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.

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.

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.

Pharmacokinetics and Bioavailability of Plant Lignan 7-Hydroxymatairesinol and Effects on Serum Enterolactone and Clinical Symptoms in Postmenopausal Women: A Single-Blinded, Parallel, Dose-Comparison Study

PubMed Central

Udani, Jay K.; Brown, Donald J.; Tan, Maria Olivia C.; Hardy, Mary

2013-01-01

Objective 7-Hydroxymaitairesinol (7-HMR) is a naturally occurring plant lignan found in whole grains and the Norway spruce (Piciea abies). The purpose of this study was to evaluate the bioavailability of a proprietary 7-HMR product (HMRlignan, Linnea SA, Locarno, Switzerland) through measurement of lignan metabolites and metabolic precursors. Methods A single-blind, parallel, pharmacokinetic and dose-comparison study was conducted on 22 post-menopausal females not receiving hormone replacement therapy. Subjects were enrolled in either a 36 mg/d (low-dose) or 72 mg/d dose (high-dose) regimen for 8 weeks. Primary measured outcomes included plasma levels of 7-HMR and enterolactone (ENL), and single-dose pharmacokinetic analysis was performed on a subset of subjects in the low-dose group. Safety data and adverse event reports were collected as well as data on hot flash frequency and severity. Results Pharmacokinetic studies demonstrated 7-HMR Cmax = 757.08 ng/ml at 1 hour and ENL Cmax = 4.8 ng/ml at 24 hours. From baseline to week 8, plasma 7-HMR levels increased by 191% in the low-dose group (p < 0.01) and by 1238% in the high-dose group (p < 0.05). Plasma ENL levels consistently increased as much as 157% from baseline in the low-dose group and 137% in the high-dose group. Additionally, the mean number of weekly hot flashes decreased by 50%, from 28.0/week to 14.3/week (p < 0.05) in the high-dose group. No significant safety issues were identified in this study. Conclusion The results demonstrate that HMRlignan is quickly absorbed into the plasma and is metabolized to ENL in healthy postmenopausal women. Clinically, the data demonstrate a statistically significant improvement in hot flash frequency. Doses up to 72 mg/d HMRlignan for 8 weeks were safe and well tolerated in this population. PMID:24606716

Pharmacokinetics and bioavailability of plant lignan 7-hydroxymatairesinol and effects on serum enterolactone and clinical symptoms in postmenopausal women: a single-blinded, parallel, dose-comparison study.

PubMed

Udani, Jay K; Brown, Donald J; Tan, Maria Olivia C; Hardy, Mary

2013-01-01

7-Hydroxymaitairesinol (7-HMR) is a naturally occurring plant lignan found in whole grains and the Norway spruce (Piciea abies). The purpose of this study was to evaluate the bioavailability of a proprietary 7-HMR product (HMRlignan, Linnea SA, Locarno, Switzerland) through measurement of lignan metabolites and metabolic precursors. A single-blind, parallel, pharmacokinetic and dose-comparison study was conducted on 22 postmenopausal females not receiving hormone replacement therapy. Subjects were enrolled in either a 36 mg/d (low-dose) or 72 mg/d dose (high-dose) regimen for 8 weeks. Primary measured outcomes included plasma levels of 7-HMR and enterolactone (ENL), and single-dose pharmacokinetic analysis was performed on a subset of subjects in the low-dose group. Safety data and adverse event reports were collected as well as data on hot flash frequency and severity. Pharmacokinetic studies demonstrated 7-HMR C max = 757.08 ng/ml at 1 hour and ENL C max = 4.8 ng/ml at 24 hours. From baseline to week 8, plasma 7-HMR levels increased by 191% in the low-dose group (p < 0.01) and by 1238% in the high-dose group (p < 0.05). Plasma ENL levels consistently increased as much as 157% from baseline in the low-dose group and 137% in the high-dose group. Additionally, the mean number of weekly hot flashes decreased by 50%, from 28.0/week to 14.3/week (p < 0.05) in the high-dose group. No significant safety issues were identified in this study. The results demonstrate that HMRlignan is quickly absorbed into the plasma and is metabolized to ENL in healthy postmenopausal women. Clinically, the data demonstrate a statistically significant improvement in hot flash frequency. Doses up to 72 mg/d HMRlignan for 8 weeks were safe and well tolerated in this population.

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

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

The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics.

PubMed

Ribas, Antoni; Zhang, Weijiang; Chang, Ilsung; Shirai, Keisuke; Ernstoff, Marc S; Daud, Adil; Cowey, C Lance; Daniels, Gregory; Seja, Elizabeth; O'Laco, Elizabeth; Glaspy, John A; Chmielowski, Bartosz; Hill, Todd; Joe, Andrew K; Grippo, Joseph F

2014-04-01

Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAF(V600) -mutant metastatic melanoma. It is important to understand the effects of a high-fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open-label, multicenter, randomized, 2-period crossover study was performed to evaluate the effect of food (high-fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high-fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0-∞ 119 to 360 µg·h/mL after a single 960 mg dose of vemurafenib (N = 13-15 patients). An effect of food on single-dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0-∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAF(V600) -mutant metastatic melanoma. A high-fat meal increased the exposure to vemurafenib without altering the mean terminal half-life. © 2014, The American College of Clinical Pharmacology.

Single-hit mechanism of tumour cell killing by radiation.

PubMed

Chapman, J D

2003-02-01

To review the relative importance of the single-hit mechanism of radiation killing for tumour response to 1.8-2.0 Gy day(-1) fractions and to low dose-rate brachytherapy. Tumour cell killing by ionizing radiation is well described by the linear-quadratic equation that contains two independent components distinguished by dose kinetics. Analyses of tumour cell survival curves that contain six or more dose points usually provide good estimates of the alpha- and beta-inactivation coefficients. Superior estimates of tumour cell intrinsic radiosensitivity are obtained when synchronized populations are employed. The characteristics of single-hit inactivation of tumour cells are reviewed and compared with the characteristics of beta-inactivation. Potential molecular targets associated with single-hit inactivation are discussed along with strategies for potentiating cell killing by this mechanism. The single-hit mechanism of tumour cell killing shows no dependence on dose-rate and, consequently, no evidence of sublethal damage repair. It is uniquely potentiated by high linear-energy-transfer radiation, exhibits a smaller oxygen enhancement ratio and exhibits a larger indirect effect by hydroxyl radicals than the beta-mechanism. alpha-inactivation coefficients vary slightly throughout interphase but mitotic cells exhibit extremely high alpha-coefficients in the range of those observed for lymphocytes and some repair-deficient cells. Evidence is accumulating to suggest that chromatin in compacted form could be a radiation-hypersensitive target associated with single-hit radiation killing. Analyses of tumour cell survival curves demonstrate that it is the single-hit mechanism (alpha) that determines the majority of cell killing after doses of 2Gy and that this mechanism is highly variable between tumour cell lines. The characteristics of single-hit inactivation are qualitatively and quantitatively distinct from those of beta-inactivation. Compacted chromatin in tumour cells should be further investigated as a radiation-hypersensitive target that could be modulated for therapeutic advantage.

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.

A Multi-Compartment, Single and Multiple Dose Pharmacokinetic Study of the Vaginal Candidate Microbicide 1% Tenofovir Gel

PubMed Central

Schwartz, Jill L.; Rountree, Wes; Kashuba, Angela D. M.; Brache, Vivian; Creinin, Mitchell D.; Poindexter, Alfred; Kearney, Brian P.

2011-01-01

Background Tenofovir (TFV) gel is being evaluated as a microbicide with pericoital and daily regimens. To inhibit viral replication locally, an adequate concentration in the genital tract is critical. Methods and Findings Forty-nine participants entered a two-phase study: single-dose (SD) and multi-dose (MD), were randomized to collection of genital tract samples (endocervical cells [ECC], cervicovaginal aspirate and vaginal biopsies) at one of seven time points [0.5, 1, 2, 4, 6, 8, or 24 hr(s)] post-dose following SD exposure of 4 mL 1% TFV gel and received a single dose. Forty-seven were randomized to once (QD) or twice daily (BID) dosing for 2 weeks and to collection of genital tract samples at 4, 8 or 24 hrs after the final dose, but two discontinued prior to gel application. Blood was collected during both phases at the seven times post-dose. TFV exposure was low in blood plasma for SD and MD; median Cmax was 4.0 and 3.4 ng/mL, respectively (C≤29 ng/mL). TFV concentrations were high in aspirates and tissue after SD and MD, ranging from 1.2×104 to 9.9×106 ng/mL and 2.1×102 to 1.4×106 ng/mL, respectively, and did not noticeably differ between proximal and distal tissue. TFV diphosphate (TFV-DP), the intracellular active metabolite, was high in ECC, ranging from 7.1×103 to 8.8×106 ng/mL. TFV-DP was detectable in approximately 40% of the tissue samples, ranging from 1.8×102 to 3.5×104 ng/mL. AUC for tissue TFV-DP was two logs higher after MD compared to SD, with no noticeable differences when comparing QD and BID. Conclusions Single-dose and multiple-dose TFV gel exposure resulted in high genital tract concentrations for at least 24 hours post-dose with minimal systemic absorption. These results support further study of TFV gel for HIV prevention. Trial registration ClinicalTrials.gov NCT00561496 PMID:22039430

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.

Low-dose right unilateral electroconvulsive therapy (ECT): effectiveness of the first treatment.

PubMed

Lapidus, Kyle A B; Shin, Joseph S W; Pasculli, Rosa M; Briggs, Mimi C; Popeo, Dennis M; Kellner, Charles H

2013-06-01

Electroconvulsive therapy (ECT) is a widely used, highly effective antidepressant treatment. Except for the most severely ill patients, right unilateral (RUL) electrode placement is the most frequent initial treatment choice. In current practice, RUL ECT is administered at several multiples of seizure threshold (ST) based on reports that lower stimulus intensity results in lower response/remission rates. Many patients, as part of an initial dose titration to determine ST, will receive a single treatment with low-dose RUL ECT and subsequent treatments with a stimulus at a multiple of ST. To assess response to the first ECT. A retrospective analysis of charts from clinical practice at Mount Sinai Medical Center was performed. A single treatment with low-dose (presumably near ST) RUL ECT had a significant and immediate antidepressant effect in our sample of patients with major depression. We determined that this response is similar to that of patients receiving a single initial treatment with high-dose RUL ECT (at a multiple of ST). These data suggest, contrary to commonly held belief, that RUL ECT may be effective at a low stimulus dose. This argues against restimulating at 6 times ST in the initial session, based on the belief that the near-threshold seizure has no antidepressant efficacy. Our findings suggest a need for further investigation of cases in which low-dose RUL ECT may be an effective antidepressant treatment. Further prospective studies, including larger numbers of patients who receive randomized treatment with low- or high-dose RUL with longer follow-up, are indicated.

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.

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

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

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.

Evaluation of the dosimetric properties of a synthetic single crystal diamond detector in high energy clinical proton beams.

