in terms of the primary endpoint (p <0.001). Secondary endpoints were generally supportive of the superiority of the combination for both single and multiple doses. Most common adverse drug reactions (ADRs) were nausea (4.6%) and vomiting (2.3%). All other ADRs were experienced by less than 2% of patients. The study results provided robust evidence of the superiority of dexketoprofen/tramadol 25 mg/75 mg over the single components in the management of moderate to severe acute pain, as confirmed by the single-dose efficacy, repeated-dose sustained effect and good safety profile observed. EU Clinical Trials Register (EudraCT number 2012-004545-32, registered 04 October 2012); Clinicaltrials.gov ( NCT01904149, registered 17 July 2013).

Health economic assessment of universal immunization of toddlers against Hepatitis A Virus (HAV) in Mexico

PubMed Central

Carlos, Fernando; Gómez, Jorge Alberto; Anaya, Pablo; Romano-Mazzotti, Luis

2016-01-01

Hepatitis A virus (HAV) has shifted from high to intermediate endemicity in Mexico, which may increase the risk of clinically significant HAV infections in older children, adolescents and adults. The objective of this study was to evaluate the cost-utility of single-dose or 2-dose universal infant HAV vaccination strategy in Mexico, compared with no vaccination. A previously published dynamic model estimated the expected number of HAV cases with each strategy, and a decision model was used to estimate the costs and quality-adjusted life-years (QALYs) expected with each strategy. The time horizon was 25 years (2012–2036) and the base case analysis was conducted from the perspective of the Mexican public health system. Costs and QALYs after the first year were discounted at 5% annually. Input data were taken from national databases and published sources where available. The single-dose HAV vaccination strategy had an incremental cost-utility ratio (ICUR) of Mexican peso (MXN) 2,270 per QALY gained, compared with no vaccination. The two-dose strategy had an ICUR of MXN 14,961/QALY compared with no vaccination, and an ICUR of MXN 78,280/QALY compared with the single-dose strategy. The estimated ICURs were below the threshold of 1 x Mexican gross domestic product per capita. When indirect costs were included (societal perspective), the single-dose HAV vaccination strategy would be expected to improve health outcomes and to be cost-saving. This analysis indicates that routine vaccination of toddlers against HAV would be cost-effective in Mexico using either a single-dose or a 2-dose vaccination strategy. GSK study identifier: HO-12-12877. PMID:26503702

Multiple-, But Not Single-, Dose of Parecoxib Reduces Shoulder Pain after Gynecologic Laparoscopy

PubMed Central

Zhang, Hufei; Shu, Haihua; Yang, Lu; Cao, Minghui; Zhang, Jingjun; Liu, Kexuan; Xiao, Liangcan; Zhang, Xuyu

2012-01-01

Background: The aim of this study was to investigate effect of single- and multiple-dose of parecoxib on shoulder pain after gynecologic laparoscopy. Methods: 126 patients requiring elective gynecologic laparoscopy were randomly allocated to three groups. Group M (multiple-dose): receiving parecoxib 40mg at 30min before the end of surgery, at 8 and 20hr after surgery, respectively; Group S (single-dose): receiving parecoxib 40mg at 30min before the end of surgery and normal saline at the corresponding time points; Group C (control): receiving normal saline at the same three time points. The shoulder pain was evaluated, both at rest and with motion, at postoperative 6, 24 and 48hr. The impact of shoulder pain on patients' recovery (activity, mood, walking and sleep) was also evaluated. Meanwhile, rescue analgesics and complications were recorded. Results: The overall incidence of shoulder pain in group M (37.5%) was lower than that in group C (61.9%) (difference=-24.4%; 95% CI: 3.4~45.4%; P=0.023). Whereas, single-dose regimen (61.0%) showed no significant reduction (difference with control=-0.9%; 95% CI: -21.9~20.0%; P=0.931). Moreover, multiple-dose regimen reduced the maximal intensity of shoulder pain and the impact for activity and mood in comparison to the control. Multiple-dose of parecoxib decreased the consumption of rescue analgesics. The complications were similar among all groups and no severe complications were observed. Conclusions: Multiple-, but not single-, dose of parecoxib may attenuate the incidence and intensity of shoulder pain and thereby improve patients' quality of recovery following gynecologic laparoscopy. PMID:23136538

A Generalized QMRA Beta-Poisson Dose-Response Model.

PubMed

Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

2016-10-01

Quantitative microbial risk assessment (QMRA) is widely accepted for characterizing the microbial risks associated with food, water, and wastewater. Single-hit dose-response models are the most commonly used dose-response models in QMRA. Denoting PI(d) as the probability of infection at a given mean dose d, a three-parameter generalized QMRA beta-Poisson dose-response model, PI(d|α,β,r*), is proposed in which the minimum number of organisms required for causing infection, K min , is not fixed, but a random variable following a geometric distribution with parameter 0

Interoceptive conditioning in rats: effects of using a single training dose or a set of 5 different doses of nicotine.

PubMed

Pittenger, Steven T; Bevins, Rick A

2013-12-01

Interoceptive conditioning contributes to the tenacity of nicotine dependence. Previous research investigating nicotine as an interoceptive stimulus has typically employed administration of a single training dose of nicotine over an extended time. This approach has allowed for careful study of the nicotine stimulus. In humans, the nicotine stimulus is unlikely to be fixed across learning episodes. Thus, from a translational perspective, systematic variation of nicotine dose in training might better approximate interoceptive conditioning in humans. Notably, training with a class or set of discrete exteroceptive stimuli (e.g., different pictures of cars) produces interesting behavioral differences relative to training with a single stimulus. The present study sought to determine whether similar differences would occur if a set of nicotine stimuli were used in place of a single dose. To investigate this question, one group of male Sprague-Dawley rats was trained on a discriminated goal-tracking task with a set of nicotine doses (0.05, 0.125, 0.2, 0.275, and 0.35mg/kg). A second group received the standard protocol of training with a single nicotine dose (0.2mg/kg). On each nicotine session, there was intermittent access to liquid sucrose (26%) in a conditioning chamber. On intermixed saline sessions, sucrose was withheld. We examined acquisition, subsequent extinction, transfer of extinction, nicotine generalization, and mecamylamine blockade. Both groups reliably discriminated between nicotine and saline sessions, were sensitive to non-reinforcement, displayed transfer of extinction, demonstrated dose-dependent nicotine generalization, and responding was blocked by mecamylamine. There were no significant differences between the two groups. The unique nature of an interoceptive pharmacological stimulus and the challenges posed for studying the impact of training with a set of interoceptive stimuli are discussed. © 2013.

Renal effects of nifedipine in healthy normotensive volunteers. Effects of dose, formulation, duration of treatment, and chlorothiazide coadministration.

PubMed

Adebayo, G I; Coker, H A; Fagbure, F

1988-01-01

Renal effects of nifedipine were assessed in 3 groups of healthy normotensive volunteers. In the first group (N = 10), a single 20-mg dose of the slow-release formulation caused an increase in 8-h sodium excretion (P less than 0.025) and urine volume (P less than 0.005). Natriuresis (P less than 0.05) and diuresis (P less than 0.05) were still evident after 1 wk of pretreatment, but were significantly attenuated (P less than 0.05), in each case, compared to levels after a single dose. Natriuresis and diuresis after 2 wk of intake were indistinguishable from control levels. In another group of 8, a single 10 mg dose of the conventional formulation (capsule) effected natriuresis (P less than 0.01) and diuresis (P less than 0.001) similar to those associated with intake of a single 20-mg dose of the slow-release formulation. Natriuresis and diuresis associated with a 20-mg single dose of the conventional formulation were not different from control but were less than those following intake of the 10-mg dose (P less than 0.025 in each case). In the third group of 6, nifedipine, though weaker than chlorothiazide, promoted natriuresis (P less than 0.025) and diuresis (P less than 0.025) of the thiazide without augmenting its kaliuresis. In all the groups, there were no changes in creatinine clearance, and nifedipine did not alter kaliuresis. It is suggested that natriuretic and diuretic effects of nifedipine in healthy normotensive individuals are dependent on the dose employed, the formulation used, and the duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Health economic assessment of universal immunization of toddlers against Hepatitis A Virus (HAV) in Mexico.

PubMed

Carlos, Fernando; Gómez, Jorge Alberto; Anaya, Pablo; Romano-Mazzotti, Luis

2016-01-01

Hepatitis A virus (HAV) has shifted from high to intermediate endemicity in Mexico, which may increase the risk of clinically significant HAV infections in older children, adolescents and adults. The objective of this study was to evaluate the cost-utility of single-dose or 2-dose universal infant HAV vaccination strategy in Mexico, compared with no vaccination. A previously published dynamic model estimated the expected number of HAV cases with each strategy, and a decision model was used to estimate the costs and quality-adjusted life-years (QALYs) expected with each strategy. The time horizon was 25 years (2012-2036) and the base case analysis was conducted from the perspective of the Mexican public health system. Costs and QALYs after the first year were discounted at 5% annually. Input data were taken from national databases and published sources where available. The single-dose HAV vaccination strategy had an incremental cost-utility ratio (ICUR) of Mexican peso (MXN) 2,270 per QALY gained, compared with no vaccination. The two-dose strategy had an ICUR of MXN 14,961/QALY compared with no vaccination, and an ICUR of MXN 78,280/QALY compared with the single-dose strategy. The estimated ICURs were below the threshold of 1 x Mexican gross domestic product per capita. When indirect costs were included (societal perspective), the single-dose HAV vaccination strategy would be expected to improve health outcomes and to be cost-saving. This analysis indicates that routine vaccination of toddlers against HAV would be cost-effective in Mexico using either a single-dose or a 2-dose vaccination strategy. GSK study identifier: HO-12-12877.

Aspirin in polycythemia vera and essential thrombocythemia: current facts and perspectives.

PubMed

Landolfi, R; Patrono, C

1996-09-01

The role of aspirin in the antithrombotic strategy of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is highly controversial. Long considered unsafe on the basis of a single clinical trial testing very high doses in PV patients, aspirin is being increasingly used at lower dosage. The rationale for the use of aspirin in patients with PV and ET is provided by the efficacy of this agent in the treatment of microcirculatory disturbances of thrombocythemic states associated with myeloproliferative disorders and by recent evidence that asymptomatic PV and ET patients have persistently increased thromboxane (TX) A2-biosynthesis. This increase, which most likely reflects enhanced platelet activation in vivo, is independent of the platelet mass and blood viscosity and largely supressed by a short term low-dose aspirin regimen (50 mg/day for 7 days). Since enhanced TXA2 biosynthesis may play a role in transducing the increased thrombotic risk associated with PV and ET, long-term low-dose aspirin administration has been proposed as a possible antithombotic strategy in these subjects. The safety of this treatment in PV patients has been recently reassessed by the Gruppo Italiano per lo Studio della Policitemia Vera (GISP) which has followed for over one year 112 patients randomized to receive 40 mg/day aspirin or placebo. In the same study, serum TXB2 measurements provided evidence that the low-dose aspirin regimen tested was fully effective in inhibiting platelet cyclooxygenase activity. On this basis, a large scale trial aimed at assessing the antithrombotic efficacy of this approach is currently being organized. In patients with ET both the minimal aspirin dose required for complete inhibition of platelet cyclooxygenase and the safety of long-term aspirin administration need to be established prior to extensive clinical evaluation of this strategy.

Colistin Nephrotoxicity in Adults: Single Centre Large Series from India.

PubMed

Ghafur, Abdul; Gohel, Swati; Devarajan, Vidyalakshmi; Raja, T; Easow, Jose; Raja, M A; Sreenivas, Sankar; Ramakrishnan, Balasubramaniam; Ramakrishnan, T; Raman, S G; Devaprasad, Dedeepiya; Venkatachalam, Balaji; Nimmagadda, Ramesh

2017-06-01

Limited Indian data are available on the rate of colistin nephrotoxicity and other risk factors contributing to the development of this important side effect. This study aims to generate data on colistin nephrotoxicity from a large cohort of Indian patients. Retrospective cohort study. Case record analysis of patients who received colistin, in an oncology center in India, between January 2011 and December 2015. Nephrotoxicity was assessed using risk, injury, failure, loss, and end-stage (RIFLE) criteria. P < 0.05 was considered as statistically significant. Out of the 229 patients, 13.1% (30/229) developed abnormal RIFLE. Abnormal RIFLE group ( n = 30), in comparison to the normal renal function group ( n = 199), had higher number of patients in intensive care unit (ICU) (96% vs. 79%, P = 0.02), higher Acute Physiology and Chronic Health Evaluation (APACHE II) score (23 vs. 19 P = 0.0001), Charlson score (5.9 vs. 4.3, P = 0.001), mechanical ventilation (90% vs. 67%, P = 0.016), 28 days mortality (63% vs. 25%, P = 0.0001), and abnormal baseline creatinine (36% vs. 8%, P = 0.001). Coadministration of vancomycin had higher rates of nephrotoxicity ( P = 0.039). There was no significant difference in nephrotoxicity between 6 and 9 MU/day dosing pattern (8.8% vs. 13.8%, P = 0.058). Nephrotoxicity rate in our retrospective single center large series of patients receiving colistin was 13.1%. Patients with abnormal baseline creatinine, ICU stay, and higher disease severity are at higher risk of nephrotoxicity while on colistin. A daily dose of 9 million does not significantly increase nephrotoxicity compared to the 6 million. Concomitant administration of vancomycin with colistin increases the risk of nephrotoxicity.

Single-dose volume regulation algorithm for a gas-compensated intrathecal infusion pump.

PubMed

Nam, Kyoung Won; Kim, Kwang Gi; Sung, Mun Hyun; Choi, Seong Wook; Kim, Dae Hyun; Jo, Yung Ho

2011-01-01

The internal pressures of medication reservoirs of gas-compensated intrathecal medication infusion pumps decrease when medication is discharged, and these discharge-induced pressure drops can decrease the volume of medication discharged. To prevent these reductions, the volumes discharged must be adjusted to maintain the required dosage levels. In this study, the authors developed an automatic control algorithm for an intrathecal infusion pump developed by the Korean National Cancer Center that regulates single-dose volumes. The proposed algorithm estimates the amount of medication remaining and adjusts control parameters automatically to maintain single-dose volumes at predetermined levels. Experimental results demonstrated that the proposed algorithm can regulate mean single-dose volumes with a variation of <3% and estimate the remaining medication volume with an accuracy of >98%. © 2010, Copyright the Authors. Artificial Organs © 2010, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

A comparative study of single-dose treatment of chancroid using thiamphenicol versus Azithromycin.

PubMed

Belda, Walter; Di Chiacchio, Nilton G; Di Chiacchio, Nilton; Romiti, Ricardo; Criado, Paulo R; Velho, Paulo Eduardo N Ferreira

2009-06-01

A study was conducted in São Paulo, Brazil, to compare azithromycin with thiamphenicol for the single-dose treatment of chancroid. In all, 54 men with chancroid were tested. The etiology was determined by clinical characterization and direct bacterioscopy with Gram staining. None of the patients had positive serology or dark-field examination indicating active infection with Treponema pallidum. Genital infections due to Neisseria gonorrhoeae and herpes simplex virus were excluded by polymerase chain reaction testing. For 54 patients with chancroid, cure rates with single-dose treatment were 73% with azithromycin and 89% with thiamphenicol. HIV seropositivity was found to be associated with treatment failure (p=0.001). The treatment failed in all HIV positive patients treated with azithromycin (p=0.002) and this drug should be avoided in these co-infected patients. In the view of the authors, thiamphenicol is the most indicated single-dose regimen for chancroid treatment.

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

PubMed

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.

Identification of consensus biomarkers for predicting non-genotoxic hepatocarcinogens

PubMed Central

Huang, Shan-Han; Tung, Chun-Wei

2017-01-01

The assessment of non-genotoxic hepatocarcinogens (NGHCs) is currently relying on two-year rodent bioassays. Toxicogenomics biomarkers provide a potential alternative method for the prioritization of NGHCs that could be useful for risk assessment. However, previous studies using inconsistently classified chemicals as the training set and a single microarray dataset concluded no consensus biomarkers. In this study, 4 consensus biomarkers of A2m, Ca3, Cxcl1, and Cyp8b1 were identified from four large-scale microarray datasets of the one-day single maximum tolerated dose and a large set of chemicals without inconsistent classifications. Machine learning techniques were subsequently applied to develop prediction models for NGHCs. The final bagging decision tree models were constructed with an average AUC performance of 0.803 for an independent test. A set of 16 chemicals with controversial classifications were reclassified according to the consensus biomarkers. The developed prediction models and identified consensus biomarkers are expected to be potential alternative methods for prioritization of NGHCs for further experimental validation. PMID:28117354

Volumetric Modulated Arc Radiotherapy for Vestibular Schwannomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lagerwaard, Frank J.; Meijer, Otto W.M.; Hoorn, Elles A.P. van der

2009-06-01

Purpose: To evaluate volumetric modulated arc radiotherapy (RapidArc [RA]), a novel approach allowing for rapid treatment delivery, for the treatment of vestibular schwannoma (VS). Methods and Materials: The RA plans were generated for a small (0.5 cm{sup 3}), intermediate (2.8 cm{sup 3}), and large (14.8 cm{sup 3}) VS. The prescription dose was 12.5 Gy to the encompassing 80% isodose. The RA plans were compared with conventional radiosurgery plans using both a single dynamic conformal arc (1DCA) and five noncoplanar dynamic conformal arcs (5DCA). Conformity indices (CI) and dose-volume histograms of critical organs were compared. The RA plan for the medium-sizedmore » VS was measured in a phantom using Gafchromic EBT films and compared with calculated dose distributions. Results: The RA planning was completed within 30 min in all cases, and calculated treatment delivery time (after patient setup) was 5 min vs. 20 min for 5DCA. A superior CI was achieved with RA, with a substantial decrease in low-dose irradiation of the normal brain achieved relative to 5DCA plans. Maximum doses to critical organs were similar for RA and 5DCA but were higher for 1DCA. Film measurements showed the differences between calculated and measured doses to be smaller than 1.5% in the high-dose area and smaller than 3% in the low-dose area. Conclusion: The RA plans consistently achieved a higher CI and decrease in areas of low-dose irradiation. This, together with shorter treatment delivery times, has led to RA replacing our conventional five-arc radiosurgery technique for VS.« less

Motion mitigation for lung cancer patients treated with active scanning proton therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grassberger, Clemens, E-mail: Grassberger.Clemens@mgh.harvard.edu; Dowdell, Stephen; Sharp, Greg

2015-05-15

Purpose: Motion interplay can affect the tumor dose in scanned proton beam therapy. This study assesses the ability of rescanning and gating to mitigate interplay effects during lung treatments. Methods: The treatments of five lung cancer patients [48 Gy(RBE)/4fx] with varying tumor size (21.1–82.3 cm{sup 3}) and motion amplitude (2.9–30.6 mm) were simulated employing 4D Monte Carlo. The authors investigated two spot sizes (σ ∼ 12 and ∼3 mm), three rescanning techniques (layered, volumetric, breath-sampled volumetric) and respiratory gating with a 30% duty cycle. Results: For 4/5 patients, layered rescanning 6/2 times (for the small/large spot size) maintains equivalent uniformmore » dose within the target >98% for a single fraction. Breath sampling the timing of rescanning is ∼2 times more effective than the same number of continuous rescans. Volumetric rescanning is sensitive to synchronization effects, which was observed in 3/5 patients, though not for layered rescanning. For the large spot size, rescanning compared favorably with gating in terms of time requirements, i.e., 2x-rescanning is on average a factor ∼2.6 faster than gating for this scenario. For the small spot size however, 6x-rescanning takes on average 65% longer compared to gating. Rescanning has no effect on normal lung V{sub 20} and mean lung dose (MLD), though it reduces the maximum lung dose by on average 6.9 ± 2.4/16.7 ± 12.2 Gy(RBE) for the large and small spot sizes, respectively. Gating leads to a similar reduction in maximum dose and additionally reduces V{sub 20} and MLD. Breath-sampled rescanning is most successful in reducing the maximum dose to the normal lung. Conclusions: Both rescanning (2–6 times, depending on the beam size) as well as gating was able to mitigate interplay effects in the target for 4/5 patients studied. Layered rescanning is superior to volumetric rescanning, as the latter suffers from synchronization effects in 3/5 patients studied. Gating minimizes the irradiated volume of normal lung more efficiently, while breath-sampled rescanning is superior in reducing maximum doses to organs at risk.« less

Critical evaluation of taeniacidal antibiotic S15-1 (SQ 21, 704) for removal of natural tapeworm infections in dogs and cats.

PubMed

Szanto, J; Lillis, W G; Brown, W E; Sutphin, C F; Maplesden, D C

1979-05-01

The new taeniacidal antibiotic S15-1 (SQ 21,704) was evaluated against naturally occuring infections of Taenia pisiformis in 53 dogs, Dipylidium caninum in 35 dogs, T taeniaformis in 18 cats, and D caninum in 33 cats. It all instances, the compound was administered in gelatine capsules in a single oral dose. The doses tested were between and 200 mg/kg of body weight in dogs and between 15 and 45 mg/kg in cats. In dogs, doses of 25 mg/kg and greater were 100% effective against T pisiformis, whereas a dose of 50 mg/kg was necessary to clear D caninum. In cats, a single oral dose of 22.5 mg/kg was 100% efficacious against T taeniaeformis, and a single dose of 45 mg/kg (the largest dose tested) clearly seven of eight cats of D caninum. The efficacy was limited to tapeworms only; there was no efficacy against nematodes. The antibiotic was well tolerated by both species with no drug-related vomiting or other side-effects observed.

Barriers to HIV Medication Adherence as a Function of Regimen Simplification.

PubMed

Chen, Yiyun; Chen, Kun; Kalichman, Seth C

2017-02-01

Barriers to HIV medication adherence may differ by levels of dosing schedules. The current study examined adherence barriers associated with medication regimen complexity and simplification. A total of 755 people living with HIV currently taking anti-retroviral therapy were recruited from community services in Atlanta, Georgia. Participants completed audio-computer-assisted self-interviews that assessed demographic and behavioral characteristics, provided their HIV viral load obtained from their health care provider, and completed unannounced phone-based pill counts to monitor medication adherence over 1 month. Participants taking a single-tablet regimen (STR) were more likely to be adherent than those taking multi-tablets in a single-dose regimen (single-dose MTR) and those taking multi-tablets in a multi-dose regimen (multi-dose MTR), with no difference between the latter two. Regarding barriers to adherence, individuals taking STR were least likely to report scheduling issues and confusion as reasons for missing doses, but they were equally likely to report multiple lifestyle and logistical barriers to adherence. Adherence interventions may need tailoring to address barriers that are specific to dosing regimens.

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

PubMed

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 the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses ≥1200 mg. Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg). Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Single-Dose and Fractionated Irradiation Promote Initiation and Progression of Atherosclerosis and Induce an Inflammatory Plaque Phenotype in ApoE{sup -/-} Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoving, Saske; Heeneman, Sylvia; Gijbels, Marion J.J.

2008-07-01

Purpose: Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin's lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE{sup -/-} mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. Methods and Materials: ApoE{sup -/-} mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examinated for presence of atherosclerotic lesions, plaquemore » size, and phenotype. Results: At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. Conclusions: We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE{sup -/-} mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.« less

Dramatic changes in muscle contractile and structural properties after 2 botulinum toxin injections.

PubMed

Minamoto, Viviane B; Suzuki, Kentaro P; Bremner, Shannon N; Lieber, Richard L; Ward, Samuel R

2015-10-01

Botulinum toxin is frequently administered serially to maintain therapeutic muscle paralysis, but the effect of repeated doses on muscle function are largely unknown. This study characterized the muscle response to 2 onabotulinum toxin (BoNT) injections separated by 3 months. Animal subjects received a single toxin injection (n = 8), 2 BoNT injections separated by 3 months (n = 14), or 1 BoNT and 1 saline injection separated by 3 months (n = 8). The functional effect of 2 serial injections was exponentially greater than the effect of a single injection. While both groups treated with a single BoNT injection had decreased torque in the injected leg by approximately 50% relative to contralateral legs, the double BoNT injected group had decreased torque by over 95% relative to the preinjection level. Both single and double BoNT injections produced clear signs of fiber-type grouping. These experiments demonstrate a disproportionately greater effect of repeated BoNT injections. © 2015 Wiley Periodicals, Inc.

Patterns of patient specific dosimetry in total body irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akino, Yuichi; Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871; McMullen, Kevin P.

2013-04-15

Purpose: Total body irradiation (TBI) has been used for bone marrow transplant for hematologic and immune deficiency conditions. The goal of TBI is to deliver a homogeneous dose to the entire body, with a generally accepted range of dose uniformity being within {+-}10% of the prescribed dose. The moving table technique for TBI could make dose uniform in whole body by adjusting couch speed. However, it is difficult to accurately estimate the actual dose by calculation and hence in vivo dosimetry (IVD) is routinely performed. Here, the authors present patterns of patient-specific IVD in 161 TBI patients treated at ourmore » institution. Methods: Cobalt-60 teletherapy unit (Model C9 Cobalt-60 teletherapy unit, Picker X-ray Corporation) with customized moving bed (SITI Industrial Products, Inc., Fishers, IN) were used for TBI treatment. During treatment, OneDose{sup TM} (Sicel Technology, NC) Metal Oxide-silicon Semiconductor Field Effect Transistor detectors were placed at patient body surface; both entrance and exit side of the beam at patient head, neck, mediastinum, umbilicus, and knee to estimate midplane dose. When large differences (>10%) between the prescribed and measured dose were observed, dose delivery was corrected for subsequent fractions by the adjustment of couch speed and/or bolus placement. Under IRB exempt status, the authors retrospectively analyzed the treatment records of 161 patients who received TBI treatment between 2006 and 2011. Results: Across the entire cohort, the median {+-} SD (range) percent variance between calculated and measured dose for head, neck, mediastinum, umbilicus, and knee was -2.3 {+-} 10.2% (-66.2 to +35.3), 1.1 {+-} 11.5% (-62.2 to +40.3), -1.9 {+-} 9.5% (-66.4 to +46.6), -1.1 {+-} 7.2% (-35.2 to +42.9), and 3.4 {+-} 12.2% (-47.9 to +108.5), respectively. More than half of treatments were within {+-}10% of the prescribed dose for all anatomical regions. For 80% of treatments (10%-90%), dose at the umbilicus was within {+-}10%. However, some large differences greater than 35% were also found at several points. For one case, the knee received double the prescribed dose. When the dose differences for multiple fractions were averaged, compliance ({+-}10%) between the prescription and measured dose was improved compared to the dose difference of the first single fraction, for example, as at umbilicus, which improved from 83.9% to 98.5%. Conclusions: Actual dose measurement analysis of TBI patients revealed a potentially wide variance from the calculated dose. Based from their IVD method for TBI using Cobalt-60 irradiator and moving table, {+-}10% over entire body is hard to achieve. However, it can be significantly improved with immediate feedback after the first fraction prior to subsequent treatments.« less

Inhibition of gamma-radiation induced DNA damage in plasmid pBR322 by TMG, a water-soluble derivative of vitamin E.

PubMed

Rajagopalan, Rema; Wani, Khalida; Huilgol, Nagaraj G; Kagiya, Tsutomu V; Nair, Cherupally K Krishnan

2002-06-01

Alpha-tocopherol monoglucoside (TMG), a water-soluble derivative of alpha-tocopherol, has been examined for its ability to protect DNA against radiation-induced strand breaks. Gamma radiation, up to a dose of 6 Gy (dose rate, 0.7 Gy/minute), induced a dose-dependent increase in single strand breaks (SSBs) in plasmid pBR322 DNA. TMG inhibited the formation of gamma-radiation induced DNA single strand breaks (SSBs) in a concentration-dependent manner; 500 microM of TMG protected the single strand breaks completely. It also protected thymine glycol formation induced by gamma-radiation in a dose-dependent manner, based on an estimation of thymine glycol by HPLC.

Single shot near edge x-ray absorption fine structure spectroscopy in the laboratory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mantouvalou, I., E-mail: ioanna.mantouvalou@tu-berlin.de; Witte, K.; Martyanov, W.

With the help of adapted off-axis reflection zone plates, near edge X-ray absorption fine structure spectra at the C and N K-absorption edge have been recorded using a single 1.2 ns long soft X-ray pulse. The transmission experiments were performed with a laser-produced plasma source in the laboratory rendering time resolved measurements feasible independent on large scale facilities. A resolving power of E/ΔE ∼ 950 at the respective edges could be demonstrated. A comparison of single shot spectra with those collected with longer measuring time proves that all features of the used reference samples (silicon nitrate and polyimide) can be resolved in 1.2 ns.more » Hence, investigations of radiation sensitive biological specimen become possible due to the high efficiency of the optical elements enabling low dose experiments.« less

Fluconazole

MedlinePlus

... during pregnancy or abnormalities in developing babies when women are exposed to a single 150 mg dose of oral fluconazole to treat ... fluconazole (400-800 mg/day) taken by pregnant women for much longer than a single dose have resulted in reports of abnormalities at ...

Steady-state pharmacokinetics of fluvastatin in healthy subjects following a new extended release fluvastatin tablet, Lescol XL.

PubMed

Barilla, Denise; Prasad, Pratapa; Hubert, Martine; Gumbhir-Shah, Kavita

2004-03-01

This was an open-label, randomized, three-period, three-treatment, multiple dose, crossover study in 12 healthy male and female subjects. This study evaluated single dose and steady-state pharmacokinetics of fluvastatin following single and multiple dose administrations of a new extended release fluvastatin 8 h matrix tablet, Lescol XL 80 mg and 160 mg doses once a day. The study also included a twice a day administration of an immediate release (IR) form of fluvastatin capsule, Lescol, for comparative purposes. All doses were administered for 7 days. The safety and tolerability were also assessed. The pharmacokinetics of fluvastatin were evaluated on days 1 and 7 following each treatment. Fluvastatin systemic exposure was 50% less when administered as Lescol XL 80 mg qd compared with Lescol IR 40 mg bid. Conversely, fluvastatin systemic exposure was 22% higher when administered as Lescol XL 160 mg qd compared with Lescol IR 40 mg bid. Single doses of Lescol XL 80 mg and 160 mg were dose proportional but, deviation (30%) from dose proportionality was observed for the Lescol XL 160 mg at steady-state. There appeared to be moderate (20%-40%) accumulation of serum fluvastatin maximal concentrations and exposure after multiple doses of Lescol XL tablets. Both Lescol XL 80 mg and 160 mg showed delayed absorption and longer apparent elimination half-life compared with fluvastatin IR capsule. Single and multiple doses of fluvastatin were generally well tolerated in this healthy volunteer population. Adverse event profiles were consistent with the published safety profile of the marketed formulations. Aside from one incidence of creatine phosphokinase (CPK) elevation (following Lescol XL 160 mg qd treatment), there were no safety concerns with any of the treatments when administered acutely (7 days). Copyright 2004 John Wiley & Sons, Ltd.

Therapeutic effect of meropenem on an experimental guinea pig model of meningitis with type b β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae.

PubMed

Fujimoto, Koichi; Kanazawa, Katsunori; Takemoto, Koji; Urasaki, Kokichi; Ueda, Yutaka; Ubukata, Kimiko; Sunakawa, Keisuke

2013-08-01

The purpose of this study was to investigate the relationship between efficacy and percentage of time above the MIC (%T>MIC) in the cerebrospinal fluid (CSF) for different dosing regimens of meropenem against an experimental lethal meningitis model in guinea pigs with type b β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (Hib BLNAR). Guinea pigs were intrathecally inoculated with 10(8) CFU/head of Hib BLNAR 8 h before the start of therapy. A single dose of 20, 40, or 80 mg/kg meropenem or multiple doses of 40 mg/kg meropenem were subcutaneously administered. Numbers of bacteria in CSF were counted 8 h after the start of therapy. Meropenem concentration in serum and CSF were determined in infected guinea pigs receiving a single dose of 40 mg/kg. In the single-dose regimen, 40 and 80 mg/kg meropenem significantly reduced the number of bacteria in CSF compared with the control, but 20 mg/kg meropenem did not. The %T>MIC for an 8-h period of 20, 40, and 80 mg/kg meropenem were 41, 52, and 62, respectively. Two and four doses of 40 mg/kg meropenem, for both of which %T>MIC was calculated as 100, had similar efficacy and were significantly superior to a single-dose of 40 mg/kg. In conclusion, meropenem had high efficacy when %T>MIC in the CSF was increased because of the high dose level and shortening of the dosing interval in a guinea pig meningitis model caused by Hib BLNAR, suggesting that high and frequent doses of meropenem are useful for treatment of meningitis with Hib BLNAR.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gonçalves, Daniela

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 amore » 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.« less

The Effect of Route, Vehicle, and Divided Doses on the Pharmacokinetics of Chlorpyrifos and its Metabolite Trichloropyridinol in Neonatal Sprague-Dawley Rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marty, M. S.; Domoradzki, J. Y.; Hansen, S. C.