PubMed

Mandapaka, A K; Ghebremedhin, A; Patyal, B; Marinelli, Marco; Prestopino, G; Verona, C; Verona-Rinati, G

2013-12-01

To investigate the dosimetric properties of a synthetic single crystal diamond Schottky diode for accurate relative dose measurements in large and small field high-energy clinical proton beams. The dosimetric properties of a synthetic single crystal diamond detector were assessed by comparison with a reference Markus parallel plate ionization chamber, an Exradin A16 microionization chamber, and Exradin T1a ion chamber. The diamond detector was operated at zero bias voltage at all times. Comparative dose distribution measurements were performed by means of Fractional depth dose curves and lateral beam profiles in clinical proton beams of energies 155 and 250 MeV for a 14 cm square cerrobend aperture and 126 MeV for 3, 2, and 1 cm diameter circular brass collimators. ICRU Report No. 78 recommended beam parameters were used to compare fractional depth dose curves and beam profiles obtained using the diamond detector and the reference ionization chamber. Warm-up∕stability of the detector response and linearity with dose were evaluated in a 250 MeV proton beam and dose rate dependence was evaluated in a 126 MeV proton beam. Stem effect and the azimuthal angle dependence of the diode response were also evaluated. A maximum deviation in diamond detector signal from the average reading of less than 0.5% was found during the warm-up irradiation procedure. The detector response showed a good linear behavior as a function of dose with observed deviations below 0.5% over a dose range from 50 to 500 cGy. The detector response was dose rate independent, with deviations below 0.5% in the investigated dose rates ranging from 85 to 300 cGy∕min. Stem effect and azimuthal angle dependence of the diode signal were within 0.5%. Fractional depth dose curves and lateral beam profiles obtained with the diamond detector were in good agreement with those measured using reference dosimeters. The observed dosimetric properties of the synthetic single crystal diamond detector indicate that its behavior is proton energy independent and dose rate independent in the investigated energy and dose rate range and it is suitable for accurate relative dosimetric measurements in large as well as in small field high energy clinical proton beams.

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

DOSE-DEPENDENT TRANSITIONS IN MECHANISMS OF TOXICITY: CASE STUDIES

EPA Science Inventory

Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed ...

A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial.

PubMed

Abbara, Ali; Clarke, Sophie; Islam, Rumana; Prague, Julia K; Comninos, Alexander N; Narayanaswamy, Shakunthala; Papadopoulou, Deborah; Roberts, Rachel; Izzi-Engbeaya, Chioma; Ratnasabapathy, Risheka; Nesbitt, Alexander; Vimalesvaran, Sunitha; Salim, Rehan; Lavery, Stuart A; Bloom, Stephen R; Huson, Les; Trew, Geoffrey H; Dhillo, Waljit S

2017-09-01

Can increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)? A second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS. Kisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12-14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS. Phase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation. Study participants: Sixty-two women aged 18-34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L). Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK. Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%. Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence. A second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2-50%, P = 0.042). Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial 'rescue' LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield ≥60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%). Further studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation. Triggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS. The study was designed, conducted, analysed and reported entirely by the authors. The Medical Research Council (MRC), Wellcome Trust & National Institute of Health Research (NIHR) provided research funding to carry out the studies. There are no competing interests to declare. Clinicaltrial.gov identifier NCT01667406. 8 August 2012. 10 August 2015. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

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.

Postoperative analgesic efficacy of single high dose and low dose rectal acetaminophen in pediatric ophthalmic surgery

PubMed Central

Gandhi, Ranju; Sunder, Rani

2012-01-01

Background: Analgesic efficacy of rectal acetaminophen is variable in different surgical procedures. Little data is available on its efficacy in ophthalmic surgeries. We conducted this prospective, randomized, double blind study to evaluate and compare the efficacy of single high dose and low dose rectal acetaminophen in pediatric ophthalmic surgery over a 24 hour period. Materials and Methods: 135 children scheduled for elective ophthalmic surgery were randomly allocated to one of the three groups, high, low, or control (H, L, or N) and received rectal acetaminophen 40 mg/kg, 20 mg/kg or no rectal drug respectively after induction of general anesthesia. Postoperative observations included recovery score, hourly observational pain score (OPS) up to 8 hours, time to first analgesic demand, and requirement of rescue analgesics and antiemetics over a 24 hour period. Results: Nineteen of 30 (63%) of children in group N required postoperative rescue analgesic versus 5/48 (10%) of group H (P <0.0001) and 10/47 (23%) of group L (P =0.0005) during 24 hour period. Mean time to requirement of first analgesic was 206±185 min in group H, 189±203min in group L, and 196 ±170 min in group N (P=0.985). OPS was significantly lower in group H and L compared to group N during first 8 hours. Requirement of rescue antiemetic was 18.7% in group H as compared to 23% each in group L and group N (P >0.5). Conclusions: Single dose rectal acetaminophen can provide effective postoperative analgesia for pediatric ophthalmic surgery at both high dose (40 mg/kg) and low dose (20 mg/kg) both in early postoperative and over a 24 hour period. PMID:23225924

Introducing iron isomaltoside 1000 (Monofer®)-development rationale and clinical experience.

PubMed

Kalra, Philip A

2011-06-01

Patients with chronic kidney disease (CKD) often suffer from iron deficiency anaemia necessitating treatment with intravenous (IV) iron. Several studies demonstrate that oral iron is insufficient in these patients and that IV supplementation is a more effective treatment. Until now, use of available parenteral iron preparations has been limited by dosing schedules and the need, in some cases, for a test dose, and despite the availability of a range of different IV iron compounds, there is still a need for improved compounds. The new IV iron, iron isomaltoside 1000 Monofer®, is composed of iron and chemically modified isomalto-oligosaccharides which have a mean molecular weight of 1000 Da and consist predominantly of 3-5 glucose units. In contrast to dextrans, the carbohydrate isomaltoside 1000 is a linear and unbranched structure with theoretically a low immunological potential. Hence, a test dose is not necessary. Iron isomaltoside 1000 contains strongly bound iron within the iron-isomaltoside formulation, which enables a controlled slow release of bioavailable iron to the iron-binding proteins, with potentially a reduced risk of free iron toxicity. This allows flexible dosing including high and rapid dosing securing convenient iron therapy for a wide range of patients. The development of Monofer® has been enthusiastically acknowledged by clinicians, and in 2009, there has been fast approval by European authorities via a decentralized registration procedure. This new IV iron is currently being marketed in several European countries. This article describes the development rationale and summarizes the clinical data assessing the use of iron isomaltoside 1000 administered without a test dose by either repeated bolus injections or fast high single iron infusions [defined as total dose infusion (TDI)] to patients suffering from CKD. Since CKD is associated with a high prevalence of cardiovascular disease, data from a small trial applying high single doses of iron isomatoside 1000 in patients with chronic heart failure (CHF) are also reviewed. Collectively, the available data demonstrate adequate efficacy and a good safety profile of iron isomaltoside 1000 in CKD and CHF patients even when administered without a test dose and as single rapid high-dose infusions.

A quality improvement project to reduce the intraoperative use of single-dose fentanyl vials across multiple patients in a pediatric institution.

PubMed

Buck, David; Subramanyam, Rajeev; Varughese, Anna

2016-01-01

The use of a single-dose vial across multiple patients presents a risk to sterility and is against CDC guidelines. We initiated a quality improvement (QI) project to reduce the intraoperative use of single-dose vials of fentanyl across multiple patients at Cincinnati Children's Hospital Medical Center (CCHMC). The initial step of the improvement project was the development of a Key Driver Diagram. The diagram has the SMART aim of the project, key drivers inherent to the process we are trying to improve, and specific interventions targeting the key drivers. The number of patients each week receiving an IV dose of fentanyl, from a vial previously accessed for another patient was tracked in a high turnover operating room (OR). The improvement model used was based on the concept of building Plan-Do-Study-Act (PDSA) cycles. Tests of change included provider education, provision of an increased number of fentanyl vials, alternate wasting processes, and provision of single-use fentanyl syringes by the pharmacy. Prior to initiation of this project, it was common for a single fentanyl vial to be accessed for multiple patients. Our data showed an average percentage of failures of just over 50%. During the end of the project, after 7 months, the mean percentage failures had dropped to 5%. Preparation of 20 mcg single-use fentanyl syringes by pharmacy, combined with education of providers on appropriate use, was successful in reducing failures to below our goal of 25%. Appropriately sized fentanyl syringes prepared by pharmacy, education on correct use of single-dose vials, and reminders in the OR, reduced the percentage of patients receiving a dose of fentanyl from a vial previously accessed for another patient in a high-volume otolaryngology room. © 2015 John Wiley & Sons Ltd.

Phase I/II trial of single-fraction high-dose-rate brachytherapy-boosted hypofractionated intensity-modulated radiation therapy for localized adenocarcinoma of the prostate.

PubMed

Myers, Michael A; Hagan, Michael P; Todor, Dorin; Gilbert, Lynn; Mukhopadhyay, Nitai; Randolf, Jessica; Heimiller, Jeffrey; Anscher, Mitchell S

2012-01-01

A Phase I/II protocol was conducted to examine the toxicity and efficacy of the combination of intensity-modulated radiation therapy (IMRT) with a single-fraction high-dose-rate (HDR) brachytherapy implant. From 2001 through 2006, 26 consecutive patients were treated on the trial. The primary objective was to demonstrate a high rate of completion without experiencing a treatment-limiting toxicity. Eligibility was limited to patients with T stage ≤2b, prostate-specific antigen (PSA) ≤20, and Gleason score ≤7. Treatment began with a single HDR fraction of 6Gy to the entire prostate and 9Gy to the peripheral zone, followed by IMRT optimized to deliver in 28 fractions with a normalized total dose of 70Gy. Patients received 50.4Gy to the pelvic lymph node. The prostate dose (IMRT and HDR) resulted in an average biologic equivalent dose >128Gy (α/β=3). Patients whose pretreatment PSA was ≥10ng/mL, Gleason score 7, or stage ≥T2b received short-term androgen ablation. Median followup was 53 months (9-68 months). There were no biochemical failures by either the American Society of Therapeutic Radiology and Oncology or the Phoenix definitions. The median nadir PSA was 0.32ng/mL. All the 26 patients completed the treatment as prescribed. The rate of Grade 3 late genitourinary toxicity was 3.8% consisting of a urethral stricture. There was no other Grade 3 or 4 genitourinary or gastrointestinal toxicities. Single-fraction HDR-boosted IMRT is a safe effective method of dose escalation for localized prostate cancer. Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Tissue responses to low protracted doses of high LET radiations or photons: Early and late damage relevant to radio-protective countermeasures

NASA Astrophysics Data System (ADS)

Ainsworth, E. J.; Afzal, S. M. J.; Crouse, D. A.; Hanson, W. R.; Fry, R. J. M.

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for γ-radiation. When total doses of 96 or 247 cGy of neutrons or γ rays were given as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and γ-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. After high single doses of neutrons or γ rays, a significant age- and radiation-related deficiency in host defense mechanisms was detected by a shorter mean survival time following challenge with transplantable leukemia cells. Comparison of dose-response curves for life shortening after irradiation with fission-spectrum neutrons or high energy silicon particles indicated high initial slopes for both radiation qualities at low doses, but for higher doses of silicon, the effect per Gy decreased to a value similar to that for γ rays. The two component life-shortening curve for silicon particles has implications for the potential efficacy of radioprotectants. Recent studies on protection against early and late effects by aminothiols, prostaglandins, and other compounds are discussed.

Meta-analysis on the Safety and Efficacy of the Reperfusion Use of a Single High Dose of Anti-T-Lymphocyte Globulin Fresenius in Kidney Transplantation.

PubMed

Du, X; Wang, W; Sun, Z-J; Su, L L; Zhang, X-D

2016-01-01

The aim of this study was to evaluate the effects of a single high dose of the anti-T-lymphocyte globulin Fresenius (ATG-F), given before kidney transplantation, on the prevention of acute rejection response and infections and on the survival rate of the renal graft and patient. Databases including PubMed, Embase, and the Cochrane Library were searched to identify randomized controlled trials relevant to studying the presurgical use of a single high dose of ATG-F. Five RCTs that included 346 patients were selected. The meta-analysis suggested that the application of ATG-F reduced the postsurgical acute rejection reaction incidence compared to that of the control group (relative risk = 0.50, 95% confidence interval = 0.35-0.71, P = .0001). However, the application of ATG-F exhibited no significant effect on the incidence of urinary tract infection, cytomegalovirus infection, and delayed graft function. Furthermore, the one-year patient survival rate and kidney graft survival rate were not affected. The meta-analysis suggested that the reperfusion use of a single high dose (9 mg/kg) of ATG-F could effectively reduce the incidence of postsurgical acute rejection response without affecting the occurrence of infections, the survival rates of kidney grafts and patients, or the incidence of delayed graft function. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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.

Behavioral effects of ketamine and toxic interactions with psychostimulants

PubMed Central

Hayase, Tamaki; Yamamoto, Yoshiko; Yamamoto, Keiichi

2006-01-01

Background The anesthetic drug ketamine (KT) has been reported to be an abused drug and fatal cases have been observed in polydrug users. In the present study, considering the possibility of KT-enhanced toxic effects of other drugs, and KT-induced promotion of an overdose without making the subject aware of the danger due to the attenuation of several painful subjective symptoms, the intraperitoneal (i.p.) KT-induced alterations in behaviors and toxic interactions with popular co-abused drugs, the psychostimulants cocaine (COC) and methamphetamine (MA), were examined in ICR mice. Results A single dose of KT caused hyperlocomotion in a low (30 mg/kg, i.p.) dose group, and hypolocomotion followed by hyperlocomotion in a high (100 mg/kg, i.p.) dose group. However, no behavioral alterations derived from enhanced stress-related depression or anxiety were observed in the forced swimming or the elevated plus-maze test. A single non-fatal dose of COC (30 mg/kg, i.p.) or MA (4 mg/kg, i.p.) caused hyperlocomotion, stress-related depression in swimming behaviors in the forced swimming test, and anxiety-related behavioral changes (preference for closed arms) in the elevated plus-maze test. For the COC (30 mg/kg) or MA (4 mg/kg) groups of mice simultaneously co-treated with KT, the psychostimulant-induced hyperlocomotion was suppressed by the high dose KT, and the psychostimulant-induced behavioral alterations in the above tests were reversed by both low and high doses of KT. For the toxic dose COC (70 mg/kg, i.p.)- or MA (15 mg/kg, i.p.)-only group, mortality and severe seizures were observed in some animals. In the toxic dose psychostimulant-KT groups, KT attenuated the severity of seizures dose-dependently. Nevertheless, the mortality rate was significantly increased by co-treatment with the high dose KT. Conclusion Our results demonstrated that, in spite of the absence of stress-related depressive and anxiety-related behavioral alterations following a single dose of KT treatment, and in spite of the KT-induced anticonvulsant effects and attenuation of stress- and anxiety-related behaviors caused by COC or MA, the lethal effects of these psychostimulants were increased by KT. PMID:16542420

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.

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects.

PubMed

Iitsuka, Hiromi; van Gelderen, Marcel; Katashima, Masataka; Takusagawa, Shin; Sawamoto, Taiji

2015-05-01

The objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects. In total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring. After administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0-∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects. Our studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

MODELING THE INTERACTION THRESHOLD: THE BREAK-POINT BETWEEN ADDITIVITY AND NON-ADDITIVITY

EPA Science Inventory

Dose-dependent changes in toxicity mechanisms of single chemicals may take place along the full dose-response spectrum. At high doses, the possibility exists for some steps in the principle mechanism of toxicity to shift to other mechanisms. The possibility of mechanism shifts fo...

Pharmacokinetics and Safety of MP-376 (Levofloxacin Inhalation Solution) in Cystic Fibrosis Subjects▿

PubMed Central

Geller, David E.; Flume, Patrick A.; Griffith, David C.; Morgan, Elizabeth; White, Dan; Loutit, Jeffery S.; Dudley, Michael N.

2011-01-01

The pharmacokinetics and tolerability of nebulized MP-376 (levofloxacin inhalation solution [Aeroquin]) were determined in cystic fibrosis (CF) subjects. Ten CF subjects received single 180-mg doses of two formulations of MP-376, followed by a multiple-dose phase of 240 mg once daily for 7 days. Serum and expectorated-sputum samples were assayed for levofloxacin content. Safety was evaluated following the single- and multiple-dose study phases. Nebulized MP-376 produced high concentrations of levofloxacin in sputum. The mean maximum plasma concentration (Cmax) ranged between 2,563 and 2,932 mg/liter for 180-mg doses of the 50- and 100-mg/ml formulations, respectively. After 7 days of dosing, the mean Cmax for the 240-mg dose was 4,691 mg/liter. The mean serum levofloxacin Cmax ranged between 0.95 and 1.28 for the 180-mg doses and was 1.71 for the 240-mg dose. MP-376 was well tolerated. Nebulized MP-376 produces high sputum and low serum levofloxacin concentrations. The pharmacokinetics, safety, and tolerability were similar for the two formulations. MP-376 240 mg (100 mg/ml) is being advanced into late-stage clinical development. PMID:21444699

Neighborhood-targeted and case-triggered use of a single dose of oral cholera vaccine in an urban setting: Feasibility and vaccine coverage.

PubMed

Parker, Lucy A; Rumunu, John; Jamet, Christine; Kenyi, Yona; Lino, Richard Laku; Wamala, Joseph F; Mpairwe, Allan M; Muller, Vincent; Llosa, Augusto E; Uzzeni, Florent; Luquero, Francisco J; Ciglenecki, Iza; Azman, Andrew S

2017-06-01

In June 2015, a cholera outbreak was declared in Juba, South Sudan. In addition to standard outbreak control measures, oral cholera vaccine (OCV) was proposed. As sufficient doses to cover the at-risk population were unavailable, a campaign using half the standard dosing regimen (one-dose) targeted high-risk neighborhoods and groups including neighbors of suspected cases. Here we report the operational details of this first public health use of a single-dose regimen of OCV and illustrate the feasibility of conducting highly targeted vaccination campaigns in an urban area. Neighborhoods of the city were prioritized for vaccination based on cumulative attack rates, active transmission and local knowledge of known cholera risk factors. OCV was offered to all persons older than 12 months at 20 fixed sites and to select groups, including neighbors of cholera cases after the main campaign ('case-triggered' interventions), through mobile teams. Vaccination coverage was estimated by multi-stage surveys using spatial sampling techniques. 162,377 individuals received a single-dose of OCV in the targeted neighborhoods. In these neighborhoods vaccine coverage was 68.8% (95% Confidence Interval (CI), 64.0-73.7) and was highest among children ages 5-14 years (90.0%, 95% CI 85.7-94.3), with adult men being less likely to be vaccinated than adult women (Relative Risk 0.81, 95% CI: 0.68-0.96). In the case-triggered interventions, each lasting 1-2 days, coverage varied (range: 30-87%) with an average of 51.0% (95% CI 41.7-60.3). Vaccine supply constraints and the complex realities where cholera outbreaks occur may warrant the use of flexible alternative vaccination strategies, including highly-targeted vaccination campaigns and single-dose regimens. We showed that such campaigns are feasible. Additional work is needed to understand how and when to use different strategies to best protect populations against epidemic cholera.

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

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.

Aerosol Delivery with Two Nebulizers Through High-Flow Nasal Cannula: A Randomized Cross-Over Single-Photon Emission Computed Tomography-Computed Tomography Study.

PubMed

Dugernier, Jonathan; Hesse, Michel; Jumetz, Thibaud; Bialais, Emilie; Roeseler, Jean; Depoortere, Virginie; Michotte, Jean-Bernard; Wittebole, Xavier; Ehrmann, Stephan; Laterre, Pierre-François; Jamar, François; Reychler, Gregory

2017-10-01

High-flow nasal cannula use is developing in ICUs. The aim of this study was to compare aerosol efficiency by using two nebulizers through a high-flow nasal cannula: the most commonly used jet nebulizer (JN) and a more efficient vibrating-mesh nebulizer (VN). Aerosol delivery of diethylenetriaminepentaacetic acid labeled with technetium-99m (4 mCi/4 mL) to the lungs by using a VN (Aerogen Solo ® ; Aerogen Ltd., Galway, Ireland) and a constant-output JN (Opti-Mist Plus Nebulizer ® ; ConvaTec, Bridgewater, NJ) through a high-flow nasal cannula (Optiflow ® ; Fisher & Paykel, New Zealand) was compared in six healthy subjects. Flow rate was set at 30 L/min through the heated humidified circuit. Pulmonary and extrapulmonary deposition was measured by single-photon emission computed tomography combined with a low-dose computed tomographic scan and by planar scintigraphy. Lung deposition was only 3.6 (2.1-4.4) and 1 (0.7-2)% of the nominal dose with the VN and the JN, respectively (p < 0.05). The JN showed higher retained doses than the VN. However, both nebulizers were associated with substantial deposition in the single limb circuit, the humidification chamber, and the nasal cannula [58.2 (51.6-61.6)% of the nominal dose with the VN versus 19.2 (15.8-22.9)% of the nominal dose with the JN, p < 0.05] and in the upper respiratory tract [17.6 (13.4-27.9)% of the nominal dose with the VN and 8.6 (6.0-11.0)% of the nominal dose with the JN, p < 0.05], especially in the nasal cavity. In the specific conditions of the study, pulmonary drug delivery through the high-flow nasal cannula is about 1%-4% of the initial amount of drugs placed in the nebulizer, despite the higher efficiency of the VN as compared with the JN.

Processing speed can monitor stimulant-medication effects in adults with attention deficit disorder with hyperactivity.

PubMed

Nielsen, Niels Peter; Wiig, Elisabeth H; Bäck, Svante; Gustafsson, Jan

2017-05-01

Treatment responses to methylphenidate by adults with ADHD are generally monitored against DSM-IV/DSM-V symptomatology, rating scales or interviews during reviews. To evaluate the use of single- and dual-dimension processing-speed and efficiency measures to monitor the effects of pharmacological treatment with methylphenidate after a short period off medication. A Quick Test of Cognitive Speed (AQT) monitored the effects of immediate-release methylphenidate in 40 previously diagnosed and medicated adults with ADHD. Processing speed was evaluated with prior prescription medication, without medication after a 2-day period off ADHD medication, and with low-dose (10/20 mg) and high-dose (20/40 mg) methylphenidate hydrochloride (Medikinet IR). Thirty-three participants responded to the experimental treatments. One-way ANOVA with post-hoc analysis (Scheffe) indicated significant main effects for single dimension colour and form and dual-dimension colour-form naming. Post-hoc analysis indicated statistical differences between the no- and high-dose medication conditions for colour and form, measures of perceptual speed. For colour-form naming, a measure of cognitive speed, there was a significant difference between no- and low-dose medication and between no- and high-dose medications, but not between low- and high-dose medications. Results indicated that the AQT tests effectively monitored incremental effects of the methylphenidate dose on processing speed after a 2-day period off medication. Thus, perceptual (colour and form) and cognitive speed (two-dimensional colour-form naming) and processing efficiency (lowered shift costs) increased measurably with high-dose medication. These preliminary findings warrant validation with added measures of associated behavioural and cognitive changes.

Sustained neuroprotection from a single intravitreal injection of PGJ₂ in a nonhuman primate model of nonarteritic anterior ischemic optic neuropathy.