2007-12-01

There is a paucity of data on neonatal systemic exposure using different dosing paradigms. Male CD (Sprague-Dawley derived) rats at postnatal day (PND) 5 were dosed with chlorpyrifos (CPF, 1 mg/kg) using different routes of exposure, vehicles, and single vs. divided doses. Blood concentrations of CPF and its primary metabolite, trichloropyridinol (TCP), were measured at multiple times through 24 h. Groups included: single gavage bolus vs. divided gavage doses in corn oil (1 vs 3 times in 24 h), single gavage bolus vs. divided gavage doses in rat milk, and subcutaneous administration in DMSO. These data were compared with lactationalmore » exposure of PND 5 pups from dams exposed to CPF in the diet at 5 mg/kg/day for four weeks or published data from dams exposed to daily gavage with CPF at 5 mg/kg/day. Maternal blood CPF levels were an order of magnitude lower from dietary exposure than gavage (1.1 vs 14.8 ng/g), and blood CPF levels in PND 5 pups that nursed dietary-exposed or gavage-exposed dams were below the limit of detection. Single gavage doses of 1 mg/kg CPF in corn oil vehicle in pups resulted in CPF blood levels of 49 ng/g, and in milk vehicle about 9 ng/g. Divided doses led to lower peak CPF levels. A bolus dose of 1 mg/kg CPF in DMSO administered sc appeared to have substantially altered pharmacokinetics from orally administered chlorpyrifos. To be meaningful for risk assessment, neonatal studies require attention to the exposure scenario, since route, vehicle, dose and frequency of administration result in different systemic exposure to the test chemical and its metabolites.« less

Biology of high single doses of IORT: RBE, 5 R's, and other biological aspects.

PubMed

Herskind, Carsten; Ma, Lin; Liu, Qi; Zhang, Bo; Schneider, Frank; Veldwijk, Marlon R; Wenz, Frederik

2017-01-19

Intraoperative radiotherapy differs from conventional, fractionated radiotherapy in several aspects that may influence its biological effect. The radiation quality influences the relative biologic effectiveness (RBE), and the role of the five R's of radiotherapy (reassortment, repair, reoxygenation, repopulation, radiosensitivity) is different. Furthermore, putative special biological effects and the small volume receiving a high single dose may be important. The present review focuses on RBE, repair, and repopulation, and gives an overview of the other factors that potentially contribute to the efficacy. The increased RBE should be taken into account for low-energy X-rays while evidence of RBE < 1 for high-energy electrons at higher doses is presented. Various evidence supports a hypothesis that saturation of the primary DNA double-strand break (DSB) repair mechanisms leads to increasing use of an error-prone backup repair system leading to genomic instability that may contribute to inactivate tumour cells at high single doses. Furthermore, the elimination of repopulation of residual tumour cells in the tumour bed implies that some patients are likely to have very few residual tumour cells which may be cured even by low doses to the tumour bed. The highly localised dose distribution of IORT has the potential to inactivate tumour cells while sparing normal tissue by minimising the volume exposed to high doses. Whether special effects of high single doses also contribute to the efficacy will require further experimental and clinical studies.

Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers.

PubMed

de Kam, Pieter-Jan; van Kuijk, Jacqueline H M; Zandvliet, Anthe S; Thomsen, Torben

2015-09-01

Corifollitropin alfa (Elonva®) is the first hybrid follicle-stimulating hormone molecule with demonstrated sustained follicle-stimulating activity after a single subcutaneous injection. This trial evaluated if corifollitropin alfa is associated with QT/QTc prolongation and/ or proarrhythmic potential as compared to placebo in healthy post-menopausal women. Participants were healthy, postmenopausal women. Study treatments were corifollitropin alfa 150 μg, corifollitropin alfa 240 μg, and moxifloxacin 400 mg with placebo. This randomized, double blind, double-dummy, 4-period crossover trial compared single doses of corifollitropin alfa 150 μg (therapeutic dose), corifollitropin alfa 240 μg (supratherapeutic dose), and moxifloxacin 400 mg (positive control) with placebo. Corifollitropin alfa was administered on day 1 and moxifloxacin on day 2. The largest time-matched mean QTcF difference versus placebo for the therapeutic dose of corifollitropin alfa was 1.4 ms (upper limit of 1-sided 95% confidence interval (UL 95% CI) = 3.4 ms), and for the supratherapeutic dose was 1.2 ms (UL 95% CI = 3.6 ms). For both the therapeutic and the supratherapeutic dose of corifollitropin alfa and at all time points, the UL 95% CI for the time matched QTcF differences compared with placebo was below 10 ms, the threshold of relevance defined by the ICH E14 guideline. Single therapeutic and supratherapeutic doses of corifollitropin alfa are not associated with clinically relevant QT/QTc-interval prolongation in healthy post-menopausal women.

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

PubMed

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-daily dosing. Doravirine at steady state slightly reduced the exposure of coadministered midazolam, to a clinically unimportant extent.

Radiosurgery for the treatment of spinal lung metastases.

PubMed

Gerszten, Peter C; Burton, Steven A; Belani, Chandra P; Ramalingam, Suresh; Friedland, David M; Ozhasoglu, Cihat; Quinn, Annette E; McCue, Kevin J; Welch, William C

2006-12-01

Spinal metastases are a common source of pain as well as neurologic deficit in patients with lung cancer. Metastases from lung cancer traditionally have been believed to be relatively responsive to radiation therapy. However, conventional external beam radiotherapy lacks the precision to allow delivery of large single-fraction doses of radiation and simultaneously limit the dose to radiosensitive structures such as the spinal cord. The current study evaluated the efficacy of single-fraction radiosurgery for the treatment of spinal lung cancer metastases. In the current prospective cohort evaluation, 87 lung cancer metastases to the spine in 77 patients were treated with a single-fraction radiosurgery technique with a follow-up period of 6 to 40 months (median, 12 months). The indication for radiosurgery treatment was pain in 73 cases, as a primary treatment modality in 7 cases, for radiographic tumor progression in 4 cases, and for progressive neurologic deficit in 3 cases. Tumor volume ranged from 0.2 to 264 cm(3) (mean, 25.7 cm(3)). The maximum tumor dose was maintained at 15 to 25 grays (Gy) (mean, 20 Gy; median, 20 Gy). No radiation-induced toxicity occurred during the follow-up period. Long-term axial and radicular pain improvement occurred in 65 of 73 patients (89%) who were treated primarily for pain. Long-term radiographic tumor control was observed in all patients who underwent radiosurgery as their primary treatment modality or for radiographic tumor progression. Spinal radiosurgery was found to be feasible, safe, and clinically effective for the treatment of spinal metastases from lung cancer. The results of the current study indicate the potential of radiosurgery in the treatment of patients with spinal lung metastases, especially those with solitary sites of spine involvement, to improve long-term palliation. (c) 2006 American Cancer Society.

Economic and Microbiologic Evaluation of Single-Dose Vial Extension for Hazardous Drugs

PubMed Central

Rowe, Erinn C.; Savage, Scott W.; Rutala, William A.; Weber, David J.; Gergen-Teague, Maria; Eckel, Stephen F.

2012-01-01

Purpose: The update of US Pharmacopeia Chapter <797> in 2008 included guidelines stating that single-dose vials (SDVs) opened and maintained in an International Organization for Standardization Class 5 environment can be used for up to 6 hours after initial puncture. A study was conducted to evaluate the cost of discarding vials after 6 hours and to further test sterility of vials beyond this time point, subsequently defined as the beyond-use date (BUD). Methods: Financial determination of SDV waste included 2 months of retrospective review of all doses prescribed. Additionally, actual waste log data were collected. Active and control vials (prepared using sterilized trypticase soy broth) were recovered, instead of discarded, at the defined 6-hour BUD. Results: The institution-specific waste of 19 selected SDV medications discarded at 6 hours was calculated at $766,000 annually, and tracking waste logs for these same medications was recorded at $770,000 annually. Microbiologic testing of vial extension beyond 6 hours showed that 11 (1.86%) of 592 samples had one colony-forming unit on one of two plates. Positive plates were negative at subsequent time points, and all positives were single isolates most likely introduced during the plating process. Conclusion: The cost of discarding vials at 6 hours was significant for hazardous medications in a large academic medical center. On the basis of microbiologic data, vial BUD extension demonstrated a contamination frequency of 1.86%, which likely represented exogenous contamination; vial BUD extension for the tested drugs showed no growth at subsequent time points and could provide an annual cost savings of more than $600,000. PMID:23180998

Basal cardiomyopathy develops in rabbits with ventricular tachyarrhythmias induced by a single injection of adrenaline.

PubMed

Ashida, Terunao; Takato, Tetsuya; Matsuzaki, Gen; Seko, Yoshinori; Fujii, Jun; Kawai, Sachio

2014-01-01

We have recently demonstrated that basal cardiomyopathy develops in rabbits with ventricular tachyarrhythmias that have been induced by electrical stimulation of the cervical vagus. This study investigated whether similar basal cardiomyopathy would develop in rabbits with ventricular tachyarrhythmias induced by a single injection of adrenaline. Adrenaline was intravenously infused for 10-360 seconds in anesthetized rabbits. Colloidal carbon was injected after adrenaline infusion. Wall movement velocity of the left ventricular base was assessed by tissue Doppler echocardiography. Animals were killed either 1 week or 3-4 weeks later. Pathological lesions were identified by deposits of carbon particles. Animals were divided into two groups according to the infused dose of adrenaline. The small-dose group (group S, n = 15) received 1-10 μg and the large-dose group (group L, n = 23) received 15-60 μg of adrenaline. Adrenaline infusion induced premature ventricular contractions followed by monomorphic ventricular tachycardias in 22 of 23 animals in group L, but in only 1 of 15 animals in group S. Wall movement velocity of the left ventricular base decreased just after adrenaline infusion, remained low after 1 week, and recovered to near-baseline levels after 3-4 weeks in group L. Unique cardiac lesions identified by deposits of carbon particles were frequently observed on the left ventricular basal portion, almost always associated with the mitral valve and papillary muscles, but were never observed in the apical area. Lesions involving all areas of the left ventricular basal portion were observed in 22 of 23 animals in group L, but in only 2 of 15 animals in group S. Basal cardiomyopathy developed in rabbits with ventricular tachycardias induced by a single injection of adrenaline.

Interaction of different antidepressants with acute and chronic methadone in mice, and possible clinical implications.

PubMed

Schreiber, Shaul; Barak, Yonatan; Hostovsky, Avner; Baratz-Goldstein, Renana; Volis, Ina; Rubovitch, Vardit; Pick, Chaim G

2014-04-01

We studied the interaction of a single dose of different antidepressant medications with a single (acute) dose or implanted mini-pump (chronic) methadone administration in mice, using the hotplate assay. For the acute experiment, subthreshold doses of six antidepressant drugs were administered separately with a single dose of methadone. The addition of a subthreshold dose of desipramine or clomipramine to methadone produced significant augmentation of the methadone effect with each drug (p < 0.05). Fluvoxamine given at a fixed subthreshold dose induced a synergistic effect only with a low methadone dose. Escitalopram, reboxetine and venlafaxine given separately, each at a fixed subthreshold dose, induced no interaction. Possible clinical implications of these findings are that while escitalopram, reboxetine and venlafaxine do not affect methadone's antinociception in mice and are safe to be given together with methadone when indicated, fluvoxamine, clomipramine and desipramine considerably augment methadone-induced effects and should be avoided in this population due to the risk of inducing opiate overdose. For the chromic experiment, when a subthreshold dose of either escitalopram, desipramine or clomipramine was injected to mice following 2 weeks of methadone administration with the mini-pump, none of the antidepressant drugs strengthened methadone's analgesic effect. Further studies are needed before possible clinical implications can be drawn.

The Role of Alveolar Epithelium in Radiation-Induced Lung Injury

PubMed Central

Almeida, Celine; Nagarajan, Devipriya; Tian, Jian; Leal, Sofia Walder; Wheeler, Kenneth; Munley, Michael; Blackstock, William; Zhao, Weiling

2013-01-01

Pneumonitis and fibrosis are major lung complications of irradiating thoracic malignancies. In the current study, we determined the effect of thoracic irradiation on the lungs of FVB/N mice. Survival data showed a dose-dependent increase in morbidity following thoracic irradiation with single (11–13 Gy) and fractionated doses (24–36 Gy) of 137Cs γ-rays. Histological examination showed a thickening of vessel walls, accumulation of inflammatory cells, collagen deposition, and regional fibrosis in the lungs 14 weeks after a single 12 Gy dose and a fractionated 30 Gy dose; this damage was also seen 5 months after a fractionated 24 Gy dose. After both single and fractionated doses, i] aquaporin-5 was markedly decreased, ii] E-cadherin was reduced and iii] prosurfactant Protein C (pro-SP-c), the number of pro-SP-c+ cells and vimentin expression were increased in the lungs. Immunofluorescence analysis revealed co-localization of pro-SP-c and α-smooth muscle actin in the alveoli after a single dose of 12 Gy. These data suggest that, i] the FVB/N mouse strain is sensitive to thoracic radiation ii] aquaporin-5, E-cadherin, and pro-SP-c may serve as sensitive indicators of radiation-induced lung injury; and iii] the epithelial-to-mesenchymal transition may play an important role in the development of radiation-induced lung fibrosis. PMID:23326473

Evaluation of the RBC Pig-a and PIGRET assays using single doses of hydroxyurea and melphalan in rats.

PubMed

Adachi, Hideki; Uematsu, Yasuaki; Yamada, Toru

2016-11-15

To evaluate the suitability of the rat Pig-a assay on reticulocytes (PIGRET assay) as a short-term test, red blood cell (RBC) Pig-a and PIGRET assays after single doses with hydroxyurea (HU) and melphalan (L-PAM) were conducted and the results of both assays were compared. HU was administered once orally to male SD rats at 250, 500 and 1000mg/kg, and both assays were conducted using peripheral blood withdrawn from the jugular vein at 1, 2 and 4 weeks after dosing. L-PAM was administered at 1.25, 2.5 and 5mg/kg in the same manner. L-PAM produced significant dose-dependent increases in mutant frequencies in the PIGRET assay after single oral doses, but did not produce dose-dependent increases in mutant frequencies in the RBC Pig-a assay. These results suggest that the PIGRET assay is more sensitive for the evaluation of the mutagenic potential of L-PAM than the RBC Pig-a assay. In contrast, HU, a clastogenic but not DNA-reactive compound, gave negative results in both assays. The results with these 2 chemicals indicate that the single-dose PIGRET assay in rats has the potential to properly detect DNA-reactive compounds that directly cause DNA damage in a short-term assay. Copyright © 2016 Elsevier B.V. All rights reserved.

A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia

PubMed Central

Qin, Yan; Han, Xiaohong; Wang, Lin; Du, Ping; Yao, Jiarui; Wu, Di; Song, Yuanyuan; Zhang, Shuxiang; Tang, Le; Shi, Yuankai

2017-01-01

Objective The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. Methods Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 μg/kg) of PEG rhG-CSF were investigated. Results A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 μg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0–2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. Conclusions The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 μg/kg, 100 μg/kg and double half dose of 30 μg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment. PMID:29142459

A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia.

PubMed

Qin, Yan; Han, Xiaohong; Wang, Lin; Du, Ping; Yao, Jiarui; Wu, Di; Song, Yuanyuan; Zhang, Shuxiang; Tang, Le; Shi, Yuankai

2017-10-01

The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 μg/kg) of PEG rhG-CSF were investigated. A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 μg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0-2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 μg/kg, 100 μg/kg and double half dose of 30 μg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment.

4D radiobiological modelling of the interplay effect in conventionally and hypofractionated lung tumour IMRT.

PubMed

Selvaraj, J; Uzan, J; Baker, C; Nahum, A

2015-01-01

To study the impact of the interplay between respiration-induced tumour motion and multileaf collimator leaf movements in intensity-modulated radiotherapy (IMRT) as a function of number of fractions, dose rate on population mean tumour control probability ([Formula: see text]) using an in-house developed dose model. Delivered dose was accumulated in a voxel-by-voxel basis inclusive of tumour motion over the course of treatment. The effect of interplay on dose and [Formula: see text] was studied for conventionally and hypofractionated treatments using digital imaging and communications in medicine data sets. Moreover, the effect of dose rate on interplay was also studied for single-fraction treatments. Simulations were repeated several times to obtain [Formula: see text] for each plan. The average variation observed in mean dose to the target volumes were -0.76% ± 0.36% for the 20-fraction treatment and -0.26% ± 0.68% and -1.05% ± 0.98% for the three- and single-fraction treatments, respectively. For the 20-fraction treatment, the drop in [Formula: see text] was -1.05% ± 0.39%, whereas for the three- and single-fraction treatments, it was -2.80% ± 1.68% and -4.00% ± 2.84%, respectively. By reducing the dose rate from 600 to 300 MU min(-1) for the single-fraction treatments, the drop in [Formula: see text] was reduced by approximately 1.5%. The effect of interplay on [Formula: see text] is negligible for conventionally fractionated treatments, whereas considerable drop in [Formula: see text] is observed for the three- and single-fraction treatments. Reduced dose rate could be used in hypofractionated treatments to reduce the interplay effect. A novel in silico dose model is presented to determine the impact of interplay effect in IMRT treatments on [Formula: see text].