PubMed

Miller, Neil R; Johnson, Mary A; Nolan, Theresa; Guo, Yan; Bernstein, Alexander M; Bernstein, Steven L

2014-10-08

Prostaglandin J₂ (PGJ₂) is neuroprotective in a murine model of nonarteritic anterior ischemic optic neuropathy (NAION). After assessing for potential toxicity, we evaluated the efficacy of a single intravitreal (IVT) injection of PGJ₂ in a nonhuman primate model of NAION (pNAION). We assessed PGJ₂ toxicity by administering it as a single high-dose intravenous (IV) injection, consecutive daily high-dose IV injections, or a single IVT injection in one eye of five adult rhesus monkeys. To assess efficacy, we induced pNAION in one eye of five adult male rhesus monkeys using a laser-activated rose bengal induction method. We then injected the eye with either PGJ₂ or phosphate-buffered saline (PBS) intravitreally immediately or 5 hours post induction. We performed a clinical assessment, optical coherence tomography, electrophysiological testing, fundus photography, and fluorescein angiography in all animals prior to induction and at 1 day, 1 week, 2 weeks, and 4 weeks after induction. Following analysis of the first eye, we induced pNAION in the contralateral eye and then injected either PGJ₂ or PBS. We euthanized all animals 5 weeks after final assessment of the fellow eye and performed both immunohistochemical and light and electron microscopic analyses of the retina and optic nerves. PGJ₂ caused no permanent systemic toxicity regardless of the amount injected or route of delivery, and there was no evidence of any ocular toxicity with the dose of PGJ₂ used in efficacy studies. Transient reduction in the amplitudes of the visual evoked potentials and the N95 component of the pattern electroretinogram (PERG) occurred after both IV and IVT administration of high doses of PGJ₂; however, the amplitudes returned to normal in all animals within 1 week. In all eyes, a single IVT dose of PGJ₂ administered immediately or shortly after induction of pNAION resulted in a significant reduction of clinical, electrophysiological, and histological damage compared with vehicle-injected eyes (P = 0.03 for both VEP and PERG; P = 0.05 for axon counts). In nonhuman primates, PGJ₂ administered either intravenously or intravitreally produces no permanent toxicity at even four times the dose given for neuroprotection. Additionally, a single IVT dose of PGJ₂ is neuroprotective when administered up to 5 hours after induction of pNAION. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Efficacy of a Single-Dose, Inactivated Oral Cholera Vaccine in Bangladesh.

PubMed

Qadri, Firdausi; Wierzba, Thomas F; Ali, Mohammad; Chowdhury, Fahima; Khan, Ashraful I; Saha, Amit; Khan, Iqbal A; Asaduzzaman, Muhammad; Akter, Afroza; Khan, Arifuzzaman; Begum, Yasmin A; Bhuiyan, Taufiqur R; Khanam, Farhana; Chowdhury, Mohiul I; Islam, Taufiqul; Chowdhury, Atique I; Rahman, Anisur; Siddique, Shah A; You, Young A; Kim, Deok R; Siddik, Ashraf U; Saha, Nirod C; Kabir, Alamgir; Cravioto, Alejandro; Desai, Sachin N; Singh, Ajit P; Clemens, John D

2016-05-05

A single-dose regimen of the current killed oral cholera vaccines that have been prequalified by the World Health Organization would make them more attractive for use against endemic and epidemic cholera. We conducted an efficacy trial of a single dose of the killed oral cholera vaccine Shanchol, which is currently given in a two-dose schedule, in an urban area in which cholera is highly endemic. Nonpregnant residents of Dhaka, Bangladesh, who were 1 year of age or older were randomly assigned to receive a single dose of oral cholera vaccine or oral placebo. The primary outcome was vaccine protective efficacy against culture-confirmed cholera occurring 7 to 180 days after dosing. Prespecified secondary outcomes included protective efficacy against severely dehydrating culture-confirmed cholera during the same interval, against cholera and severe cholera occurring 7 to 90 versus 91 to 180 days after dosing, and against cholera and severe cholera according to age at baseline. A total of 101 episodes of cholera, 37 associated with severe dehydration, were detected among the 204,700 persons who received one dose of vaccine or placebo. The vaccine protective efficacy was 40% (95% confidence interval [CI], 11 to 60%; 0.37 cases per 1000 vaccine recipients vs. 0.62 cases per 1000 placebo recipients) against all cholera episodes, 63% (95% CI, 24 to 82%; 0.10 vs. 0.26 cases per 1000 recipients) against severely dehydrating cholera episodes, and 63% (95% CI, -39 to 90%), 56% (95% CI, 16 to 77%), and 16% (95% CI, -49% to 53%) against all cholera episodes among persons vaccinated at the age of 5 to 14 years, 15 or more years, and 1 to 4 years, respectively, although the differences according to age were not significant (P=0.25). Adverse events occurred at similar frequencies in the two groups. A single dose of the oral cholera vaccine was efficacious in older children (≥5 years of age) and in adults in a setting with a high level of cholera endemicity. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02027207.).

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.

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.

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

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

The Combination of Micro Diaphragm Pumps and Flow Sensors for Single Stroke Based Liquid Flow Control

PubMed Central

Jenke, Christoph; Pallejà Rubio, Jaume; Kibler, Sebastian; Häfner, Johannes; Richter, Martin; Kutter, Christoph

2017-01-01

With the combination of micropumps and flow sensors, highly accurate and secure closed-loop controlled micro dosing systems for liquids are possible. Implementing a single stroke based control mode with piezoelectrically driven micro diaphragm pumps can provide a solution for dosing of volumes down to nanoliters or variable average flow rates in the range of nL/min to μL/min. However, sensor technologies feature a yet undetermined accuracy for measuring highly pulsatile micropump flow. Two miniaturizable in-line sensor types providing electrical readout—differential pressure based flow sensors and thermal calorimetric flow sensors—are evaluated for their suitability of combining them with mircopumps. Single stroke based calibration of the sensors was carried out with a new method, comparing displacement volumes and sensor flow volumes. Limitations of accuracy and performance for single stroke based flow control are described. Results showed that besides particle robustness of sensors, controlling resistive and capacitive damping are key aspects for setting up reproducible and reliable liquid dosing systems. Depending on the required average flow or defined volume, dosing systems with an accuracy of better than 5% for the differential pressure based sensor and better than 6.5% for the thermal calorimeter were achieved. PMID:28368344

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.

Quality and efficiency of statin prescribing across countries with a special focus on South Africa: findings and future implications.

PubMed

Godman, Brian; Bishop, Iain; Campbell, Stephen M; Malmström, Rickard E; Truter, Ilse

2015-04-01

Statins are recommended first-line treatment for hyperlipidemia, with published studies suggesting limited differences between them. However, there are reports of under-dosing. South Africa has introduced measures to enhance generic utilization. Part one documents prescribed doses of statins in 2011. Part two determines the extent of generics versus originator and single-sourced statins in 2011 and their costs. Underdosing of simvastatin in 2011 with average prescribed dose of 23.7 mg; however, not for atorvastatin (20.91 mg) or rosuvastatin (15.02 mg). High utilization of generics versus originators at 93-99% for atorvastatin and simvastatin, with limited utilization of single-sourced statins (22% of total statins - defined daily dose basis), mirroring Netherlands, Sweden and UK. Generics priced 33-51% below originator prices. Opportunity to increase simvastatin dosing through education, prescribing targets and incentives. Opportunity to lower generic prices with generic simvastatin 96-98% below single-sourced prices in some European countries.

Bioavailability of a Sustained Release Formulation of Curcumin

PubMed Central

Madhavi, Doddabele; Kagan, Daniel

2014-01-01

Context Curcumin has a number of beneficial effects, such as functioning as a potent antioxidant,1 anti-inflammatory, 2 and anticancer agent. Because of its poor oral bioavailability, very high oral doses and repeated dosing have been used to obtain effective plasma levels, with mixed results. High doses of curcumin may cause gastric disturbance, often resulting in poor patient compliance. Objective The objective of this study was to compare the relative bioavailability of MicroActive Curcumin—an advanced, micronized formulation of curcumin that is 25% curcuminoids in a sustained release matrix—with that of an unformulated, 95% pure curcumin powder. Design A dissolution study compared the solubility of the formulated and the unformulated curcumin. The research team also performed a single-dose, 12-h, crossover uptake study with 10 participants and a high-dose tolerability and accumulation study with 3 participants, comparing the 2 forms of curcumin. Setting The study was done in MAZE Laboratories (Purchase, NY, USA). Participants Ten healthy male and female volunteers, aged 21–66 y, took part in the single-dose study. Three participants, 2 female and 1 male aged 40–55 y, took part in the tolerability and accumulation study. The participants were people from the community. Intervention For the dissolution study, the research team filled hard gelatin capsules with unformulated 95% curcumin powder and the MicroActive Curcumin powder to the equivalent of 25 mg curcuminoids. For the single-dose study, participants received 500 mg of curcumin in 2 forms. MicroActive Curcumin capsules were administered after breakfast, and blood samples were drawn at 1, 2, 4, 8, and 12 h postdose. After a 7-d washout period, the protocol was repeated for unformulated, 95% curcumin powder capsules. For the tolerability study, the unformulated, 95% curcumin powder was given at a dose that provided 2 g of curcumin for 7 d followed by 5 g of curcumin for an additional 7 d. After a washout period of 14 d, the protocol was repeated with MicroActive Curcumin. Participants then continued to take the MicroActive Curcumin for >3 mo. Outcome Measures For the dissolution study, the curcumin was quantified at room temperature using reverse-phase, high-performance liquid chromatography (HPLC) with a Phenomenex Luna column (150 × 4.6 mm, 5 μm) (Phenomenex Inc, Torrance, CA, USA). For the single-dose and the tolerability studies, hydrolysis of conjugates and extraction of curcuminoids from the plasma were performed. The curcuminoids were quantified using reverse-phase HPLC with an ultraviolet-visible detector as described above. Results The dissolution study indicated that the sustained-release curcumin had greater dissolution for 12 h at all points tested, compared with the unformulated curcumin. Very little of the unformulated curcumin powder had been released at the end of the 12 h. The results of the single-dose uptake study indicated that the sustained-release formula was 9.7 × more bioavailable than the unformulated powder (P < .001, paired t test). Additionally, all participants showed uptake from the sustained-release formulation. That formulation also resulted in significant increases in the plasma demethoxylated curcuminoids, but the research team did not observe the same increases for the unformulated curcumin powder. The sustained-release formulation was well tolerated, without adverse effects in the high-dose tolerability study. Conclusions Formulation of micronized curcumin in a combination of surfactants, oils, and polymers improves the absorption of curcumin. In addition, the unique plasma demethylated curcuminoid profile may enhance the therapeutic effects of MicroActive Curcumin not observed with unformulated curcumin at moderate and well-tolerated doses. MicroActive Curcumin was well tolerated, without any adverse effects in a high-dose tolerability study. These properties have the potential to make high-dose curcumin supplementation more accessible through simplified incorporation into food and beverage preparations. PMID:26770097

The atypical excretion profile of meldonium: Comparison of urinary detection windows after single- and multiple-dose application in healthy volunteers.

PubMed

Görgens, Christian; Guddat, Sven; Bosse, Christina; Geyer, Hans; Pop, Valentin; Schänzer, Wilhelm; Thevis, Mario

2017-05-10

Following a one-year monitoring program providing unequivocal analytical evidence for a high prevalence in international elite sports, meldonium has been included in the World Anti-Doping Agency's (WADA) list of prohibited substances that came into effect on 1 January 2016. Despite of the polar and hydrophilic nature of the molecule, an unusual long detection window was observed in pilot elimination studies. Consequently, in the present study, urinary excretion profiles after single-dose (5 volunteers, 1×500mg) and multiple-dose oral application (5 volunteers; 2×500mg/day for 6days) were determined in order to facilitate the result management concerning meldonium findings in doping controls. Particularly the option to differentiate between recent use and tapering concentrations was studied. Urinary meldonium concentrations were determined using an analytical approach based on hydrophilic interaction liquid chromatography and high resolution tandem mass spectrometry. The study corroborates the hypothesis of a non-linear, dose-depended and biphasic excretion profile after oral application of meldonium and demonstrates that urinary detection windows are of considerable extent with up to 65 and 117days (concentrations>LOQ of 10ng/mL) following single- and multiple-dose applications, respectively. Copyright © 2017 Elsevier B.V. All rights reserved.