4D radiobiological modelling of the interplay effect in conventionally and hypofractionated lung tumour IMRT

PubMed Central

Uzan, J; Baker, C; Nahum, A

2015-01-01

Objective: To study the impact of the interplay between respiration-induced tumour motion and multileaf collimator leaf movements in intensity-modulated radiotherapy (IMRT) as a function of number of fractions, dose rate on population mean tumour control probability () using an in-house developed dose model. Methods: Delivered dose was accumulated in a voxel-by-voxel basis inclusive of tumour motion over the course of treatment. The effect of interplay on dose and was studied for conventionally and hypofractionated treatments using digital imaging and communications in medicine data sets. Moreover, the effect of dose rate on interplay was also studied for single-fraction treatments. Simulations were repeated several times to obtain for each plan. Results: The average variation observed in mean dose to the target volumes were −0.76% ± 0.36% for the 20-fraction treatment and −0.26% ± 0.68% and −1.05% ± 0.98% for the three- and single-fraction treatments, respectively. For the 20-fraction treatment, the drop in was −1.05% ± 0.39%, whereas for the three- and single-fraction treatments, it was −2.80% ± 1.68% and −4.00% ± 2.84%, respectively. By reducing the dose rate from 600 to 300 MU min−1 for the single-fraction treatments, the drop in was reduced by approximately 1.5%. Conclusion: The effect of interplay on is negligible for conventionally fractionated treatments, whereas considerable drop in is observed for the three- and single-fraction treatments. Reduced dose rate could be used in hypofractionated treatments to reduce the interplay effect. Advances in knowledge: A novel in silico dose model is presented to determine the impact of interplay effect in IMRT treatments on . PMID:25251400

Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

PubMed Central

Frost, Charles; Wang, Jessie; Nepal, Sunil; Schuster, Alan; Barrett, Yu Chen; Mosqueda-Garcia, Rogelio; Reeves, Richard A; LaCreta, Frank

2013-01-01

Aims To evaluate apixaban single dose safety, tolerability, pharmacokinetics and pharmacodynamics and assess the effect of food on apixaban pharmacokinetics. Methods A double-blind, placebo-controlled, single ascending-dose, first-in-human study assessed apixaban safety, pharmacokinetics and pharmacodynamics in healthy subjects randomized to oral apixaban (n = 43; 0.5–2.5 mg as solution or 5–50 mg as tablets) or placebo (n = 14) under fasted conditions. An open label, randomized, two treatment crossover study investigated apixaban pharmacokinetics/pharmacodynamics in healthy subjects (n = 21) administered apixaban 10 mg in fasted and fed states. Both studies measured apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT) or a modified PT (mPT). Results In the single ascending-dose study increases in apixaban exposure appeared dose-proportional. Median tmax occurred 1.5–3.3 h following oral administration. Mean terminal half-life ranged between 3.6 and 6.8 h following administration of solution doses ≤2.5 mg and between 11.1 and 26.8 h for tablet doses ≥5 mg. Concentration-related changes in pharmacodynamic assessments were observed. After a 50 mg dose, peak aPTT, INR and mPT increased by 1.2-, 1.6- and 2.9-fold, respectively, from baseline. In the food effect study: 90% confidence intervals of geometric mean ratios of apixaban Cmax and AUC in a fed vs. fasted state were within the predefined no effect (80–125%) range. Apixaban half-life was approximately 11.5 h. The effect of apixaban on INR, PT and aPTT was comparable following fed and fasted administration. Conclusions Single doses of apixaban were well tolerated with a predictable pharmacokinetic/pharmacodynamic profile and a half-life of approximately 12 h. Apixaban can be administered with or without food. PMID:22759198

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease

PubMed Central

Jia, Jing-ying; Zhao, Qian-hua; Liu, Yun; Gui, Yu-zhou; Liu, Gang-yi; Zhu, Da-yuan; Yu, Chen; Hong, Zhen

2013-01-01

Aim: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. Methods: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0–72 h and AUC0–∞ were calculated. Tolerance assessments were conducted throughout the study. Results: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76–0.82 h; the AUC0–72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. Conclusion: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers. PMID:23624756

A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception.

PubMed

Shohel, Mohammad; Rahman, Mohammad Mahfuzur; Zaman, Asif; Uddin, Mir Muhammad Nasir; Al-Amin, Md Mamun; Reza, Hasan Mahmud

2014-04-04

Unintended pregnancy is a complex phenomenon which raise to take an emergency decision. Low contraceptive prevalence and high user failure rates are the leading causes of this unexpected situation. High user failure rates suggest the vital role of emergency contraception to prevent unplanned pregnancy. Levonorgestrel - a commonly used progestin for emergency contraception. However, little is known about its pharmacokinetics and optimal dose for use. Hence, there is a need to conduct a systematic review of the available evidences. Randomized, double-blind trials were sought, evaluating healthy women with regular menstrual cycles, who requested emergency contraception within 72 h of unprotected coitus, to one of three regimens: 1.5 mg single dose levonorgestrel, two doses of 0.75 mg levonorgestrel given 12 h apart or two doses of 0.75 mg levonorgestrel given 24 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. Every trial under consideration successfully established the contraceptive effectiveness of levonorgestrel for preventing unintended pregnancy. Moreover, a single dose of levonorgestrel 1.5 mg for emergency contraception supports its safety and efficacy profile. If two doses of levonorgestrel 0.75 mg are intended for administration, the second dose can positively be taken 12-24 h after the first dose without compromising its contraceptive efficacy. The main side effect was frequent menstrual irregularities. No serious adverse events were reported. The review shows that, emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen. All the regimens studied were very efficacious for emergency contraception and prevented a high proportion of pregnancies if taken within 72 h of unprotected coitus. Single levonorgestrel dose (1.5 mg) can substitute two 0.75 mg doses 12 or 24 h apart. With either regimen, the earlier the treatment is given, the more effective it seems to be.

A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception

PubMed Central

2014-01-01

Background Unintended pregnancy is a complex phenomenon which raise to take an emergency decision. Low contraceptive prevalence and high user failure rates are the leading causes of this unexpected situation. High user failure rates suggest the vital role of emergency contraception to prevent unplanned pregnancy. Levonorgestrel - a commonly used progestin for emergency contraception. However, little is known about its pharmacokinetics and optimal dose for use. Hence, there is a need to conduct a systematic review of the available evidences. Methods Randomized, double-blind trials were sought, evaluating healthy women with regular menstrual cycles, who requested emergency contraception within 72 h of unprotected coitus, to one of three regimens: 1.5 mg single dose levonorgestrel, two doses of 0.75 mg levonorgestrel given 12 h apart or two doses of 0.75 mg levonorgestrel given 24 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. Results Every trial under consideration successfully established the contraceptive effectiveness of levonorgestrel for preventing unintended pregnancy. Moreover, a single dose of levonorgestrel 1.5 mg for emergency contraception supports its safety and efficacy profile. If two doses of levonorgestrel 0.75 mg are intended for administration, the second dose can positively be taken 12–24 h after the first dose without compromising its contraceptive efficacy. The main side effect was frequent menstrual irregularities. No serious adverse events were reported. Conclusions The review shows that, emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen. All the regimens studied were very efficacious for emergency contraception and prevented a high proportion of pregnancies if taken within 72 h of unprotected coitus. Single levonorgestrel dose (1.5 mg) can substitute two 0.75 mg doses 12 or 24 h apart. With either regimen, the earlier the treatment is given, the more effective it seems to be. PMID:24708837

A comprehensive formulation for volumetric modulated arc therapy planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Dan; Lyu, Qihui; Ruan, Dan

2016-07-15

Purpose: Volumetric modulated arc therapy (VMAT) is a widely employed radiation therapy technique, showing comparable dosimetry to static beam intensity modulated radiation therapy (IMRT) with reduced monitor units and treatment time. However, the current VMAT optimization has various greedy heuristics employed for an empirical solution, which jeopardizes plan consistency and quality. The authors introduce a novel direct aperture optimization method for VMAT to overcome these limitations. Methods: The comprehensive VMAT (comVMAT) planning was formulated as an optimization problem with an L2-norm fidelity term to penalize the difference between the optimized dose and the prescribed dose, as well as an anisotropicmore » total variation term to promote piecewise continuity in the fluence maps, preparing it for direct aperture optimization. A level set function was used to describe the aperture shapes and the difference between aperture shapes at adjacent angles was penalized to control MLC motion range. A proximal-class optimization solver was adopted to solve the large scale optimization problem, and an alternating optimization strategy was implemented to solve the fluence intensity and aperture shapes simultaneously. Single arc comVMAT plans, utilizing 180 beams with 2° angular resolution, were generated for a glioblastoma multiforme case, a lung (LNG) case, and two head and neck cases—one with three PTVs (H&N{sub 3PTV}) and one with foue PTVs (H&N{sub 4PTV})—to test the efficacy. The plans were optimized using an alternating optimization strategy. The plans were compared against the clinical VMAT (clnVMAT) plans utilizing two overlapping coplanar arcs for treatment. Results: The optimization of the comVMAT plans had converged within 600 iterations of the block minimization algorithm. comVMAT plans were able to consistently reduce the dose to all organs-at-risk (OARs) as compared to the clnVMAT plans. On average, comVMAT plans reduced the max and mean OAR dose by 6.59% and 7.45%, respectively, of the prescription dose. Reductions in max dose and mean dose were as high as 14.5 Gy in the LNG case and 15.3 Gy in the H&N{sub 3PTV} case. PTV coverages measured by D95, D98, and D99 were within 0.25% of the prescription dose. By comprehensively optimizing all beams, the comVMAT optimizer gained the freedom to allow some selected beams to deliver higher intensities, yielding a dose distribution that resembles a static beam IMRT plan with beam orientation optimization. Conclusions: The novel nongreedy VMAT approach simultaneously optimizes all beams in an arc and then directly generates deliverable apertures. The single arc VMAT approach thus fully utilizes the digital Linac’s capability in dose rate and gantry rotation speed modulation. In practice, the new single VMAT algorithm generates plans superior to existing VMAT algorithms utilizing two arcs.« less

Use of volumetric-modulated arc therapy for treatment of Hodgkin lymphoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Young K., E-mail: Young.Lee@rmh.nhs.uk; Bedford, James L.; Taj, Mary

To evaluate volumetric-modulated arc therapy (VMAT) for treatment of Hodgkin lymphoma (HL) in patients where conventional radiotherapy was not deliverable. A planning computed tomography (CT) scan was acquired for a twelve-year-old boy with Stage IIIB nodular sclerosing HL postchemotherapy with positive positron emission tomography scan. VMAT was used for Phase 1 (19.8 Gy in 11 fractions) and Phase 2 (10.8 Gy in 6 fractions) treatment plans. Single anticlockwise arc plans were constructed using SmartArc (Philips Radiation Oncology Systems, Fitchburg, WI) with control points spaced at 4°. The inverse-planning objectives were to uniformly irradiate the planning target volume (PTV) with themore » prescription dose while keeping the volume of lung receiving greater than 20 Gy (V{sub 20} {sub Gy}) to less than 30% and minimize the dose to the other adjacent organs at risk (OAR). Pretreatment verification was conducted and the treatment delivery was on an MLCi Synergy linear accelerator (Elekta Ltd, Crawley, UK). The planning results were retrospectively confirmed in a further 4 patients using a single PTV with a prescribed dose of 19.8 Gy in 11 fractions. Acceptable dose coverage and homogeneity were achieved for both Phase 1 and 2 plans while keeping the lung V{sub 20} {sub Gy} at 22.5% for the composite plan. The beam-on times for Phase 1 and Phase 2 plans were 109 and 200 seconds, respectively, and the total monitor units were 337.2 MU and 292.5 MU, respectively. The percentage of measured dose points within 3% and 3 mm for Phase 1 and Phase 2 were 92% and 98%, respectively. Both plans were delivered successfully. The retrospective planning study showed that VMAT improved PTV dose uniformity and reduced the irradiated volume of heart and lung, although the volume of lung irradiated to low doses increased. Two-phased VMAT offers an attractive option for large volume sites, such as HL, giving a high level of target coverage and significant OAR sparing together with efficient delivery.« less

Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization

PubMed Central

Cao, G; Zhang, J; Wu, X; Yu, J; Chen, Y; Ye, X; Zhu, D; Zhang, Y; Guo, B; Shi, Y

2013-01-01

What is known and objective The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen. Methods The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fCmax/MIC ≥5 and fAUC24 h/MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated. Results and discussion The results of PK study showed that the Cmax and AUC0–∞ of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean Css,max, Css,min and AUC0–τ of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fCmax/MIC and fAUC/MIC targets. What is new and conclusion The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results. PMID:23701411

Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization.

PubMed

Cao, G; Zhang, J; Wu, X; Yu, J; Chen, Y; Ye, X; Zhu, D; Zhang, Y; Guo, B; Shi, Y

2013-10-01

The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen. The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fC(max) /MIC ≥5 and fAUC(24 h) /MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated. The results of PK study showed that the C(max) and AUC(0-∞) of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean C(ss,max), C(ss,min) and AUC(0-τ) of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fC(max) /MIC and fAUC/MIC targets. The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results. © 2013 John Wiley & Sons Ltd.

An Automated Test of Rat Forelimb Supination Quantifies Motor Function Loss and Recovery After Corticospinal Injury.

PubMed

Sindhurakar, Anil; Butensky, Samuel D; Meyers, Eric; Santos, Joshua; Bethea, Thelma; Khalili, Ashley; Sloan, Andrew P; Rennaker, Robert L; Carmel, Jason B

2017-02-01

Rodents are the primary animal model of corticospinal injury and repair, yet current behavioral tests do not show the large deficits after injury observed in humans. Forearm supination is critical for hand function and is highly impaired by corticospinal injury in both humans and rats. Current tests of rodent forelimb function do not measure this movement. To determine if quantification of forelimb supination in rats reveals large-scale functional loss and partial recovery after corticospinal injury. We developed a knob supination device that quantifies supination using automated and objective methods. Rats in a reaching box have to grasp and turn a knob in supination in order to receive a food reward. Performance on this task and the single pellet reaching task were measured before and after 2 manipulations of the pyramidal tract: a cut lesion of 1 pyramid and inactivation of motor cortex using 2 different drug doses. A cut lesion of the corticospinal tract produced a large deficit in supination. In contrast, there was no change in pellet retrieval success. Supination function recovered partially over 6 weeks after injury, and a large deficit remained. Motor cortex inactivation produced a dose-dependent loss of knob supination; the effect on pellet reaching was more subtle. The knob supination task reveals in rodents 3 signature hand function changes observed in humans with corticospinal injury: (1) large-scale loss with injury, (2) partial recovery in the weeks after injury, and (3) loss proportional to degree of dysfunction.

Low dose digital X-ray imaging with avalanche amorphous selenium

NASA Astrophysics Data System (ADS)

Scheuermann, James R.; Goldan, Amir H.; Tousignant, Olivier; Léveillé, Sébastien; Zhao, Wei

2015-03-01

Active Matrix Flat Panel Imagers (AMFPI) based on an array of thin film transistors (TFT) have become the dominant technology for digital x-ray imaging. In low dose applications, the performance of both direct and indirect conversion detectors are limited by the electronic noise associated with the TFT array. New concepts of direct and indirect detectors have been proposed using avalanche amorphous selenium (a-Se), referred to as high gain avalanche rushing photoconductor (HARP). The indirect detector utilizes a planar layer of HARP to detect light from an x-ray scintillator and amplify the photogenerated charge. The direct detector utilizes separate interaction (non-avalanche) and amplification (avalanche) regions within the a-Se to achieve depth-independent signal gain. Both detectors require the development of large area, solid state HARP. We have previously reported the first avalanche gain in a-Se with deposition techniques scalable to large area detectors. The goal of the present work is to demonstrate the feasibility of large area HARP fabrication in an a-Se deposition facility established for commercial large area AMFPI. We also examine the effect of alternative pixel electrode materials on avalanche gain. The results show that avalanche gain > 50 is achievable in the HARP layers developed in large area coaters, which is sufficient to achieve x-ray quantum noise limited performance down to a single x-ray photon per pixel. Both chromium (Cr) and indium tin oxide (ITO) have been successfully tested as pixel electrodes.

Single oral dose of 1-5g. talampicillin in the treatment of gonorrhoea.

PubMed Central

Willcox, R R

1976-01-01

81 patients have been treated with single oral doses of 1-5 g. (6 tablets) of talampicillin without probenecid. The failure rate amongst those followed was only 4-2 per cent. No side-effects were reported. These results were superior to those obtained with 2-0g. or equivalent of ampicillin, amoxycillin, or pivampicillin with probenecid. Talampicillin is thus the most potent ampicillin-like antibiotic so far available for the treatment of gonorrhoea and is capable of curing the disease with a smaller single dose without probenecid than is necessary for other preparations. PMID:1276866

The maximum single dose of resistant maltodextrin that does not cause diarrhea in humans.

PubMed

Kishimoto, Yuka; Kanahori, Sumiko; Sakano, Katsuhisa; Ebihara, Shukuko

2013-01-01

The objective of the present study was to determine the maximum dose of resistant maltodextrin (Fibersol)-2, a non-viscous water-soluble dietary fiber), that does not induce transitory diarrhea. Ten healthy adult subjects (5 men and 5 women) ingested Fibersol-2 at increasing dose levels of 0.7, 0.8, 0.9, 1.0, and 1.1 g/kg body weight (bw). Each administration was separated from the previous dose by an interval of 1 wk. The highest dose level that did not cause diarrhea in any subject was regarded as the maximum non-effective level for a single dose. The results showed that no subject of either sex experienced diarrhea at dose levels of 0.7, 0.8, 0.9, or 1.0 g/kg bw. At the highest dose level of 1.1 g/kg bw, no female subject experienced diarrhea, whereas 1 male subject developed diarrhea with muddy stools 2 h after ingestion of the test substance. Consequently, the maximum non-effective level for a single dose of the resistant maltodextrin Fibersol-2 is 1.0 g/kg bw for men and >1.1 g/kg bw for women. Gastrointestinal symptoms were gurgling sounds in 4 subjects (7 events) and flatus in 5 subjects (9 events), although no association with dose level was observed. These symptoms were mild and transient and resolved without treatment.

Single dose (400 mg) versus 7 day (200 mg) daily dose itraconazole in the treatment of tinea versicolor: a randomized clinical trial.

PubMed

Wahab, M A; Ali, M E; Rahman, M H; Chowdhury, S A; Monamie, N S; Sultana, N; Khondoker, L

2010-01-01

Tinea (pityriasis) versicolor is a superficial fungal infection and one of the most commonly found pigmentary disorders of skin caused by the yeast Malassezia. Multiple topical as well as systemic therapies are available for treatment. Systemic therapies are used for extensive disease, frequent relapse or where topical agents have failed. The aim that translates the rationale of the study was to compare the efficacy, safety, tolerability and cost effectiveness of single dose 400mg versus 7 day 200 mg daily dose of itraconazole in the treatment of tinea versicolor. A clinical study was done to compare the efficacy of single dose (400 mg) of itraconazole and 7 day 200 mg daily dose of itraconazole in the treatment of extensive tinea versicolor. Total 60 patients (aged 18-50 years) were selected for the study during the period of June 2007 to May 2008 in the department of Dermatology of three different hospitals in Bangladesh. Cases having with extensive involvement, diagnosed clinically and confirmed by wood's lamp and KOH microscopy were taken. Patients were randomly allocated into equal groups. Group A was given single dose 400 mg itraconazole and Group B was given 7 day 200 mg daily itraconazole. Fifty three (88%) male and 7(12%) female were included in the study. The mean age of group A was 32.37+/-9 years and in group B 33.23+/-8 years. The mean duration of the disease in group A was 2.63+/-2 months and 2.76+/-2 months in group B. In group A clinical responders was found cure 22(73.33%) and improvement 5(16.33%) and in group B it was found cure 24(79.99%) and improvement 4(13.33%). The measure at the End point (EP1) equals to 90% response and in-group B it was found cure 24 (79.99%) and improvement 4(13.33%). (Here the End point EP2) equals to 93.33%. The EP clinical analysis however shows 91.66% response. Both single dose and 7 day daily dose of itraconazole can be effective in the treatment of tinea versicolor with extensive involvement but single dose appears to be better for improving compliance and decreasing the cost of treatment.

Pharmacokinetics and food interaction of a novel prodrug of tenofovir, tenofovir dipivoxil fumarate, in healthy volunteers.

PubMed

Lu, C; Jia, Y; Chen, L; Ding, Y; Yang, J; Chen, M; Song, Y; Sun, X; Wen, A

2013-04-01

Tenofovir dipivoxil fumarate is a novel ester prodrug of tenofovir, a specific anti-hepatitis B virus (HBV) drug candidate. The pharmacokinetic properties and the effects of food intake on tenofovir dipivoxil have not yet been reported in healthy adults. The aim of this study was to evaluate the pharmacokinetic properties and food interaction of tenofovir dipivoxil in healthy Chinese volunteers. Pharmacokinetic studies included an ascending single dose of 150, 300, 600 mg and multiple doses of 300 mg. Food interaction was evaluated following a single oral dose of tenofovir dipivoxil fumarate 300 mg administered with a high-fat and high-energy standard breakfast or after a 12-h fast. Pharmacokinetic parameters of tenofovir given in each treatment period were calculated using non-compartmental analysis. After a single dose of 150, 300 and 600 mg, the main pharmacokinetic parameters for tenofovir were as follows: Cmax 209·6, 456·7, 989·8 ng/mL; AUClast 1744·9, 2663·5, 6010·2 ng h/mL, respectively. After multiple doses of 300 mg, the main pharmacokinetic parameters for tenofovir were Cmax 523·4 ng/mL, AUClast 4152·4 ng h/mL. After a single dose of 300 mg with a high-fat and high-energy standard breakfast, the main pharmacokinetic parameters for tenofovir were Cmax 448·5 ng/mL, AUClast 3286·8 ng h/mL. The plasma Cmax and AUC of tenofovir showed significance difference between a single dose of 300 mg and the accordingly multiple doses (P < 0·05). A standard high-fat meal enhanced mean AUClast values of tenofovir (relative AUClast  = 125·8%; 90% CI 114·5, 136·2); however, food did not show any significant on Cmax (relative Cmax  = 103·4%; 90% CI 94·6, 112·6). Oral tenofovir dipivoxil fumarate produced predictable and dose-proportional plasma tenofovir pharmacokinetics. The accumulation ratio was 1·51, suggesting tenofovir dipivoxil fumarate displayed accumulation after repeated administration. The bioavailability of tenofovir dipivoxil fumarate was increased by approximately 25% as measured by AUClast after a single dose when taken with food, compared with fasting. © 2012 Blackwell Publishing Ltd.

Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies.

PubMed

Planchard, David; Brown, Kathryn H; Kim, Dong-Wan; Kim, Sang-We; Ohe, Yuichiro; Felip, Enriqueta; Leese, Philip; Cantarini, Mireille; Vishwanathan, Karthick; Jänne, Pasi A; Ranson, Malcolm; Dickinson, Paul A

2016-04-01

Osimertinib (AZD9291) 80 mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure. AURA (NCT01802632): single- and multiple-dose PK of osimertinib (20-240 mg daily) was determined in patients with advanced NSCLC. Bioavailability study (NCT01951599): single-dose PK of osimertinib (20 mg) was determined in healthy volunteers with administration of capsule, solution, or tablet formulations fasted, and as a tablet in the fed and fasted state. Osimertinib was slowly absorbed and displayed dose-proportional increases in exposure from 20 to 240 mg. Distribution was extensive and clearance low to moderate, resulting in a mean half-life of 48.3 h. Steady state was achieved by 15 days of dosing, consistent with single-dose PK, with a peak-to-trough ratio of 1.6. Two active metabolites circulated at ~10 % of osimertinib exposure. Ethnicity did not appear to affect exposure. Osimertinib PK profiles in healthy volunteers were similar to those in patients and were unaffected by formulation. Food caused a clinically insignificant increase in exposure. Osimertinib PK supports once-daily dosing; the same dose for Asian and non-Asian populations; a fixed-dosing approach; a minimal effect of food on exposure; and a switch to tablet formulation without alteration to dose or schedule. Osimertinib plasma concentrations are sustained throughout the dosing period, which is considered optimal for efficacy.

Single-dose ceftriaxone for chancroid.

PubMed Central

Bowmer, M I; Nsanze, H; D'Costa, L J; Dylewski, J; Fransen, L; Piot, P; Ronald, A R

1987-01-01

Men with genital ulcers that were culture positive for Haemophilus ducreyi were treated with intramuscular ceftriaxone and randomized to three different dose regimens. All but 1 of 50 men treated with 1 g of intramuscular ceftriaxone were cured. Similarly, 0.5 and 0.25 g cured 43 of 44 men and 37 of 38 men, respectively. A single dose of 250 mg of intramuscular ceftriaxone is an effective treatment for chancroid. PMID:3566241

Failure Rate of Single Dose Methotrexate in Managment of Ectopic Pregnancy

PubMed Central

Sendy, Feras; AlShehri, Eman; AlAjmi, Amani; Bamanie, Elham; Appani, Surekha; Shams, Taghreed

2015-01-01

Background. One of the treatment modalities for ectopic pregnancy is methotrexate. The purpose of this study is to identify the failure rate of methotrexate in treating patients with ectopic pregnancy as well as the risk factors leading to treatment failure. Methods. A retrospective chart review of 225 patients who received methotrexate as a primary management option for ectopic pregnancy. Failure of single dose of methotrexate was defined as drop of BHCG level less than or equal to 14% in the seventh day after administration of methotrexate. Results. 225 patients had methotrexate. Most of the patients (151 (67%)) received methotrexate based on the following formula: f 50 mg X body surface area. Single dose of methotrexate was successful in 72% (162/225) of the patients. 28% (63/225) were labeled as failure of single dose of methotrexate because of suboptimal drop in BhCG. 63% (40/63) of failure received a second dose of methotrexate, and 37% (23/63) underwent surgical treatment. Among patient who received initial dose of methotrexate, 71% had moderate or severe pain, and 58% had ectopic mass size of more than 4 cm on ultrasound. Conclusion. Liberal use of medical treatment of ectopic pregnancy results in 71% success rate. PMID:25861275

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects.

PubMed

Krishna, Rajesh; Gheyas, Ferdous; Liu, Yang; Cote, Josee; Laterza, Omar; Ruckle, Jon L; Wagner, John A; Denker, Andrew E

2018-02-01

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects. © 2017, The American College of Clinical Pharmacology.

Bioequivalence of fixed-dose combination Myrin®-P Forte and reference drugs in loose combination.

PubMed

Wang, H F; Wang, R; O'Gorman, M; Crownover, P; Naqvi, A; Jafri, I

2013-12-01

Myrin®-P Forte is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg), isoniazid (INH, 75 mg), ethambutol (EMB) hydrochloride (275 mg) and pyrazinamide (PZA, 400 mg) developed for the treatment of tuberculosis (TB). This study was conducted at a single centre--the Pfizer Clinical Research Unit in Singapore. To demonstrate the bioequivalence of each drug component of the Myrin-P Forte FDC and the individual product in loose combination. In a randomized, open-label, single-dose, two-way, crossover study, subjects received single doses of Myrin-P Forte or four individual products under fasting conditions in a crossover fashion with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (C(max)) and the area under plasma concentration-time curve (AUC). Of 36 subjects enrolled, 35 completed the study. The adjusted geometric mean ratios and 90% confidence intervals for C(max) and AUC values were completely contained within bioequivalence limits (80%, 125%) for all four drugs in both formulations. Both treatments were generally well tolerated in the study. The Myrin-P Forte FDC tablet formulation is bioequivalent to the four single-drug references for RMP, INH, EMB hydrochloride and PZA at equivalent doses.

Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and Patch Administration in Rats.

PubMed

Lee, Soo-Han; Kim, Seung-Hyun; Noh, Yook-Hwan; Choi, Byung-Moon; Noh, Gyu-Jeong; Park, Woo-Dae; Kim, Eun-Jung; Cho, Ik-Hyun; Bae, Chun-Sik

2016-02-01

Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Pharmacokinetics of pregabalin controlled-release in healthy volunteers: effect of food in five single-dose, randomized, clinical pharmacology studies.

PubMed

Chew, Marci L; Plotka, Anna; Alvey, Christine W; Pitman, Verne W; Alebic-Kolbah, Tanja; Scavone, Joseph M; Bockbrader, Howard N

2014-09-01

The pharmacokinetic properties of the immediate-release (IR) and the recently developed controlled-release (CR) formulation of pregabalin are dose proportional. Pregabalin IR can be taken with or without food. This analysis characterizes the effect of food on pregabalin CR. The objectives of this analysis were: (1) to evaluate the effect of administration time and fat or caloric content of an accompanying meal on the pharmacokinetic properties of a single dose of pregabalin CR (330 mg) relative to a single dose of pregabalin IR (300 mg); (2) to evaluate the pharmacokinetic properties of a single dose of pregabalin CR administered fasted relative to a single dose of pregabalin CR administered immediately after food; and (3) to determine the safety and tolerability of single-dose administration of pregabalin CR and IR with and without food. The effect of food on the pharmacokinetic properties of pregabalin CR was determined in five phase I, open-label, single-dose, crossover studies (24-28 participants/study). Caloric and fat content of meals were varied and treatments were administered in the morning, at midday, or in the evening. Blood samples were collected up to 48 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. One hundred and twenty-eight healthy participants (19-54 years of age) received pregabalin. Peak plasma concentrations (C max) were lower for CR than the respective pregabalin IR doses, and time to C max occurred later. When pregabalin CR was administered with food at midday or in the evening, total exposures [area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC∞)] were equivalent for pregabalin CR and IR formulations regardless of fat or caloric content. When pregabalin CR was administered with an 800-1,000 calorie medium-fat breakfast, AUC∞ was equivalent for pregabalin CR and IR. Bioequivalence criteria for comparison of pregabalin CR after a low- or medium-calorie breakfast relative to pregabalin IR were not met; however, bioavailability of the pregabalin CR vs. IR formulation was relatively high (75-86 %). When pregabalin CR was administered fasted, the AUC∞ was 70-78 % of the AUC∞ of pregabalin CR administered with food and bioequivalence criteria were not met. Additionally, the AUC∞ of the pregabalin CR formulation administered fasted was 62-69 % of that of pregabalin IR administered fasted and bioequivalence criteria were not met. Single-dose pregabalin CR and IR were well tolerated in all studies, with no serious or severe adverse events reported. Time of day of administration and the fat and caloric content of the accompanying meal had minimal overall effect on the pharmacokinetic properties and bioavailability of the pregabalin CR formulation.

SU-E-T-13: Comparison of Dose Rates with and without Gold Backing of USC #9 Radioactive Eye Plaque Using MCNP5.

PubMed

Aryal, P; Molloy, J

2012-06-01

To show the effect of gold backing on dose rates for the USC #9 radioactive eye plaque. An I125 source (IsoAid model IAI-125A) and gold backing was modeled using MCNP5 Monte Carlo code. A single iodine seed was simulated with and without gold backing. Dose rates were calculated in two orthogonal planes. Dose calculation points were structured in two orthogonal planes that bisect the center of the source. A 2×2 cm matrix of spherical points of radius 0.2 mm was created in a water phantom of 10 cm radius. 0.2 billion particle histories were tracked. Dose differences with and without the gold backing were analyzed using Matlab. The gold backing produced a 3% increase in the dose rate near the source surface (<1mm) relative to that without the backing. This was presumably caused by fluorescent photons from the gold. At distances between 1 and 2 cm, the gold backing reduced the dose rate by up to 12%, which we attribute to a lack of scatter resulting from the attenuation from the gold. Dose differences were most pronounced in the radial direction near the source center but off axis. The dose decreased by 25%, 65% and 81% at 1, 2, and 3 mm off axis at a distance of 1 mm from the source surface. These effects were less pronounced in the perpendicular dimension near the source tip, where maximum dose decreases of 2% were noted. I 125 sources embedded directly into gold troughs display dose differences of 2 - 90%, relative to doses without the gold backing. This is relevant for certain types of plaques used in treatment of ocular melanoma. Large dose reductions can be observed and may have implications for scleral dose reduction. © 2012 American Association of Physicists in Medicine.

Nasal decongestants in monotherapy for the common cold.