Single-dose Universal Hepatitis A Immunization in One-year-old Children in Argentina: High Prevalence of Protective Antibodies up to 9 Years After Vaccination.

PubMed

Urueña, Analía; González, Jorge E; Rearte, Analía; Pérez Carrega, María E; Calli, Rogelio; Pagani, María F; Uboldi, Andrea; Vicentín, Rosalía; Caglio, Patricia; Cañero-Velasco, María C; Gentile, Angela; Ramonet, Margarita; Vizzotti, Carla

2016-12-01

Single-dose hepatitis A virus (HAV) vaccination was implemented in all Argentinean children 12 months of age in 2005. Previous studies demonstrated high prevalence of protective antibody response 4 years after single-dose vaccination. This study assessed long-term seroprotection against HAV after vaccination. Children who received 1 dose of HAV vaccine at 1 year of age at least 6 years before enrollment were included at 5 centers in Argentina between 2013 and 2014. Demographic and socioeconomic characteristics were collected through a questionnaire. Blood samples were tested for anti-HAV antibodies. Antibody values ≥10 mIU/mL were considered seroprotective. Logistic regression analysis was performed to evaluate the association between demographic and socioeconomic variables and seroprotection. A total of 1088 children were included, with a median postvaccination interval of 7.7 years (range 6.3-9.2 years). Of these children, 97.4% (95% confidence interval: 96.3%-98.3%) had protective antibodies against HAV. No association between demographic or socioeconomic variables and seroprotection was found. Geometric mean concentration of antibody levels against HAV was 170.5 mUI/mL (95% confidence interval: 163.2-178.2 mUI/mL). Single-dose universal hepatitis A immunization in 1-year-old children resulted in sustained immunologic protection for up to 9 years in Argentina. These findings, along with the low current disease burden, confirm the success of the intervention.

Linac-based extracranial radiosurgery with Elekta volumetric modulated arc therapy and an anatomy-based treatment planning system: Feasibility and initial experience

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

Cilla, Savino, E-mail: savinocilla@gmail.com; Deodato, Francesco; Macchia, Gabriella

We reported our initial experience in using Elekta volumetric modulated arc therapy (VMAT) and an anatomy-based treatment planning system (TPS) for single high-dose radiosurgery (SRS-VMAT) of liver metastases. This study included a cohort of 12 patients treated with a 26-Gy single fraction. Single-arc VMAT plans were generated with Ergo++ TPS. The prescription isodose surface (IDS) was selected to fulfill the 2 following criteria: 95% of planning target volume (PTV) reached 100% of the prescription dose and 99% of PTV reached a minimum of 90% of prescription dose. A 1-mm multileaf collimator (MLC) block margin was added around the PTV. Formore » a comparison of dose distributions with literature data, several conformity indexes (conformity index [CI], conformation number [CN], and gradient index [GI]) were calculated. Treatment efficiency and pretreatment dosimetric verification were assessed. Early clinical data were also reported. Our results reported that target and organ-at-risk objectives were met for all patients. Mean and maximum doses to PTVs were on average 112.9% and 121.5% of prescribed dose, respectively. A very high degree of dose conformity was obtained, with CI, CN, and GI average values equal to 1.29, 0.80, and 3.63, respectively. The beam-on-time was on average 9.3 minutes, i.e., 0.36 min/Gy. The mean number of monitor units was 3162, i.e., 121.6 MU/Gy. Pretreatment verification (3%-3 mm) showed an optimal agreement with calculated values; mean γ value was 0.27 and 98.2% of measured points resulted with γ < 1. With a median follow-up of 16 months complete response was observed in 12/14 (86%) lesions; partial response was observed in 2/14 (14%) lesions. No radiation-induced liver disease (RILD) was observed in any patients as well no duodenal ulceration or esophagitis or gastric hemorrhage. In conclusion, this analysis demonstrated the feasibility and the appropriateness of high-dose single-fraction SRS-VMAT in liver metastases performed with Elekta VMAT and Ergo++ TPS. Preliminary clinical outcomes showed a high rate of local control and minimum incidence of acute toxicity.« less

Role of (-)-epigallocatechin gallate in the pharmacokinetic interaction between nadolol and green tea in healthy volunteers.

PubMed

Abe, Osamu; Ono, Tomoyuki; Sato, Hideyuki; Müller, Fabian; Ogata, Hiroshi; Miura, Itaru; Shikama, Yayoi; Yabe, Hirooki; Onoue, Satomi; Fromm, Martin F; Kimura, Junko; Misaka, Shingen

2018-06-01

The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans. In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose. Plasma concentrations and urinary excretion of nadolol were determined up to 48 h. In addition, blood pressure and pulse rate were monitored. In vitro transport kinetic experiments were performed using human embryonic kidney 293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated substrate transport. Single coadministration of low and high dose GTE significantly reduced the plasma concentrations of nadolol. The geometric mean ratios with 90% CI for area under the plasma concentration-time curves from 0 to infinity of nadolol were 0.72 (0.56-0.87) for the low and 0.60 (0.51-0.69) for the high dose. There were no significant differences in T max , elimination half-life, and renal clearance between GTE and water phases. No significant changes were observed for blood pressure and pulse rate between phases. EGCG competitively inhibited OATP1A2-mediated uptake of sulphobromophthalein and nadolol with K i values of 21.6 and 19.4 μM, respectively. EGCG is suggested to be a key contributor to the interaction of green tea with nadolol. Moreover, even a single coadministration of green tea may significantly affect nadolol pharmacokinetics.

Chronic consumption of a low calorie, high polyphenol cranberry beverage attenuates inflammation and improves glucoregulation and HDL cholesterol in healthy overweight humans: a randomized controlled trial.

PubMed

Chew, Boon; Mathison, Bridget; Kimble, Lindsey; McKay, Diane; Kaspar, Kerrie; Khoo, Christina; Chen, C-Y Oliver; Blumberg, Jeffrey

2018-02-23

We studied the health benefits of low calorie cranberry beverage consumption on glucoregulation, oxidative damage, inflammation, and lipid metabolism in overweight but otherwise healthy humans. 78 overweight or obese men and women (30-70 years; BMI 27-35 kg/m 2 ) with abdominal adiposity (waist: hip > 0.8 for women and > 0.9 for men; waist: height ≥ 0.5) consumed 450 mL placebo or low calorie, high polyphenol cranberry extract beverage (CEB) daily for 8 week in a randomized, double-blind, placebo-controlled, parallel design trial. Blood and urine samples were collected after overnight fast at baseline and after 8 weeks of daily beverage consumption. Blood and urine samples were also collected during 3 oral glucose tolerance test (OGTT) challenges: (1) pre-intervention without the test beverages, (2) following a single dose of placebo or CEB at baseline (week 0), and (3) following a single dose of placebo or CEB at 8 week. Compared to placebo, a single CEB dose at baseline lowered endothelin-1 and elevated nitric oxide and the reduced:oxidized glutathione ratio (P < 0.05). Interferon-γ was elevated (P < 0.05) after a single CEB dose at baseline; however, after 8 week of CEB intervention, fasting C-reactive protein was lower (P < 0.05). CEB consumption for 8 week also reduced serum insulin and increased HDL cholesterol compared to placebo (P < 0.05). An acute dose of low calorie, high polyphenol cranberry beverage improved antioxidant status, while 8 week daily consumption reduced cardiovascular disease risk factors by improving glucoregulation, downregulating inflammatory biomarkers, and increasing HDL cholesterol.

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.

Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine.

PubMed

Tfelt-Hansen, Peer; Ågesen, Frederik Nybye; Pavbro, Agniezka; Tfelt-Hansen, Jacob

2017-05-01

In this review, we evaluate the variability in the pharmacokinetics of 11 drugs with established prophylactic effects in migraine to facilitate 'personalized medicine' with these drugs. PubMed was searched for 'single-dose' and 'steady-state' pharmacokinetic studies of these 11 drugs. The maximum plasma concentration was reported in 248 single-dose and 115 steady-state pharmacokinetic studies, and the area under the plasma concentration-time curve was reported in 299 single-dose studies and 112 steady-state pharmacokinetic studies. For each study, the coefficient of variation was calculated for maximum plasma concentration and area under the plasma concentration-time curve, and we divided the drug variability into two categories; high variability, coefficient of variation >40%, or low or moderate variability, coefficient of variation <40%. Based on the area under the plasma concentration-time curve in steady-state studies, the following drugs have high pharmacokinetic variability: propranolol in 92% (33/36), metoprolol in 85% (33/39), and amitriptyline in 60% (3/5) of studies. The following drugs have low or moderate variability: atenolol in 100% (2/2), valproate in 100% (15/15), topiramate in 88% (7/8), and naproxen and candesartan in 100% (2/2) of studies. For drugs with low or moderate pharmacokinetic variability, treatment can start without initial titration of doses, whereas titration is used to possibly enhance tolerability of topiramate and amitriptyline. The very high pharmacokinetic variability of metoprolol and propranolol can result in very high plasma concentrations in a small minority of patients, and those drugs should therefore be titrated up from a low initial dose, depending mainly on the occurrence of adverse events.

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

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

Streitparth, Florian; Pech, Maciej; Boehmig, Michael

2006-08-01

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

The incidence of the different sources of noise on the uncertainty in radiochromic film dosimetry using single channel and multichannel methods

NASA Astrophysics Data System (ADS)

González-López, Antonio; Vera-Sánchez, Juan Antonio; Ruiz-Morales, Carmen

2017-11-01

The influence of the various sources of noise on the uncertainty in radiochromic film (RCF) dosimetry using single channel and multichannel methods is investigated in this work. These sources of noise are extracted from pixel value (PV) readings and dose maps. Pieces of an RCF were each irradiated to different uniform doses, ranging from 0 to 1092 cGy. Then, the pieces were read at two resolutions (72 and 150 ppp) with two flatbed scanners: Epson 10000XL and Epson V800, representing two states of technology. Noise was extracted as described in ISO 15739 (2013), separating its distinct constituents: random noise and fixed pattern (FP) noise. Regarding the PV maps, FP noise is the main source of noise for both models of digitizer. Also, the standard deviation of the random noise in the 10000XL model is almost twice that of the V800 model. In the dose maps, the FP noise is smaller in the multichannel method than in the single channel ones. However, random noise is higher in this method, throughout the dose range. In the multichannel method, FP noise is reduced, as a consequence of this method’s ability to eliminate channel independent perturbations. However, the random noise increases, because the dose is calculated as a linear combination of the doses obtained by the single channel methods. The values of the coefficients of this linear combination are obtained in the present study, and the root of the sum of their squares is shown to range between 0.9 and 1.9 over the dose range studied. These results indicate the random noise to play a fundamental role in the uncertainty of RCF dosimetry: low levels of random noise are required in the digitizer to fully exploit the advantages of the multichannel dosimetry method. This is particularly important for measuring high doses at high spatial resolutions.

High-dose tranexamic acid reduces intraoperative and postoperative blood loss in posterior lumbar interbody fusion.