PubMed

Deckx, Laura; De Sutter, An Im; Guo, Linda; Mir, Nabiel A; van Driel, Mieke L

2016-10-17

Many treatments for the common cold exist and are sold over-the-counter. Nevertheless, evidence on the effectiveness and safety of nasal decongestants is limited. To assess the efficacy, and short- and long-term safety, of nasal decongestants used in monotherapy to alleviate symptoms of the common cold in adults and children. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 6, June 2016), which contains the Cochrane Acute Respiratory Infections (ARI) Specialised Register, MEDLINE (1946 to July 2016), Embase (2010 to 15 July 2016), CINAHL (1981 to 15 July 2016), LILACS (1982 to July 2016), Web of Science (1955 to July 2016) and clinical trials registers. Randomised controlled trials (RCTs) and cluster-RCTs investigating the effectiveness and adverse effects of nasal decongestants compared with placebo for treating the common cold in adults and children. We excluded quasi-RCTs. Three review authors independently extracted and summarised data on subjective measures of nasal congestion, overall patient well-being score, objective measures of nasal airway resistance, adverse effects and general recovery. One review author acted as arbiter in cases of disagreement. We categorised trials as single and multi-dose and analysed data both separately and together. We also analysed studies using an oral or topical nasal decongestant separately and together. We included 15 trials with 1838 participants. Fourteen studies included adult participants only (aged 18 years and over). In six studies the intervention was a single dose and in nine studies multiple doses were used. Nine studies used pseudoephedrine and three studies used oxymetazoline. Other decongestants included phenylpropanolamine, norephedrine and xylometazoline. Phenylpropanolamine (or norephedrine) is no longer available on the market therefore we did not include the results of these studies in the meta-analyses. Eleven studies used oral decongestants; four studies used topical decongestants.Participants were included after contracting the common cold. The duration of symptoms differed among studies; in 10 studies participants had symptoms for less than three days, in three studies symptoms were present for less than five days, one study counted the number of colds over one year, and one study experimentally induced the common cold. In the single-dose studies, the effectiveness of a nasal decongestant was measured on the same day, whereas the follow-up in multi-dose studies ranged between one and 10 days.Most studies were conducted in university settings (N = eight), six at a specific university common cold centre. Three studies were conducted at a university in collaboration with a hospital and two in a hospital only setting. In two studies the setting was unclear.There were large differences in the reporting of outcomes and the reporting of methods in most studies was limited. Therefore, we judged most studies to be at low or unclear risk of bias. Pooling was possible for a limited number of studies only; measures of effect are expressed as standardised mean differences (SMDs). A positive SMD represents an improvement in congestion. There is no defined minimal clinically important difference for measures of subjective improvement in nasal congestion, therefore we used the SMDs as a guide to assess whether an effect was small (0.2 to 0.49), moderate (0.5 to 0.79) or large (≥ 0.8).Single-dose decongestant versus placebo: 10 studies compared a single dose of nasal decongestant with placebo and their effectiveness was tested between 15 minutes and 10 hours after dosing. Seven of 10 studies reported subjective symptom scores for nasal congestion; none reported overall patient well-being. However, pooling was not possible due to the large diversity in the measurement and reporting of symptoms of congestion. Two studies recorded adverse events. Both studies used an oral decongestant and each of them showed that there was no statistical difference between the number of adverse events in the treatment group versus the placebo group.Multi-dose decongestant versus placebo: nine studies compared multiple doses of nasal decongestants with placebo, but only five reported on the primary outcome, subjective symptom scores for nasal congestion. Only one study used a topical decongestant; none reported overall patient well-being. Subjective measures of congestion were significantly better for the treatment group compared with placebo approximately three hours after the last dose (SMD 0.49, 95% confidence interval (CI) 0.07 to 0.92; P = 0.02; GRADE: low-quality evidence). However, the SMD of 0.49 only indicates a small clinical effect. Pooling was based on two studies, one oral and one topical, therefore we were unable to assess the effects of oral and topical decongestants separately. Seven studies reported adverse events (six oral and one topical decongestant); meta-analysis showed that there was no statistical difference between the number of adverse events in the treatment group (125 per 1000) compared to the placebo group (126 per 1000). The odds ratio (OR) for adverse events in the treatment group was 0.98 (95% CI 0.68 to 1.40; P = 0.90; GRADE: low-quality evidence). The results remained the same when we only considered studies using an oral decongestant (OR 0.95, 95% CI 0.65 to 1.39; P = 0.80; GRADE: low-quality evidence). We were unable to draw conclusions on the effectiveness of single-dose nasal decongestants due to the limited evidence available. For multiple doses of nasal decongestants, the current evidence suggests that these may have a small positive effect on subjective measures of nasal congestion in adults with the common cold. However, the clinical relevance of this small effect is unknown and there is insufficient good-quality evidence to draw any firm conclusions. Due to the small number of studies that used a topical nasal decongestant, we were also unable to draw conclusions on the effectiveness of oral versus topical decongestants. Nasal decongestants do not seem to increase the risk of adverse events in adults in the short term. The effectiveness and safety of nasal decongestants in children and the clinical relevance of their small effect in adults is yet to be determined.

Incorporating single-side sparing in models for predicting parotid dose sparing in head and neck IMRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yuan, Lulin, E-mail: lulin.yuan@duke.edu; Wu, Q. Jackie; Yin, Fang-Fang

2014-02-15

Purpose: Sparing of single-side parotid gland is a common practice in head-and-neck (HN) intensity modulated radiation therapy (IMRT) planning. It is a special case of dose sparing tradeoff between different organs-at-risk. The authors describe an improved mathematical model for predicting achievable dose sparing in parotid glands in HN IMRT planning that incorporates single-side sparing considerations based on patient anatomy and learning from prior plan data. Methods: Among 68 HN cases analyzed retrospectively, 35 cases had physician prescribed single-side parotid sparing preferences. The single-side sparing model was trained with cases which had single-side sparing preferences, while the standard model was trainedmore » with the remainder of cases. A receiver operating characteristics (ROC) analysis was performed to determine the best criterion that separates the two case groups using the physician's single-side sparing prescription as ground truth. The final predictive model (combined model) takes into account the single-side sparing by switching between the standard and single-side sparing models according to the single-side sparing criterion. The models were tested with 20 additional cases. The significance of the improvement of prediction accuracy by the combined model over the standard model was evaluated using the Wilcoxon rank-sum test. Results: Using the ROC analysis, the best single-side sparing criterion is (1) the predicted median dose of one parotid is higher than 24 Gy; and (2) that of the other is higher than 7 Gy. This criterion gives a true positive rate of 0.82 and a false positive rate of 0.19, respectively. For the bilateral sparing cases, the combined and the standard models performed equally well, with the median of the prediction errors for parotid median dose being 0.34 Gy by both models (p = 0.81). For the single-side sparing cases, the standard model overestimates the median dose by 7.8 Gy on average, while the predictions by the combined model differ from actual values by only 2.2 Gy (p = 0.005). Similarly, the sum of residues between the modeled and the actual plan DVHs is the same for the bilateral sparing cases by both models (p = 0.67), while the standard model predicts significantly higher DVHs than the combined model for the single-side sparing cases (p = 0.01). Conclusions: The combined model for predicting parotid sparing that takes into account single-side sparing improves the prediction accuracy over the previous model.« less

Incorporating single-side sparing in models for predicting parotid dose sparing in head and neck IMRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yuan, Lulin, E-mail: lulin.yuan@duke.edu; Wu, Q. Jackie; Yin, Fang-Fang

Purpose: Sparing of single-side parotid gland is a common practice in head-and-neck (HN) intensity modulated radiation therapy (IMRT) planning. It is a special case of dose sparing tradeoff between different organs-at-risk. The authors describe an improved mathematical model for predicting achievable dose sparing in parotid glands in HN IMRT planning that incorporates single-side sparing considerations based on patient anatomy and learning from prior plan data. Methods: Among 68 HN cases analyzed retrospectively, 35 cases had physician prescribed single-side parotid sparing preferences. The single-side sparing model was trained with cases which had single-side sparing preferences, while the standard model was trainedmore » with the remainder of cases. A receiver operating characteristics (ROC) analysis was performed to determine the best criterion that separates the two case groups using the physician's single-side sparing prescription as ground truth. The final predictive model (combined model) takes into account the single-side sparing by switching between the standard and single-side sparing models according to the single-side sparing criterion. The models were tested with 20 additional cases. The significance of the improvement of prediction accuracy by the combined model over the standard model was evaluated using the Wilcoxon rank-sum test. Results: Using the ROC analysis, the best single-side sparing criterion is (1) the predicted median dose of one parotid is higher than 24 Gy; and (2) that of the other is higher than 7 Gy. This criterion gives a true positive rate of 0.82 and a false positive rate of 0.19, respectively. For the bilateral sparing cases, the combined and the standard models performed equally well, with the median of the prediction errors for parotid median dose being 0.34 Gy by both models (p = 0.81). For the single-side sparing cases, the standard model overestimates the median dose by 7.8 Gy on average, while the predictions by the combined model differ from actual values by only 2.2 Gy (p = 0.005). Similarly, the sum of residues between the modeled and the actual plan DVHs is the same for the bilateral sparing cases by both models (p = 0.67), while the standard model predicts significantly higher DVHs than the combined model for the single-side sparing cases (p = 0.01). Conclusions: The combined model for predicting parotid sparing that takes into account single-side sparing improves the prediction accuracy over the previous model.« less

Single point estimation of phenytoin dosing: a reappraisal.

PubMed

Koup, J R; Gibaldi, M; Godolphin, W

1981-11-01

A previously proposed method for estimation of phenytoin dosing requirement using a single serum sample obtained 24 hours after intravenous loading dose (18 mg/Kg) has been re-evaluated. Using more realistic values for the volume of distribution of phenytoin (0.4 to 1.2 L/Kg), simulations indicate that the proposed method will fail to consistently predict dosage requirements. Additional simulations indicate that two samples obtained during the 24 hour interval following the iv loading dose could be used to more reliably predict phenytoin dose requirement. Because of the nonlinear relationship which exists between phenytoin dose administration rate (RO) and the mean steady state serum concentration (CSS), small errors in prediction of the required RO result in much larger errors in CSS.

Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study

PubMed Central

Morain, P; Robin, J L; De Nanteuil, G; Jochemsen, R; Heidet, V; Guez, D

2000-01-01

Aims The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers. Methods This was a double-blind, randomized, placebo-controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection. Results PEP activity in plasma was dose-dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5–2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half-life (t½) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose. Conclusions S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once-daily dosing without any serious adverse events. PMID:11012558

Patient dosimetry audit for establishing local diagnostic reference levels for nuclear medicine CT.

PubMed

Gardner, Matthew; Katsidzira, Ngonidzashe M; Ross, Erin; Larkin, Elizabeth A

2017-03-01

To establish a system for patient dosimetry audit and setting of local diagnostic reference levels (LDRLs) for nuclear medicine (NM) CT. Computed radiological information system (CRIS) data were matched with NM paper records, which provided the body region and dose mode for NMCT carried out at a large UK hospital. It was necessary to divide data in terms of the NM examination type, body region and dose mode. The mean and standard deviation dose-length products (DLPs) for common NMCT examinations were then calculated and compared with the proposed National Diagnostic Reference Levels (NDRLs). Only procedures which have 10 or more patients will be used to suggest LDRLs. For most examinations, the mean DLPs do not exceed the proposed NDRLs. The bone single-photon emission CT/CT lumbar spine data clearly show the need to divide data according to the purpose of the scan (dose mode), with mean (±standard error) DLPs ranging from 51 ± 5 mGy cm (low dose) to 1086 ± 124 mGy cm (metal dose). A system for NMCT patient dose audit has been developed, but there are non-trivial challenges which make the process labour intensive. These include limited information provided by CRIS downloads, dependence on paper records and limited number of examinations available owing to the need to subdivide data. Advances in knowledge: This article demonstrates that a system can be developed for NMCT patient dose audit, but also highlights the challenges associated with such audit, which may not be encountered with more routine audit of radiology CT.

Ceruletide intravenous dose-response study by a simplified scintigraphic technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krishnamurthy, G.T.; Turner, F.E.; Mangham, D.

1985-04-01

The intravenous dose response of a ceruletide diethylamine (ceruletide) was established by a simplified scintigraphic technique where multiple graded doses were given sequentially on a single occasion. The gallbladder volume was presented nongeometrically by /sup 99m/Tc-IDA counts. The mean latent period, ejection period, and ejection rate were similar for all four groups of subjects given 1-20 ng/kg of ceruletide. The ejection fractions were similar to the values when the identical dose of ceruletide was administered sequentially either before or after another dose. A dose of 5 ng/kg produced the most physiologic type of emptying. Intravenous doses of 10 ng/kg andmore » larger caused adverse reactions in 42% of the total doses in the form of abdominal pain, nausea, systolic and diastolic hypotension, or bradycardia. It is concluded that the dose response of a cholecystokininlike agent (ceruletide) can be established reliably by a scintigraphic technique where multiple graded doses are given on a single occasion.« less

GaAs/GaAlAs distributed Bragg reflector laser with a focused ion beam, low dose dopant implanted grating

NASA Technical Reports Server (NTRS)

Wu, M. C.; Boenke, M. M.; Wang, S.; Clark, W. M., Jr.; Stevens, E. H.

1988-01-01

The performance of a GaAs/GaAlAs distributed Bragg reflector (DBR) laser using a focused ion beam implanted grating (FIB-DBR) is reported for the first time. Stripes of Si(2+) with a period of 2300 A and a dose about 10 to the 14th/sq cm are directly implanted into the passive large optical cavity layer to provide the distributed feedback. Surface-emitting light from the second-order grating is observed. Threshold current of 110 mA and single DBR mode operation from 20 to 40 C are obtained. The wavelength tuning rate with temperature is 0.8 A/C. The coupling coefficient is estimated to be 15/cm. The results show that FIB technology is practical for distributed feedback and DBR lasers and optoelectronic integrated circuits.

Protection of rhesus macaques against inhalational anthrax with a Bacillus anthracis capsule conjugate vaccine.

PubMed

Chabot, Donald J; Ribot, Wilson J; Joyce, Joseph; Cook, James; Hepler, Robert; Nahas, Debbie; Chua, Jennifer; Friedlander, Arthur M

2016-07-25

The efficacy of currently licensed anthrax vaccines is largely attributable to a single Bacillus anthracis immunogen, protective antigen. To broaden protection against possible strains resistant to protective antigen-based vaccines, we previously developed a vaccine in which the anthrax polyglutamic acid capsule was covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B and demonstrated that two doses of 2.5μg of this vaccine conferred partial protection of rhesus macaques against inhalational anthrax . Here, we demonstrate complete protection of rhesus macaques against inhalational anthrax with a higher 50μg dose of the same capsule conjugate vaccine. These results indicate that B. anthracis capsule is a highly effective vaccine component that should be considered for incorporation in future generation anthrax vaccines. Published by Elsevier Ltd.

Optima MDxt: A high throughput 335 keV mid-dose implanter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eisner, Edward; David, Jonathan; Justesen, Perry

2012-11-06

The continuing demand for both energy purity and implant angle control along with high wafer throughput drove the development of the Axcelis Optima MDxt mid-dose ion implanter. The system utilizes electrostatic scanning, an electrostatic parallelizing lens and an electrostatic energy filter to produce energetically pure beams with high angular integrity. Based on field proven components, the Optima MDxt beamline architecture offers the high beam currents possible with singly charged species including arsenic at energies up to 335 keV as well as large currents from multiply charged species at energies extending over 1 MeV. Conversely, the excellent energy filtering capability allowsmore » high currents at low beam energies, since it is safe to utilize large deceleration ratios. This beamline is coupled with the >500 WPH capable endstation technology used on the Axcelis Optima XEx high energy ion implanter. The endstation includes in-situ angle measurements of the beam in order to maintain excellent beam-to-wafer implant angle control in both the horizontal and vertical directions. The Optima platform control system provides new generation dose control system that assures excellent dosimetry and charge control. This paper will describe the features and technologies that allow the Optima MDxt to provide superior process performance at the highest wafer throughput, and will provide examples of the process performance achievable.« less

A Dose-Rate Effect in Single-Particle Electron Microscopy

PubMed Central

Chen, James Z.; Sachse, Carsten; Xu, Chen; Mielke, Thorsten; Spahn, Christian M. T.; Grigorieff, Nikolaus

2008-01-01

A low beam-intensity, low electron-dose imaging method has been developed for single-particle electron cryo-microscopy (cryo-EM). Experiments indicate that the new technique can reduce beam-induced specimen movement and secondary radiolytic effects, such as “bubbling”. The improvement in image quality, especially for multiple-exposure data collection, will help single-particle cryo-EM to reach higher resolution. PMID:17977018

Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine

PubMed Central

Peng, Shiwen; Lyford-Pike, Sofia; Akpeng, Belinda; Wu, Annie; Hung, Chien-Fu; Hannaman, Drew; Saunders, John R.; Wu, T.-C.

2012-01-01

Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8+ T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8+ T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8+ T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic anti-tumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8+ T cells, which led to higher ratios of CD8+/Treg and CD8+/CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8+ T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. PMID:23011589

SLI381 (Adderall XR), a two-component, extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparison of fasted, fed, and sprinkled administration.