PubMed

Kushioka, Junichi; Yamashita, Tomoya; Okuda, Shinya; Maeno, Takafumi; Matsumoto, Tomiya; Yamasaki, Ryoji; Iwasaki, Motoki

2017-03-01

OBJECTIVE Tranexamic acid (TXA), a synthetic antifibrinolytic drug, has been reported to reduce blood loss in orthopedic surgery, but there have been few reports of its use in spine surgery. Previous studies included limitations in terms of different TXA dose regimens, different levels and numbers of fused segments, and different surgical techniques. Therefore, the authors decided to strictly limit TXA dose regimens, surgical techniques, and fused segments in this study. There have been no reports of using TXA for prevention of intraoperative and postoperative blood loss in posterior lumbar interbody fusion (PLIF). The purpose of the study was to evaluate the efficacy of high-dose TXA in reducing blood loss and its safety during single-level PLIF. METHODS The study was a nonrandomized, case-controlled trial. Sixty consecutive patients underwent single-level PLIF at a single institution. The first 30 patients did not receive TXA. The next 30 patients received 2000 mg of intravenous TXA 15 minutes before the skin incision was performed and received the same dose again 16 hours after the surgery. Intra- and postoperative blood loss was compared between the groups. RESULTS There were no statistically significant differences in preoperative parameters of age, sex, body mass index, preoperative diagnosis, or operating time. The TXA group experienced significantly less intraoperative blood loss (mean 253 ml) compared with the control group (mean 415 ml; p < 0.01). The TXA group also had significantly less postoperative blood loss over 40 hours (mean 321 ml) compared with the control group (mean 668 ml; p < 0.01). Total blood loss in the TXA group (mean 574 ml) was significantly lower than in the control group (mean 1080 ml; p < 0.01). From 2 hours to 40 hours, postoperative blood loss in the TXA group was consistently significantly lower. There were no perioperative complications, including thromboembolic events. CONCLUSIONS High-dose TXA significantly reduced both intra- and postoperative blood loss without causing any complications during or after single-level PLIF.

Nevirapine Resistance by Timing of HIV Type 1 Infection in Infants Treated with Single-Dose Nevirapine

PubMed Central

Micek, Mark A.; Blanco, Ana Judith; Beck, Ingrid A.; Dross, Sandra; Matunha, Laurinda; Montoya, Pablo; Seidel, Kristy; Gantt, Soren; Matediane, Eduardo; Jamisse, Lilia; Gloyd, Stephen; Frenkel, Lisa M.

2011-01-01

Background In women, single-dose nevirapine for prophylaxis against mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) selects for nevirapine-resistant HIV-1, which subsequently decays rapidly. We hypothesized that the selection, acquisition, and decay of nevirapine-resistant HIV-1 differs in infants, varying by the timing of HIV-1 infection. Methods We conducted a prospective, observational study of 740 Mozambican infants receiving single-dose nevirapine prophylaxis and determined the timing of infection and concentrations of nevirapine-resistant HIV-1 over time. Results Infants with established in utero infection had a high rate (87.0%) of selection of nevirapine-resistant HIV-1 mutants, which rapidly decayed to undetectable levels. The few without nevirapine resistance received zidovudine with single-dose nevirapine and/or their mothers took alternative antiretroviral drugs. Infants with acute in utero infection had a lower rate of nevirapine-resistant HIV-1 (33.3%; P =.006, compared with established in utero infection), but mutants persisted over time. Infants with peripartum infection also had a lower rate of nevirapine-resistant HIV-1 (38.1%; P =.001, compared with established in utero infection) but often acquired 100% mutant virus that persisted over time (P =.017, compared with established in utero infection). Conclusions The detection and persistence of nevirapine-resistant HIV-1 in infants after single-dose nevirapine therapy vary by the timing of infection and the antiretroviral regimen. In infants with persistent high-level nevirapine-resistant HIV-1, nevirapine-based antiretroviral therapy is unlikely to ever be efficacious because of concentrations in long-lived viral reservoirs. However, the absence or decay of nevirapine-resistant HIV-1 in many infants suggests that nevirapine antiretroviral therapy may be effective if testing can identify these individuals. PMID:20384494

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

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.

Effects of food on the pharmacokinetics of ponatinib in healthy subjects.

PubMed

Narasimhan, N I; Dorer, D J; Niland, K; Haluska, F; Sonnichsen, Daryl

2013-12-01

Ponatinib is a potent oral tyrosine kinase inhibitor with activity against BCR-ABL, the primary driver of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. This single-centre, single-dose, randomized, open-label, three-period crossover study evaluated the pharmacokinetics and bioavailability of a single oral dose of ponatinib (45-mg tablet) under fasting conditions and following consumption of high- and low-fat meals by healthy subjects. Subjects were randomly assigned to one of the six possible treatment sequences, each evaluating three ponatinib 45-mg treatments: administered under fasting conditions; administered after a high-fat meal; or administered after a standardized low-fat meal. The high-fat meal derived approximately 50% of its total caloric content from fat, with approximately 150, 250 and 500-600 calories derived from protein, carbohydrates and fat, respectively (total of approximately 900-1000 calories). The standardized low-fat meal derived no more than 20% of total caloric content from fat, with approximately 56, 428 and 63 calories derived from protein, carbohydrates and fat, respectively (total of approximately 547 calories). During each of the three treatment periods, blood samples were collected predose and at 13 time points over the 96-h post-dose interval. Plasma concentrations of ponatinib were measured by liquid chromatography/tandem mass spectrometry. Mixed-model analyses of variance (anova) were performed on natural log-transformed PK parameters Cmax and AUC0-∞. Geometric mean maximum plasma concentration (Cmax) values for the fasted, low-fat and high-fat regimens were 54·7, 51·6 and 51·5 ng/mL, respectively. Geometric mean area under the concentration-time curve from time zero to infinity (AUC0-∞) values for the fasted, low-fat and high-fat regimens were 1273, 1244 and 1392 h × ng/mL, respectively. All limits of the 90% CIs of the estimated geometric mean ratios for Cmax and all AUC comparisons fell within the 80%-125% margins. These results indicate that consumption of a high- or low-fat meal within 30 min prior to administration of ponatinib had no effect on the single-dose pharmacokinetics of ponatinib. Food does not affect the single-dose pharmacokinetics of ponatinib. These data demonstrate that ponatinib may be administered with or without food. © 2013 The Authors. Journal of Clinical Pharmacy and Therapeutics published by John Wiley & Sons Ltd.

Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery

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

Moussazadeh, Nelson; Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York; Lis, Eric

Purpose: To characterize local tumor control and toxicity risk in very long-term survivors (>5 years) after high-dose spinal image guided, intensity modulated radiation therapy delivered as single-dose stereotactic radiosurgery (SRS). Previously published spinal SRS outcome analyses have included a heterogeneous population of cancer patients, mostly with short survival. This is the first study reporting the long-term tumor control and toxicity profiles after high-dose single-fraction spinal SRS. Methods and Materials: The study population included all patients treated from June 2004 to July 2009 with single-fraction spinal SRS (dose 24 Gy) who had survived at least 5 years after treatment. The endpoints examined included diseasemore » progression, surgical or radiation retreatment, in-field fracture development, and radiation-associated toxicity, scored using the Radiation Therapy Oncology Group radiation morbidity scoring criteria and the Common Terminology Criteria for Adverse Events, version 4.0. Local control and fracture development were assessed using Kaplan-Meier analysis. Results: Of 278 patients, 31 (11.1%), with 36 segments treated for spinal tumors, survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 6.1 years (maximum 102 months). The histopathologic findings for the 5-year survivors included radiation-resistant metastases in 58%, radiation-sensitive metastases in 22%, and primary bone tumors in 19%. In this selected cohort, 3 treatment failures occurred at a median of 48.6 months, including 2 recurrences in the radiation field and 1 patient with demonstrated progression at the treatment margins. Ten lesions (27.8%) were associated with acute grade 1 cutaneous or gastrointestinal toxicity. Delayed toxicity ≥3 months after treatment included 8 cases (22.2%) of mild neuropathy, 2 (5.6%) of gastrointestinal discomfort, 8 (22.2%) of dermatitides, and 3 (8.3%) of myalgias/myositis. Thirteen treated levels (36.1%) in 12 patients demonstrated progressive vertebral body collapse or endplate fractures at a median of 25.7 months (range 11.6-76.0), of which 5 (14%) became symptomatic and subsequently required percutaneous cement augmentation or surgery. Conclusions: In the longest-term series to date, high-dose single-fraction spinal SRS retained an excellent safety profile among long-term survivors (>5 years)« less

The modification of high-dose therapy shortens the duration of neutropaenia by delay of leucocyte nadir.

PubMed

Kiefer, T; Krüger, W H; Schüler, F; Lotze, C; Hirt, C; Dölken, G

2006-06-01

Infections during neutropaenia contribute still significantly to mortality and morbidity after high-dose therapy and autologous stem cell transplantation. Further acceleration of haemopoietic recovery seems impossible for biological reasons. Another approach to shorten neutropaenia could be to remove drugs from high-dose therapy protocols with strong contribution to immunosuppression and neutropaenia and unproven antineoplastic activity. In this retrospective matched-pair analysis, conventional busulphan/cyclophosphamide (Bu/Cy) high-dose therapy was compared to single-agent busulphan conditioning before autologous stem cell transplantation. This modification led to a significant shorter neutropaenic interval by protraction of cell decrease and to a significant mitigation of neutropaenia. After single-agent busulphan conditioning, leucocytes dropped below 1/nl at median 1.5 days later when compared to the patients from the busulphanBu/Cy control group (P=0.001). In a significant percentage of patients (n=6, 60%) leucocytes did not fall below 0.5 cells/nl at any time. In contrast, all patients from the Bu/Cy control group experienced deep neutropaenia (P=0.004). Thrombocytopaenia and requirement for transfusions of platelets or red cells were not influenced. Antineoplastic activity seemed to be preserved as determined by survival analysis. In conclusion, modification of high-dose regimen with the intention to shorten neutropaenia with preserved antitumour activity could be an approach to reduce infection-related morbidity and mortality and to consider economic necessities.

Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge.

PubMed

Sun, Jialei; Ennis, Jane; Turner, Jeffrey D; Chu, Justin Jang Hann

2016-10-01

Enterovirus 71 (EV71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. Interferon (IFN) can inhibit the replication of many viruses with low cytotoxic effects. Previously, an adenovirus vectored mouse interferon-α (DEF201), subtype 5, was generated by Wu et al, 2007. In this study, the antiviral effects of DEF201 against EV71 were evaluated in a murine model. 6-day-old BALB/c mice were administered a single dose of DEF201 before or after infection with lethal dose of EV71. The survival rate, clinical symptoms, tissue viral loads and histology pathogenesis were evaluated. IFN gene expression following a single dose of DEF201 maintained high concentrations of 100-9000 pg/mL for more than 7 days in mice serum. Pre-infection administration of a single dose of 10 6  PFU of DEF201 offered full protection of the mice against EV71 infection compared with the empty Ad5 vector control. In addition, virus load in DEF201-treated mice muscle tissue was significantly decreased as compared with empty vector control. Histopathology analysis revealed that DEF201 significantly prevented the development of severe tissue damage with reduction of viral antigen in the murine muscle tissue. Post-infection treatment at 6 h offered full protection and partial protection at 12 h, indicating that DEF201 could be used as an anti-EV71 therapeutic agent in early stage of EV71 infection. In addition, our study showed that DEF201 enhanced the neutralization ability of serum in EV71-vaccinated mice, implying that DEF201 could promote the production of specific anti-EV71 antibodies. In conclusion, single dose of DEF201 is highly efficacious as a prophylactic agent against EV71 infection in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

Sustained Neuroprotection From a Single Intravitreal Injection of PGJ2 in a Nonhuman Primate Model of Nonarteritic Anterior Ischemic Optic Neuropathy

PubMed Central

Miller, Neil R.; Johnson, Mary A.; Nolan, Theresa; Guo, Yan; Bernstein, Alexander M.; Bernstein, Steven L.