PubMed

Tulloch, Simon J; Zhang, Yuxin; McLean, Angus; Wolf, Kathleen N

2002-11-01

To assess the bioavailability of three test formulations of a single dose of extended-release Adderall 20-mg capsules compared with two doses of immediate-release Adderall 10-mg tablets, and to assess the bioequivalence of a single 30-mg dose of the chosen extended-release Adderall formulation (designated as SLI381) administered in applesauce (sprinkled) and the same dose administered as an intact capsule with or without food. Randomized, open-label, crossover study. Clinical research unit. Forty-one healthy adults. Study A had four treatment sequences: three test formulations (A, B, and C) of a single dose of extended-release Adderall 20 mg, and two 10-mg doses of Adderall given 4 hours apart. Study B had three treatment sequences: a single dose of SLI381 30 mg as an intact capsule after overnight fast, an intact capsule after a high-fat breakfast, and the contents of a capsule sprinkled in 1 tablespoon of applesauce. The 20-mg test formulation A had comparable pharmacokinetic profiles and bioequivalence in rate and extent of drug absorption to Adderall 10 mg twice/day for both d- and l-amphetamine. Formulations B and C had statistically significant differences from the reference drug in some pharmacokinetic parameters. A 30-mg dose of SLI381 showed no significant differences in rate and extent of absorption of d- and l-amphetamine for fasted or sprinkled conditions compared with the high-fat meal condition. SLI381 20 mg/day is bioequivalent to Adderall 10 mg twice/day. SLI381 30 mg administered in applesauce is bioequivalent in terms of both rate and extent of absorption to the same dose administered as an intact capsule in both fasted and fed states.

Serum tocopherol levels in very preterm infants after a single dose of vitamin E at birth.

PubMed

Bell, Edward F; Hansen, Nellie I; Brion, Luc P; Ehrenkranz, Richard A; Kennedy, Kathleen A; Walsh, Michele C; Shankaran, Seetha; Acarregui, Michael J; Johnson, Karen J; Hale, Ellen C; Messina, Lynn A; Crawford, Margaret M; Laptook, Abbot R; Goldberg, Ronald N; Van Meurs, Krisa P; Carlo, Waldemar A; Poindexter, Brenda B; Faix, Roger G; Carlton, David P; Watterberg, Kristi L; Ellsbury, Dan L; Das, Abhik; Higgins, Rosemary D

2013-12-01

Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage. Ninety-three infants <27 weeks' gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-α-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing. Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs. 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels <0.5 mg/dL. A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.

PubMed

Boettcher, Michael-Friedrich; Heinig, Roland; Schmeck, Carsten; Kohlsdorfer, Christian; Ludwig, Matthias; Schaefer, Anja; Gelfert-Peukert, Sabine; Wensing, Georg; Weber, Olaf

2012-02-01

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose.

PubMed

Viscardi, Rose M; Othman, Ahmed A; Hassan, Hazem E; Eddington, Natalie D; Abebe, Elias; Terrin, Michael L; Kaufman, David A; Waites, Ken B

2013-05-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.

Azithromycin To Prevent Bronchopulmonary Dysplasia in Ureaplasma-Infected Preterm Infants: Pharmacokinetics, Safety, Microbial Response, and Clinical Outcomes with a 20-Milligram-per-Kilogram Single Intravenous Dose

PubMed Central

Othman, Ahmed A.; Hassan, Hazem E.; Eddington, Natalie D.; Abebe, Elias; Terrin, Michael L.; Kaufman, David A.; Waites, Ken B.

2013-01-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)0.75 [WT(kg)0.75 indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)0.75; central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined. PMID:23439637

Is high–dose rate RapidArc-based radiosurgery dosimetrically advantageous for the treatment of intracranial tumors?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Bo; Yang, Yong, E-mail: yangy2@upmc.edu; Li, Xiang

In linac-based stereotactic radiosurgery (SRS) and radiotherapy (SRT), circular cone(s) or conformal arc(s) are conventionally used to treat intracranial lesions. However, when the target is in close proximity to critical structures, it is frequently quite challenging to generate a quality plan using these techniques. In this study, we investigated the dosimetric characteristics of using high–dose rate RapidArc (RA) technique for radiosurgical treatment of intracranial lesions. A total of 10 intracranial SRS/SRT cases previously planned using dynamic conformal arc (DCA) or cone-based techniques have been included in this study. For each case, 3 treatment plans were generated: (1) a DCA planmore » with multiple noncoplanar arcs, (2) a high–dose rate RA plan with arcs oriented the same as DCA (multiple-arc RA), and 3) a high–dose rate RA plan with a single coplanar arc (single-arc RA). All treatment plans were generated under the same prescription and similar critical structure dose limits. Plan quality for different plans was evaluated by comparing various dosimetric parameters such as target coverage, conformity index (CI), homogeneity index (HI), critical structures, and normal brain tissue doses as well as beam delivery time. With similar critical structure sparing, high–dose rate RA plans can achieve much better target coverage, dose conformity, and dose homogeneity than the DCA plans can. Plan quality indices CI and HI, for the DCA, multiple-arc RA, and single-arc RA techniques, were measured as 1.67 ± 0.39, 1.32 ± 0.28, and 1.38 ± 0.30 and 1.24 ± 0.11, 1.10 ± 0.04, and 1.12 ± 0.07, respectively. Normal brain tissue dose (V{sub 12} {sub Gy}) was found to be similar for DCA and multiple-arc RA plans but much larger for the single-arc RA plans. Beam delivery was similar for DCA and multiple-arc RA plans but shorter with single-arc RA plans. Multiple-arc RA SRS/SRT can provide better treatment plans than conventional DCA plans, especially for complex cases.« less

Prehospital Care for the Adult and Pediatric Seizure Patient: Current Evidence-based Recommendations.

PubMed

Silverman, Eric C; Sporer, Karl A; Lemieux, Justin M; Brown, John F; Koenig, Kristi L; Gausche-Hill, Marianne; Rudnick, Eric M; Salvucci, Angelo A; Gilbert, Greg H

2017-04-01

We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of adult and pediatric patients with a seizure and to compare these recommendations against the current protocol used by the 33 emergency medical services (EMS) agencies in California. We performed a review of the evidence in the prehospital treatment of patients with a seizure, and then compared the seizure protocols of each of the 33 EMS agencies for consistency with these recommendations. We analyzed the type and route of medication administered, number of additional rescue doses permitted, and requirements for glucose testing prior to medication. The treatment for eclampsia and seizures in pediatric patients were analyzed separately. Protocols across EMS Agencies in California varied widely. We identified multiple drugs, dosages, routes of administration, re-dosing instructions, and requirement for blood glucose testing prior to medication delivery. Blood glucose testing prior to benzodiazepine administration is required by 61% (20/33) of agencies for adult patients and 76% (25/33) for pediatric patients. All agencies have protocols for giving intramuscular benzodiazepines and 76% (25/33) have protocols for intranasal benzodiazepines. Intramuscular midazolam dosages ranged from 2 to 10 mg per single adult dose, 2 to 8 mg per single pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intranasal midazolam dosages ranged from 2 to 10 mg per single adult or pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intravenous/intrasosseous midazolam dosages ranged from 1 to 6 mg per single adult dose, 1 to 5 mg per single pediatric dose, and 0.05 to 0.1 mg/kg as a weight-based dose. Eclampsia is specifically addressed by 85% (28/33) of agencies. Forty-two percent (14/33) have a protocol for administering magnesium sulfate, with intravenous dosages ranging from 2 to 6 mg, and 58% (19/33) allow benzodiazepines to be administered. Protocols for a patient with a seizure, including eclampsia and febrile seizures, vary widely across California. These recommendations for the prehospital diagnosis and treatment of seizures may be useful for EMS medical directors tasked with creating and revising these protocols.

Dual HER2\\PIK3CA targeting overcomes single-agent acquired resistance in HER2 amplified uterine serous carcinoma cell lines in vitro and in vivo

PubMed Central

Lopez, Salvatore; Cocco, Emiliano; Black, Jonathan; Bellone, Stefania; Bonazzoli, Elena; Predolini, Federica; Ferrari, Francesca; Schwab, Carlton L.; English, Diana P.; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E.; Terranova, Corrado; Angioli, Roberto; Santin, Alessandro D.

2015-01-01

HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC), and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA mutated and PIK3CA-wild type HER2/neu amplified USC cell lines. Cell viability and cell cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC-xenografts. We found both single agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long lasting growth inhibition in both USC xenografts when compared to single agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single agent-treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA or pan-ErbB inhibitor-resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild type PIK3CA resistant to chemotherapy. PMID:26333383

Efficacy of a single dose of milbemycin oxime/praziquantel combination tablets, Milpro(®), against adult Echinococcus multilocularis in dogs and both adult and immature E. multilocularis in young cats.

PubMed

Cvejic, Dejan; Schneider, Claudia; Fourie, Josephus; de Vos, Christa; Bonneau, Stephane; Bernachon, Natalia; Hellmann, Klaus

2016-03-01

Two single-site, laboratory, negatively controlled, masked, randomised dose confirmation studies were performed: one in dogs, the other in cats. After a period of acclimatisation, both the dogs and cats were orally infected with Echinococcus multilocularis protoscoleces. In the dog study, 10 dogs received a single dose of Milpro® tablets at a minimum dose of 0.5 mg/kg milbemycin oxime and 5 mg/kg praziquantel 18 days post-infection and 10 dogs received no treatment. In the cat study, 10 cats received a single dose of Milpro® tablets at a minimum dose of 2 mg/kg milbemycin oxime and 5 mg/kg praziquantel 7 days post-infection, 10 cats received a single dose of the treatment 18 days post-infection and 10 cats remained untreated. In both studies, intestinal worm counts were performed 23 days post-infection at necropsy. No worms were retrieved from any of the 30 treated animals. Nine of 10 control dogs had multiple worms (geometric mean 91, arithmetic mean 304) and all 10 control cats had multiple worms (geometric mean 216, arithmetic mean 481). The difference in worm counts between all three treated groups and their controls was highly significant (ANOVA p values of log transformed data <0.0001). Efficacy of 100 % was demonstrated for the elimination of adult E. multilocularis in dogs and cats as well as for elimination of immature E. multilocularis in cats as evidenced by the effectiveness of treatment 7 days post-infection. The treatments were well accepted and tolerated, and there were no adverse drug reactions observed.

Vitamin D in newborns. A randomised controlled trial comparing daily and single oral bolus vitamin D in infants.

PubMed

Huynh, Julie; Lu, Thao; Liew, Danny; Doery, James Cg; Tudball, Ronald; Jona, Madeleine; Bhamjee, Roisin; Rodda, Christine P

2017-02-01

There are no published data to demonstrate the efficacy of bolus dose vitamin D in newborn infants. The study sought to evaluate this alternative approach of supplementation. This single centre, open randomised controlled trial was conducted from August 2013 to May 2014. It compared the efficacy and safety of daily (400 IU) versus a bolus dose (50 000 IU) of cholecalciferol in newborn infants of vitamin D deficient mothers. The primary outcome measure was the rate of 25 hydroxyvitamin D (25OHD) repletion-defined as 25OHD greater than 50 nmol/L. The secondary objective was determining safety using adjusted total serum calcium. Of 70 eligible infants, 36 received a daily dose and 34 received a single high-dose cholecalciferol. Mean 25OHD in the bolus group (154 nmol/L, 95% confidence interval (CI) 131-177) was higher than the daily group (48 nmol/L, 95% CI 42-54) at 1-2 weeks of age. This was reversed at 3-4 months, (65 nmol/L, 95% CI 59-71) compared with the daily group (81 nmol/L, 95% CI 77-85). More infants in the single bolus group achieved vitamin D repletion (100 vs. 31%) at 1-2 weeks. By 3-4 months, both groups achieved similar vitamin D repletion rates (91 vs. 89%). Mean adjusted total serum calcium in the bolus group were normal at 1-2 weeks (2.73 mmol/L) and 3-4 months (2.55 mmol/L). Single bolus dosing of 50 000 IU cholecalciferol achieves higher 25OHD repletion rates at 1-2 weeks of age compared with daily dosing, but repletion rates were similar by 3-4 months. There was no hypercalcaemia documented with single bolus dosing in this study. © 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Safety and immunogenicity of ricin vaccine, RVEc™, in a Phase 1 clinical trial.

PubMed

Pittman, Phillip R; Reisler, Ronald B; Lindsey, Changhong Y; Güereña, Fernando; Rivard, Robert; Clizbe, Denise P; Chambers, Matthew; Norris, Sarah; Smith, Leonard A

2015-12-16

Ricin is a potent toxin and potential bioterrorism weapon for which no specific licensed countermeasures are available. We report the safety and immunogenicity of the ricin vaccine RVEc™ in a Phase 1 (N=30) multiple-dose, open-label, non-placebo-controlled, dose-escalating (20, 50, and 100μg), single-center study. Each subject in the 20- and 50-μg dose groups (n=10 for each group) received three injections at 4-week intervals and was observed carefully for untoward effects of the vaccine; blood was drawn at predetermined intervals after each dose for up to 1 year. RVEc™ was safe and well tolerated at the 20- and 50-μg doses. The most common adverse events were pain at the injection site and headache. Of the 10 subjects who received a single 100-μg dose, two developed elevated creatine phosphokinase levels, which resolved without sequelae. No additional doses were administered to subjects in the 100-μg group. Immunogenicity of the vaccine was evaluated by measuring antibody response using the well standardized enzyme-linked immunosorbent assay (ELISA) and toxin neutralization assay (TNA). Of the subjects in the 20- and 50-μg dose groups, 100% achieved ELISA anti-ricin IgG titers of 1:500 to 1:121,500 and 50% produced neutralizing anti-ricin antibodies measurable by TNA. Four subjects in the 50-μg group received a single booster dose of RVEc™ 20-21 months after the initial dose. The single booster was safe and well tolerated, resulting in no serious adverse events, and significantly enhanced immunogenicity of the vaccine in human subjects. Each booster recipient developed a robust anamnestic response with ELISA anti-ricin IgG titers of 1:13,500 to 1:121,500 and neutralizing antibody titers of 1:400 to 1:3200. Future studies will attempt to optimize dose, scheduling, and route of administration. This study is registered at clinicaltrials.gov (NCT01317667 and NCT01846104). Published by Elsevier Ltd.

Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies.

PubMed

Martin, Paul; Cheung, S Y Amy; Yen, Mark; Han, David; Gillen, Michael

2016-01-01

The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. Mean maximum plasma concentration (C max) and area under total plasma concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses. Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.

Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women
.

PubMed

Schultze-Mosgau, Marcus-Hillert; Schuett, Barbara; Hafner, Frank-Thorsten; Zollmann, Frank; Kaiser, Andreas; Hoechel, Joachim; Rohde, Beate

2017-01-01

Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids. In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and - after a wash-out period - daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28). Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 - 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 µg/L (1 mg) to 68.6 µg/L (30 mg) and 58.5 µg×h/L to 1,590 µg×h/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0-24)md/AUC(0-24)sd ratios: 1.9 to 3.2). The ratio AUC(0-24)md/AUCsd increased with dose from ~ 1 (1 mg) to 1.5 (30 mg). Exposure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t1/2, indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range.
.

SU-E-I-49: Influence of Scanner Output Measurement Technique on KERMA Ratios in CT.

PubMed

Ogden, K; Roskopf, M; Scalzetti, E

2012-06-01

KERMA ratios (RK) are defined as the ratio of KERMA measured at a specific phantom location (K) to in-air isocenter CT scanner output (KCT). In this work we investigate the impact of measurement methodology on KCT values. OSL dosimeter chips were used to measure KCT for a GE VCT scanner (GE Medical Systems, Waukesha WI), using the 40 mm nominal beam width. Methods included a single point measurement at the center of the beam (1 tube rotation), and extended z-axis measurements using multiple adjacent OSL's (7.5 cm extent), with single tube rotation, multiple contiguous axial scans, and helical scans (pitch of 1.375). Measurements were made in air and on the scan table at 80 and 120 kV. Averaged single point measurements were consistent, with a mean coefficient of variation of 2.5%. For extended measurements with a single tube rotation, the mean value was equivalent to the single point measurements. For multiple contiguous axial scans, the in-air KCT values were higher than the single rotation mean value and single point measurements by 13% and 10.3% at 120 and 80 kV, respectively, and for the on-table measurements the values were 14.9% and 8.1% higher at 120 and 80 kV, respectively. The increase is due to beam overlap caused by z- axis over-beaming. Extended measurements using helical scanning were equivalent to the multiple rotation axial measurements when corrected for the helical pitch. For all methodologies, the in-air values exceeded the on- table measurements by an average of 23% and 19.4% at 80 and 120 kV, respectively. Scanner KCT values must be measured to allow organ dose estimation using published RK values. It is imperative that the KCT measurement methodology is the same as for the published values, or large errors may be introduced into the resulting organ dose estimates. © 2012 American Association of Physicists in Medicine.