2014-01-01

Purpose. Prostaglandin J2 (PGJ2) is neuroprotective in a murine model of nonarteritic anterior ischemic optic neuropathy (NAION). After assessing for potential toxicity, we evaluated the efficacy of a single intravitreal (IVT) injection of PGJ2 in a nonhuman primate model of NAION (pNAION). Methods. We assessed PGJ2 toxicity by administering it as a single high-dose intravenous (IV) injection, consecutive daily high-dose IV injections, or a single IVT injection in one eye of five adult rhesus monkeys. To assess efficacy, we induced pNAION in one eye of five adult male rhesus monkeys using a laser-activated rose bengal induction method. We then injected the eye with either PGJ2 or phosphate-buffered saline (PBS) intravitreally immediately or 5 hours post induction. We performed a clinical assessment, optical coherence tomography, electrophysiological testing, fundus photography, and fluorescein angiography in all animals prior to induction and at 1 day, 1 week, 2 weeks, and 4 weeks after induction. Following analysis of the first eye, we induced pNAION in the contralateral eye and then injected either PGJ2 or PBS. We euthanized all animals 5 weeks after final assessment of the fellow eye and performed both immunohistochemical and light and electron microscopic analyses of the retina and optic nerves. Results. Toxicity: PGJ2 caused no permanent systemic toxicity regardless of the amount injected or route of delivery, and there was no evidence of any ocular toxicity with the dose of PGJ2 used in efficacy studies. Transient reduction in the amplitudes of the visual evoked potentials and the N95 component of the pattern electroretinogram (PERG) occurred after both IV and IVT administration of high doses of PGJ2; however, the amplitudes returned to normal in all animals within 1 week. Efficacy: In all eyes, a single IVT dose of PGJ2 administered immediately or shortly after induction of pNAION resulted in a significant reduction of clinical, electrophysiological, and histological damage compared with vehicle-injected eyes (P = 0.03 for both VEP and PERG; P = 0.05 for axon counts). Conclusions. In nonhuman primates, PGJ2 administered either intravenously or intravitreally produces no permanent toxicity at even four times the dose given for neuroprotection. Additionally, a single IVT dose of PGJ2 is neuroprotective when administered up to 5 hours after induction of pNAION. PMID:25298416

Factors impacting short and long-term kidney graft survival: modification by single intra-operative -high-dose induction with ATG-Fresenius.

PubMed

Kaden, Jürgen; May, Gottfried; Völp, Andreas; Wesslau, Claus

2011-01-01

A majority of recipients benefited from the intra-operative single high-dose induction (HDI) with ATG-Fresenius (ATG-F) still leaving a group of recipients who did not profit from this kind of induction. Therefore the aim of this retrospective analysis was 1st to identify the risk factors impacting short and long-term graft survival, and 2nd to assess the efficacy of this type of induction in kidney graft recipients with or without these risk factors. A total of 606 recipients receiving two different immunosuppressive treatment regimens (1st: Triple drug therapy [TDT, n=196] consisting mainly of steroids, azathioprine and cyclosporine; 2nd: TDT + 9 mg/kg ATG-F intra-operatively [HDI, n=410]) were included in this analysis and grouped according to their kidney graft survival time (short GST: ≤1 yr, n=100 and long GST: >5 yrs, n=506). The main risk factors associated with a shortened graft survival were pre-transplant sensitization, re-transplantation, rejections (in particular vascular or mixed ones) and the necessity of a long-term anti-rejection therapy. Adding ATG-F single high dose induction to TDT was more efficient in prolonging kidney graft survival than TDT alone not only in recipients without any risk factors (p<0.005) but also in recipients with at least one risk factor (p<0.021). Only in 4.6% of recipients having two or more risk factors this effect could not be demonstrated. The intra-operative single high-dose induction with ATG-F significantly improves the kidney graft survival in recipients with or without risk factors and can therefore be recommended.

Excellent Result With the Use of Single-Dose OK-432 in Cervical Macrocystic Lymphangioma.

PubMed

Efe, Nihal; Altas, Enver; Mazlumoglu, Muhammet Recai; Aktan, Bulent; Ucuncu, Harun; Eren, Suat; Oner, Fatih

2016-10-01

Though the lymphangioma is a benign neoplasm, it may make an invasion to vital structures by progressively growing. For lymphangioma, which progressed in such a way, surgical treatment has high morbidity and recurrence risk. On these cases, OK-432 is a frequently used sclerotherapy agent. The authors report the result they obtained by the use of single-dose OK-432 on an inoperable pediatric cervical macrocystic lymphangioma case and also their experiences.

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

Correlation of local failure with measures of dose insufficiency in the high-dose single-fraction treatment of bony metastases.

PubMed

Lovelock, D Michael; Zhang, Zhigang; Jackson, Andrew; Keam, Jennifer; Bekelman, Justin; Bilsky, Mark; Lis, Eric; Yamada, Yoshiya

2010-07-15

In the setting of high-dose single-fraction image-guided radiotherapy of spine metastases, the delivered dose is hypothesized to be a significant factor in local control. We investigated the dependence of local control on measures of dose insufficiency. The minimum doses received by the hottest 100%, 98%, and 95% (D(min), D(98), and D(95)) of the gross target volume (GTV) were computed for 91 consecutively treated lesions observed in 79 patients. Prescribed doses of 18-24 Gy were delivered in a single fraction. The spinal cord and cauda equina were constrained to a maximum dose of 12-14 Gy and 16 Gy, respectively. A rank-sum test was used to assess the differences between radiographic local failure and local control. With a median follow-up of 18 months, seven local failures have occurred. The distributions of GTV D(min), D(98), and D(95) for treatments resulting in local failure were found to be statistically different from the corresponding distributions of the patient group as a whole. Taking no account of histology, p values calculated for D(min), D(98), and D(95) were 0.004, 0.012, and 0.031, respectively. No correlations between local failure and target volume or between local failure and anatomic location were found. The results indicate that D(min), D(98), and D(95) may be important risk factors for local failure. No local failures in any histology were observed when D(min) was >15 Gy, suggesting that this metric may be an important predictor of local control. Copyright 2010 Elsevier Inc. All rights reserved.

CORRELATION OF LOCAL FAILURE WITH MEASURES OF DOSE INSUFFICIENCY IN THE HIGH-DOSE SINGLE-FRACTION TREATMENT OF BONY METASTASES

PubMed Central

Lovelock, D. Michael; Zhang, Zhigang; Jackson, Andrew; Keam, Jennifer; Bekelman, Justin; Bilsky, Mark; Lis, Eric; Yamada, Yoshiya

2011-01-01

Purpose In the setting of high-dose single-fraction image-guided radiotherapy of spine metastases, the delivered dose is hypothesized to be a significant factor in local control. We investigated the dependence of local control on measures of dose insufficiency. Methods and Materials The minimum doses received by the hottest 100%, 98%, and 95% (Dmin, D98, and D95) of the gross target volume (GTV) were computed for 91 consecutively treated lesions observed in 79 patients. Prescribed doses of 18–24 Gy were delivered in a single fraction. The spinal cord and cauda equina were constrained to a maximum dose of 12–14 Gy and 16 Gy, respectively. A rank-sum test was used to assess the differences between radiographic local failure and local control. Results With a median follow-up of 18 months, seven local failures have occurred. The distributions of GTV Dmin, D98, and D95 for treatments resulting in local failure were found to be statistically different from the corresponding distributions of the patient group as a whole. Taking no account of histology, p values calculated for Dmin, D98, and D95 were 0.004, 0.012, and 0.031, respectively. No correlations between local failure and target volume or between local failure and anatomic location were found. Conclusions The results indicate that Dmin, D98, and D95 may be important risk factors for local failure. No local failures in any histology were observed when Dmin was >15 Gy, suggesting that this metric may be an important predictor of local control. PMID:20350795

SU-E-T-224: Considerations for the Proper Treatment of Multiple Cranial Metastases with Single Isocenter Volumetric Modulated Arc Therapy

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

Audet, C; Poffenbarger, B; Hwang, A

2015-06-15

Purpose: To investigate some limitations of single isocenter VMAT for cranial multiple met cases. Methods: A single isocenter VMAT plan (Varian, Eclipse AAA10 commissioned down to 1 cm) was designed for two 7mm diameter spherical targets in a rectangular Solid Water (Gammex) phantom. The targets were separated by a distance of 6cm and the isocenter was centered in one of the targets. The plan was delivered (Varian, Truebeam STx) three separate times with different artificial couch angle errors of 0, 0.5 and 1 degree. The coronal dose distributions were measured with calibrated EBT3 film placed at mid-phantom. EBT3 film dosimetrymore » was also performed on the delivery of separate multiple arc vmat plans to targets below 6mm in diameter. Results: Measurements of the sup/inf dose profiles through the high dose distributions show no movement of the central axis high dose region and shifts of the high dose region intended for the off-axis target. For the 1 degree rotation error, the high dose region was shifted 1.04mm from the target. This corresponds to the shift expected from triangulation (60mmxTan(1deg)=1.047mm). Furthermore, a streak of 10% interleaf leakage dose was observed and is likely a Result of the off axis target traveling a wide path such that a long length of MLC is exposed for the whole arc. The calculated dose was about 10% to 15% low compared to that measured on film for a 5mm diameter target. Conclusion: Judicious use of additional margin for off axis targets or limits on the span of multiple mets treated with one isocenter is recommended. The magnitude of the margin should be based on the rotational errors evaluated for the positioning system and the distance of the target from the isocenter. A lower limit of lesion size that can be accurately treated with VMAT should be determined.« less

Irradiation effects in UO2 and CeO2

NASA Astrophysics Data System (ADS)

Ye, Bei; Oaks, Aaron; Kirk, Mark; Yun, Di; Chen, Wei-Ying; Holtzman, Benjamin; Stubbins, James F.

2013-10-01

Single crystal CeO2, as a surrogate material to UO2, was irradiated with 500 keV xenon ions at 800 °C while being observed using in situ transmission electron microscopy (TEM). Experimental results show the formation and growth of defect clusters including dislocation loops and cavities as a function of increasing atomic displacement dose. At high dose, the dislocation loop structure evolves into an extended dislocation line structure, which appears to remain stable to the high dose levels examined in this study. A high concentration of cavities was also present in the microstructure. Despite high atomic displacement doses, the specimen remained crystalline to a cumulated dose of 5 × 1015 ions/cm2, which is consistent with the known stability of the fluorite structure under high dose irradiation. Kinetic Monte Carlo calculations show that oxygen mobility is substantially higher in hypo-stoichiometric UO2/CeO2 than hyper-stoichiometric systems. This result is consistent with the ability of irradiation damage to recover even at intermediate irradiation temperatures.