Effects of Radioprotective Agents on Foot Deformities and Gait Defects in the Prenatally X-Irradiated Rat.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ershoff, B. H.; Steers, C. W.; Kruger, L.

1962-11-01

The radioprotective agents AET, cysteamine, and MEG largely prevented the occurrence of foot deformities and a defect in gait in the young of rats exposed to a single dose of 150 r total-body x irradiation on the 14th day og pregnancy'. These substances also prevented in part the occurrence of an abnormality in development of the cerebral hemispheres of such young but were without significant effect in altering an attendant reduction in the ratio of brain to body weight.

[Forensic toxicology, a growing scientific discipline].

PubMed

Augsburger, Marc; Staub, Christian

2008-07-02

Forensic toxicology has to bring evidence of substances that could have been involved directly or indirectly in the cause of death or that could influence the behaviour of somebody. The increase of the consumption of illegal and legal drugs in modern societies during last decades gave a boost to forensic toxicology. Moreover, improvement with analytical technology gave tools with high degrees of sensitivity and specificity for the screening and quantification of a large amount of substances in various biological specimens, even with very low concentration resulting of a single dose of medication.

Phase I clinical studies of the advanced glycation end-product (AGE)-breaker TRC4186: safety, tolerability and pharmacokinetics in healthy subjects.

PubMed

Chandra, Kumar P; Shiwalkar, Ajay; Kotecha, Jignesh; Thakkar, Purav; Srivastava, Ambrish; Chauthaiwale, Vijay; Sharma, Sanjay K; Cross, Maurice R; Dutt, Chaitanya

2009-01-01

Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic complications through a variety of mechanisms including endothelial dysfunction and structural abnormalities in the vasculature and myocardium. Reducing the AGEs burden and their ensuing pro-inflammatory, pro-oxidative and pro-coagulant effect with associated dysfunctional proteins in various target tissues may retard the progression of and even reverse diabetic macro- and microvascular complications. Pyridinium, 3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]-chloride (TRC4186) has demonstrated AGE-breaking activities in in vitro experiments and improvement in the endothelial and myocardial function in animal models of diabetes mellitus with reduction of AGEs accumulation in tissues over time. The safety of TRC4186 has been established in in vitro and in vivo preclinical studies. Thus, this drug is being developed for the treatment of complications associated with diabetes. This investigation set out to evaluate the safety, tolerability and pharmacokinetics of TRC4186 in healthy human subjects after single and multiple ascending doses, fixed doses in elderly male and female subjects, and with food and different formulations of the compound. Four studies were conducted during phase I clinical development of TRC4186. These were: (i) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in healthy male subjects with doses of TRC4186 ranging from 250 to 2500 mg administered as an oral solution (total six doses); (ii) a randomized, double-blind, placebo-controlled, multiple-dose, dose-ascending study in healthy male subjects with three doses of TRC4186 ranging from 500 to 2000 mg twice daily for 6 days with a final single dose on day 7; (iii) a randomized, open-label, three-way crossover study to assess the effect of food (fasted vs fed) and formulation (solution vs tablet) with TRC4186 500 mg; (iv) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in elderly male and female subjects at a dose of TRC4186 500 mg followed by TRC4186 1000 mg after a 7-day washout period. The safety and tolerability of TRC4186 were assessed by considering adverse events (AEs), ECG findings, vital signs and laboratory investigation results. TRC4186 was rapidly absorbed, with maximum plasma concentrations (C(max)) attained within 1-4 hours. C(max) and area under the plasma concentration-time curve (AUC) were dose proportional over the range 250-2500 mg for a single dose and 500-2000 mg for multiple doses with twice-daily administration. Steady-state conditions were attained within 6 days at different dose levels. C(max) and AUC were not affected by age, sex, race or type of formulation. The tablet formulation of TRC4186 was bioequivalent with the solution form of the drug under fasting conditions and systemic availability of the tablet formulation was reduced by 40% when administered under fed conditions. Terminal elimination and renal clearance in the elderly male (age 69.1 +/- 6.0 years) were not significantly different compared with younger subjects (age 31 +/- 8.6 years). TRC4186 was safe and well tolerated when administered orally with either a single or multiple doses across the different ages, sexes, races and formulations studied. A dose-proportional increase in plasma TRC4186 concentration was seen, with steady state being achieved within 6 days.

A bounding estimate of neutron dose based on measured photon dose around single pass reactors at the Hanford site.

PubMed

Taulbee, Timothy D; Glover, Samuel E; Macievic, Gregory V; Hunacek, Mickey; Smith, Cheryl; DeBord, Gary W; Morris, Donald; Fix, Jack

2010-07-01

Neutron and photon radiation survey records have been used to evaluate and develop a neutron to photon (NP) ratio to reconstruct neutron doses to workers around Hanford's single pass reactors that operated from 1945 to 1972. A total of 5,773 paired neutron and photon measurements extracted from 57 boxes of survey records were used in the development of the NP ratio. The development of the NP ratio enables the use of the recorded dose from an individual's photon dosimeter badge to be used to estimate the unmonitored neutron dose. The Pearson rank correlation between the neutron and photon measurements was 0.71. The NP ratio best fit a lognormal distribution with a geometric mean (GM) of 0.8, a geometric standard deviation (GSD) of 2.95, and the upper 95 th % of this distribution was 4.75. An estimate of the neutron dose based on this NP ratio is considered bounding due to evidence that up to 70% of the total photon exposure received by workers around the single pass reactors occurs during shutdown maintenance and refueling activities when there is no significant neutron exposure. Thus when this NP ratio is applied to the total measured photon dose from an individual film badge dosimeter, the resulting neutron dose is considered bounded.

[In vivo study of the pharmacokinetic interaction of afobazole and losartan (cytochrome CYP2C9 substrate)].

PubMed

Gribakina, O G; Kolyvanov, G B; Litvin, A A; Zherdev, V P; Seredin, S B

2013-01-01

The influence of afobazole on isoenzyme CYP2C9 production in rats was studied using losartan as the marker drug. Single dose of losartan was administered orally without afobazole in a dose of 30 mg/kg and in the same single (30 mg/kg) on the background of 3- and 4-day administration of afobazole in a dose of 5, 25, 75, 100, and 125 mg/kg. At 5 mg/kg (effective dose for anxiolytic effect), afobazole did not cause any induction/inhibition effect on CYP2C9 isoenzyme. A multiple increase in afobazole dose was manifested by a moderate induction effect. The maximum induction effect of afobazole was achieved in a dose of 75 mg/kg. At doses above 75 mg/kg, the induction effect of afobazole was less pronounced.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bazalova, Magdalena, E-mail: bazalova@stanford.edu; Nelson, Geoff; Noll, John M.

Purpose: Small animal radiation therapy has advanced significantly in recent years. Whereas in the past dose was delivered using a single beam and a lead shield for sparing of healthy tissue, conformal doses can be now delivered using more complex dedicated small animal radiotherapy systems with image guidance. The goal of this paper is to investigate dose distributions for three small animal radiation treatment modalities. Methods: This paper presents a comparison of dose distributions generated by the three approaches—a single-field irradiator with a 200 kV beam and no image guidance, a small animal image-guided conformal system based on a modified microCTmore » scanner with a 120 kV beam developed at Stanford University, and a dedicated conformal system, SARRP, using a 220 kV beam developed at Johns Hopkins University. The authors present a comparison of treatment plans for the three modalities using two cases: a mouse with a subcutaneous tumor and a mouse with a spontaneous lung tumor. A 5 Gy target dose was calculated using the EGSnrc Monte Carlo codes. Results: All treatment modalities generated similar dose distributions for the subcutaneous tumor case, with the highest mean dose to the ipsilateral lung and bones in the single-field plan (0.4 and 0.4 Gy) compared to the microCT (0.1 and 0.2 Gy) and SARRP (0.1 and 0.3 Gy) plans. The lung case demonstrated that due to the nine-beam arrangements in the conformal plans, the mean doses to the ipsilateral lung, spinal cord, and bones were significantly lower in the microCT plan (2.0, 0.4, and 1.9 Gy) and the SARRP plan (1.5, 0.5, and 1.8 Gy) than in single-field irradiator plan (4.5, 3.8, and 3.3 Gy). Similarly, the mean doses to the contralateral lung and the heart were lowest in the microCT plan (1.5 and 2.0 Gy), followed by the SARRP plan (1.7 and 2.2 Gy), and they were highest in the single-field plan (2.5 and 2.4 Gy). For both cases, dose uniformity was greatest in the single-field irradiator plan followed by the SARRP plan due to the sensitivity of the lower energy microCT beam to target heterogeneities and image noise. Conclusions: The two treatment planning examples demonstrate that modern small animal radiotherapy techniques employing image guidance, variable collimation, and multiple beam angles deliver superior dose distributions to small animal tumors as compared to conventional treatments using a single-field irradiator. For deep-seated mouse tumors, however, higher-energy conformal radiotherapy could result in higher doses to critical organs compared to lower-energy conformal radiotherapy. Treatment planning optimization for small animal radiotherapy should therefore be developed to take full advantage of the novel conformal systems.« less

Modality comparison for small animal radiotherapy: A simulation study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bazalova, Magdalena, E-mail: bazalova@stanford.edu; Nelson, Geoff; Noll, John M.

Purpose: Small animal radiation therapy has advanced significantly in recent years. Whereas in the past dose was delivered using a single beam and a lead shield for sparing of healthy tissue, conformal doses can be now delivered using more complex dedicated small animal radiotherapy systems with image guidance. The goal of this paper is to investigate dose distributions for three small animal radiation treatment modalities. Methods: This paper presents a comparison of dose distributions generated by the three approaches—a single-field irradiator with a 200 kV beam and no image guidance, a small animal image-guided conformal system based on a modified microCTmore » scanner with a 120 kV beam developed at Stanford University, and a dedicated conformal system, SARRP, using a 220 kV beam developed at Johns Hopkins University. The authors present a comparison of treatment plans for the three modalities using two cases: a mouse with a subcutaneous tumor and a mouse with a spontaneous lung tumor. A 5 Gy target dose was calculated using the EGSnrc Monte Carlo codes. Results: All treatment modalities generated similar dose distributions for the subcutaneous tumor case, with the highest mean dose to the ipsilateral lung and bones in the single-field plan (0.4 and 0.4 Gy) compared to the microCT (0.1 and 0.2 Gy) and SARRP (0.1 and 0.3 Gy) plans. The lung case demonstrated that due to the nine-beam arrangements in the conformal plans, the mean doses to the ipsilateral lung, spinal cord, and bones were significantly lower in the microCT plan (2.0, 0.4, and 1.9 Gy) and the SARRP plan (1.5, 0.5, and 1.8 Gy) than in single-field irradiator plan (4.5, 3.8, and 3.3 Gy). Similarly, the mean doses to the contralateral lung and the heart were lowest in the microCT plan (1.5 and 2.0 Gy), followed by the SARRP plan (1.7 and 2.2 Gy), and they were highest in the single-field plan (2.5 and 2.4 Gy). For both cases, dose uniformity was greatest in the single-field irradiator plan followed by the SARRP plan due to the sensitivity of the lower energy microCT beam to target heterogeneities and image noise. Conclusions: The two treatment planning examples demonstrate that modern small animal radiotherapy techniques employing image guidance, variable collimation, and multiple beam angles deliver superior dose distributions to small animal tumors as compared to conventional treatments using a single-field irradiator. For deep-seated mouse tumors, however, higher-energy conformal radiotherapy could result in higher doses to critical organs compared to lower-energy conformal radiotherapy. Treatment planning optimization for small animal radiotherapy should therefore be developed to take full advantage of the novel conformal systems.« less

Compendium of Single-Event Latchup and Total Ionizing Dose Test Results of Commercial Analog to Digital Converters

NASA Technical Reports Server (NTRS)

Irom, Farokh; Agarwal, Shri G.

2012-01-01

This paper reports single-event latchup and total dose results for a variety of analog to digital converters targeted for possible use in NASA spacecraft's. The compendium covers devices tested over the last 15 years.

Effect of a single dose of propofol and lack of dextrose administration in a child with mitochondrial disease: a case report.

PubMed

Mtaweh, Haifa; Bayır, Hülya; Kochanek, Patrick M; Bell, Michael J

2014-08-01

Propofol infusion syndrome is a recognized complication of prolonged propofol use in the pediatric population, but little is reported on other metabolic effects of propofol, especially in children with mitochondrial disorders. We report on a child with metabolic encephalopathy, lactic acidosis, and stroke-like syndrome who received a single dose of propofol for procedural sedation. The patient's initial presentation was consistent with a mild exacerbation of her underlying disease. She received a single dose of propofol and non-dextrose-containing fluids during a magnetic resonance imaging (MRI) study to rule out stroke and progressed to develop severe acidosis, neurologic deterioration, and cardiorespiratory compromise. This is the first case report of severe metabolic disturbances after a single dose of propofol administered for procedural sedation in a patient with metabolic encephalopathy, lactic acidosis, and stroke-like syndrome and it questions the safety of propofol and absence of dextrose infusions during an acute illness in patients with mitochondrial disorders. © The Author(s) 2013.

Modification of CCNU pharmacokinetics by misonidazole--a major mechanism of chemosensitization in mice.

PubMed Central

Lee, F. Y.; Workman, P.

1983-01-01

We have investigated the effect of misonidazole (MISO) on the pharmacokinetics of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in mice. CCNU and its monohydroxylated metabolites were measured using a high performance liquid chromatography (HPLC) method. In the absence of MISO the plasma disappearance of CCNU was biphasic with a t 1/2 alpha of 2.3 min and a t 1/2 beta of 53 min. The monohydroxylated metabolites of CCNU also followed biphasic clearance kinetics. A large single dose of MISO (0.5 mg g-1), given i.p. 30 min prior to CCNU, prolonged the t 1/2 alpha by a factor of 2.6 but had no effect on t 1/2 beta. In addition, the apparent volume of distribution was decreased by a factor of 1.6. Consequently, the plasma area under the curve (AUC0 - infinity) was increased by a factor of 1.7 for CCNU and by a factor of 2.0 for total nitrosourea (CCNU + monohydroxylated metabolites). The effects of MISO on CCNU kinetics were dependent on MISO dose and plasma concentration and on the interval between MISO and CCNU administration. The concentration of CCNU was measured in 4 tumours: the KHT, RIF-1 and EMT6 mouse tumours, and the HT29 xenograft. For all 4 tumours, 0.5 mg g-1 MISO raised the tumour concentrations of CCNU and total nitrosourea by a considerable amount (2-2.5 times). More detailed studies in the KHT tumour demonstrated that there was a significant lag period before peak tumour CCNU concentrations were reached, and that MISO increased the peak concentrations by a factor of about 2.4. In contrast, there was no such lag period for the plasma and MISO did not increase the plasma peak CCNU concentrations. These data strongly suggest that modification of the pharmacokinetics may be a major contributory factor in the enhancement of CCNU cytotoxicity by large single doses of MISO in vivo. PMID:6849803

Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study.

PubMed

Sankaranarayanan, Rengaswamy; Joshi, Smita; Muwonge, Richard; Esmy, Pulikottil Okkuru; Basu, Partha; Prabhu, Priya; Bhatla, Neerja; Nene, Bhagwan M; Shaw, Janmesh; Poli, Usha Rani Reddy; Verma, Yogesh; Zomawia, Eric; Pimple, Sharmila; Tommasino, Massimo; Pawlita, Michael; Gheit, Tarik; Waterboer, Tim; Sehr, Peter; Pillai, Madhavan Radhakrishna

2018-03-15

Human papillomavirus (HPV) vaccination is a major strategy for preventing cervical and other ano-genital cancers. Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to 'no vaccination'. In a multi-centre cluster randomized trial of two vs three doses of quadrivalent HPV vaccination (Gardasil™) in India, suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10-18 year old girls leading to four study groups, two by design and two by default. They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity for the vaccine-targeted HPV types and HPV infections. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. Of the 17,729 vaccinated girls, 4348 (25%) received three doses on days 1, 60, 180 or later, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses on days 1 and 60, and 4950 (28%) received one dose. One dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18, albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period. The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients. The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women. Our results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules, although the study suffer from some limitations. Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented. Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current standard of care for cervical cancer prevention is 'no intervention'. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons

PubMed Central

Robarge, Jason D.; Duarte, Djane B.; Shariati, Behzad; Wang, Ruizhong; Flockhart, David A.; Vasko, Michael R.

2016-01-01

Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5 mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5 mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5 mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000 nmol of adenosine 5′-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats. PMID:27072527