Implementation of dual-energy technique for virtual monochromatic and linearly mixed CBCTs

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

Li Hao; Giles, William; Ren Lei

Purpose: To implement dual-energy imaging technique for virtual monochromatic (VM) and linearly mixed (LM) cone beam CTs (CBCTs) and to demonstrate their potential applications in metal artifact reduction and contrast enhancement in image-guided radiation therapy (IGRT). Methods: A bench-top CBCT system was used to acquire 80 kVp and 150 kVp projections, with an additional 0.8 mm tin filtration. To implement the VM technique, these projections were first decomposed into acrylic and aluminum basis material projections to synthesize VM projections, which were then used to reconstruct VM CBCTs. The effect of VM CBCT on the metal artifact reduction was evaluated withmore » an in-house titanium-BB phantom. The optimal VM energy to maximize contrast-to-noise ratio (CNR) for iodine contrast and minimize beam hardening in VM CBCT was determined using a water phantom containing two iodine concentrations. The LM technique was implemented by linearly combining the low-energy (80 kVp) and high-energy (150 kVp) CBCTs. The dose partitioning between low-energy and high-energy CBCTs was varied (20%, 40%, 60%, and 80% for low-energy) while keeping total dose approximately equal to single-energy CBCTs, measured using an ion chamber. Noise levels and CNRs for four tissue types were investigated for dual-energy LM CBCTs in comparison with single-energy CBCTs at 80, 100, 125, and 150 kVp. Results: The VM technique showed substantial reduction of metal artifacts at 100 keV with a 40% reduction in the background standard deviation compared to a 125 kVp single-energy scan of equal dose. The VM energy to maximize CNR for both iodine concentrations and minimize beam hardening in the metal-free object was 50 keV and 60 keV, respectively. The difference of average noise levels measured in the phantom background was 1.2% between dual-energy LM CBCTs and equivalent-dose single-energy CBCTs. CNR values in the LM CBCTs of any dose partitioning are better than those of 150 kVp single-energy CBCTs. The average CNR for four tissue types with 80% dose fraction at low-energy showed 9.0% and 4.1% improvement relative to 100 kVp and 125 kVp single-energy CBCTs, respectively. CNRs for low-contrast objects improved as dose partitioning was more heavily weighted toward low-energy (80 kVp) for LM CBCTs. Conclusions: Dual-energy CBCT imaging techniques were implemented to synthesize VM CBCT and LM CBCTs. VM CBCT was effective at achieving metal artifact reduction. Depending on the dose-partitioning scheme, LM CBCT demonstrated the potential to improve CNR for low contrast objects compared to single-energy CBCT acquired with equivalent dose.« less

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

Transcriptomic Dose-Response Analysis for Mode of Action and Risk Assessment

EPA Science Inventory

Microarray and RNA-seq technologies can play an important role in assessing the health risks associated with environmental exposures. The utility of gene expression data to predict hazard has been well documented. Early toxicogenomics studies used relatively high, single doses w...

Inactivated yellow fever 17D vaccine: development and nonclinical safety, immunogenicity and protective activity.

PubMed

Monath, Thomas P; Lee, Cynthia K; Julander, Justin G; Brown, Alicja; Beasley, David W; Watts, Douglas M; Hayman, Edward; Guertin, Patrick; Makowiecki, Joseph; Crowell, Joseph; Levesque, Philip; Bowick, Gavin C; Morin, Merribeth; Fowler, Elizabeth; Trent, Dennis W

2010-05-14

In the last 10 years new concerns have arisen about safety of the live, attenuated yellow fever (YF) 17D vaccine, in particular viscerotropic adverse events, which have a case-fatality rate of 64%. A non-replicating cell culture-based vaccine would not cause these adverse events, and potentially could be used in persons with precautions or contraindications to use of the live vaccine, including age <9 months and >60 years, egg allergy, immune suppression, and pregnancy. We developed a whole virion vaccine from the 17D strain inactivated with beta-propiolactone, and adsorbed to aluminum hydroxide. The inactivated vaccine was highly immunogenic in mice, hamsters, and cynomolgus macaques. After a single dose in hamsters and macaques, neutralizing antibody titers were similar to those elicited by the live 17D vaccine (YF-VAX, Sanofi Pasteur). After two doses of inactivated vaccine, neutralizing antibody titers in hamsters were significantly higher than after a single dose of YF-VAX [geometric mean titer (GMT) 20,480 vs. 1940, respectively (P<0.001, ANOVA)]. Hamsters given a single dose or two doses of inactivated vaccine or a single dose of YF-VAX were fully protected against hepatitis, viremia, weight loss and death after challenge with YF virus (Jimenez strain). A clinical trial of the inactivated vaccine (XRX-001) has been initiated. Copyright 2010 Elsevier Ltd. All rights reserved.

Mutagenic effects of a single and an exact number of alpha particles in mammalian cells

NASA Technical Reports Server (NTRS)

Hei, T. K.; Wu, L. J.; Liu, S. X.; Vannais, D.; Waldren, C. A.; Randers-Pehrson, G.

1997-01-01

One of the main uncertainties in risk estimation for environmental radon exposure using lung cancer data from underground miners is the extrapolation from high- to low-dose exposure where multiple traversal is extremely rare. The biological effects of a single alpha particle are currently unknown. Using the recently available microbeam source at the Radiological Research Accelerator Facility at Columbia University, we examined the frequencies and molecular spectrum of S1- mutants induced in human-hamster hybrid (A(L)) cells by either a single or an exact number of alpha particles. Exponentially growing cells were stained briefly with a nontoxic concentration of Hoechst dye for image analysis, and the location of individual cells was computer-monitored. The nucleus of each cell was irradiated with either 1,2,4, or 8 alpha particles at a linear energy transfer of 90 keV/microm consistent with the energy spectrum of domestic radon exposure. Although single-particle traversal was only slightly cytotoxic to A(L) cells (survival fraction approximately 0.82), it was highly mutagenic, and the induced mutant fraction averaged 110 mutants per 10(5) survivors. In addition, both toxicity and mutant induction were dose-dependent. Multiplex PCR analysis of mutant DNA showed that the proportion of mutants with multilocus deletions increased with the number of particle traversals. These data provide direct evidence that a single a particle traversing a nucleus will have a high probability of resulting in a mutation and highlight the need for radiation protection at low doses.

Mutagenic effects of a single and an exact number of alpha particles in mammalian cells.

PubMed

Hei, T K; Wu, L J; Liu, S X; Vannais, D; Waldren, C A; Randers-Pehrson, G

1997-04-15

One of the main uncertainties in risk estimation for environmental radon exposure using lung cancer data from underground miners is the extrapolation from high- to low-dose exposure where multiple traversal is extremely rare. The biological effects of a single alpha particle are currently unknown. Using the recently available microbeam source at the Radiological Research Accelerator Facility at Columbia University, we examined the frequencies and molecular spectrum of S1- mutants induced in human-hamster hybrid (A(L)) cells by either a single or an exact number of alpha particles. Exponentially growing cells were stained briefly with a nontoxic concentration of Hoechst dye for image analysis, and the location of individual cells was computer-monitored. The nucleus of each cell was irradiated with either 1,2,4, or 8 alpha particles at a linear energy transfer of 90 keV/microm consistent with the energy spectrum of domestic radon exposure. Although single-particle traversal was only slightly cytotoxic to A(L) cells (survival fraction approximately 0.82), it was highly mutagenic, and the induced mutant fraction averaged 110 mutants per 10(5) survivors. In addition, both toxicity and mutant induction were dose-dependent. Multiplex PCR analysis of mutant DNA showed that the proportion of mutants with multilocus deletions increased with the number of particle traversals. These data provide direct evidence that a single a particle traversing a nucleus will have a high probability of resulting in a mutation and highlight the need for radiation protection at low doses.

Microdose Induced Drain Leakage Effects in Power Trench MOSFETs: Experiment and Modeling

NASA Astrophysics Data System (ADS)

Zebrev, Gennady I.; Vatuev, Alexander S.; Useinov, Rustem G.; Emeliyanov, Vladimir V.; Anashin, Vasily S.; Gorbunov, Maxim S.; Turin, Valentin O.; Yesenkov, Kirill A.

2014-08-01

We study experimentally and theoretically the micro-dose induced drain-source leakage current in the trench power MOSFETs under irradiation with high-LET heavy ions. We found experimentally that cumulative increase of leakage current occurs by means of stochastic spikes corresponding to a strike of single heavy ion into the MOSFET gate oxide. We simulate this effect with the proposed analytic model allowing to describe (including Monte Carlo methods) both the deterministic (cumulative dose) and stochastic (single event) aspects of the problem. Based on this model the survival probability assessment in space heavy ion environment with high LETs was proposed.

Micronucleus induction in Vicia faba roots. Part 1. Absence of dose-rate, fractionation, and oxygen effect at low doses of low LET radiations.

PubMed

Marshall, I; Bianchi, M

1983-08-01

Micronucleus indication in Vicia faba roots has been evaluated after irradiation with 60Co gamma-rays. The dependence of the damage on dose, dose rate, fractionation, and oxygen has been studied. The best fit to the experimental data in the dose region between 7 and 190 cGy is represented, for single-dose exposures, by a linear + quadratic relationship. In the low-dose region, between 7 and 20 cGy, where the linear dose dependence is dominant, no dose-rate, fractionation, or oxygen effect could be observed. These effects were, however, present in the high-dose region, where the quadratic dependence is dominant.

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

PubMed

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

2008-07-01

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

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.

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.

Cysteine proteinases from papaya (Carica papaya) in the treatment of experimental Trichuris suis infection in pigs: two randomized controlled trials.

PubMed

Levecke, Bruno; Buttle, David J; Behnke, Jerzy M; Duce, Ian R; Vercruysse, Jozef

2014-05-30

Cysteine proteinases (CPs) from papaya (Carica papaya) possess anthelmintic properties against human soil-transmitted helminths (STH, Ascaris lumbricoides, Trichuris trichiura and hookworm), but there is a lack of supportive and up-to-date efficacy data. We therefore conducted two randomized controlled trials in pigs to assess the efficacy of papaya CPs against experimental infections with T. suis. First, we assessed efficacy by means of egg (ERR) and adult worm reduction rate (WRR) of a single-oral dose of 450 μmol active CPs (CP450) against low (inoculum of 300 eggs) and high (inoculum of 3,000 eggs) intensity T. suis infections and compared the efficacy with those obtained after a single-oral dose of 400 mg albendazole (ALB). In the second trial, we determined and compared the efficacy of a series of CP doses (45 [CP45], 115 [CP115], 225 [CP225], and 450 [CP450] μmol) against high intensity infections. CP450 was highly efficacious against both levels of infection intensity, resulting in ERR and WRR of more than 97%. For both levels of infection intensity, CP450 was significantly more efficacious compared to ALB by means of WRR (low infection intensity: 99.0% vs. 39.0%; high infection intensity; 97.4% vs. 23.2%). When the efficacy was assessed by ERR, a significant difference was only observed for high intensity infections, CP450 being more efficacious than ALB (98.9% vs. 59.0%). For low infection intensities, there was no significant difference in ERR between CP450 (98.3%) and ALB (64.4%). The efficacy of CPs increased as a function of increasing dose. When determined by ERR, the efficacy ranged from 2.1% for CP45 to 99.2% for CP450. For WRR the results varied from -14.0% to 99.0%, respectively. Pairwise comparison revealed a significant difference in ERR and WRR only between CP45 and CP450, the latter being more efficacious. A single dose of 450 μmol CPs provided greater efficacy against T. suis infections in pigs than a single-oral dose of 400 mg ALB. Although these results highlight the possibility of papaya CPs for controlling human STH, further development is needed in order to obtain and validate an oral formulation for human application.

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.
.

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

High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Transplantation in Metastatic Breast Cancer: Overview of Six Randomized Trials

PubMed Central

Berry, Donald A.; Ueno, Naoto T.; Johnson, Marcella M.; Lei, Xiudong; Caputo, Jean; Smith, Dori A.; Yancey, Linda J.; Crump, Michael; Stadtmauer, Edward A.; Biron, Pierre; Crown, John P.; Schmid, Peter; Lotz, Jean-Pierre; Rosti, Giovanni; Bregni, Marco; Demirer, Taner

2011-01-01

Purpose High doses of effective chemotherapy are compelling if they can be delivered safely. Substantial interest in supporting high-dose chemotherapy with bone marrow or autologous hematopoietic stem-cell transplantation in the 1980s and 1990s led to the initiation of randomized trials to evaluate its effect in the treatment of metastatic breast cancer. Methods We identified six randomized trials in metastatic breast cancer that evaluated high doses of chemotherapy with transplant support versus a control regimen without stem-cell support. We assembled a single database containing individual patient information from these trials. The primary analysis of overall survival was a log-rank test comparing high dose versus control. We also used Cox proportional hazards regression, adjusting for known covariates. We addressed potential treatment differences within subsets of patients. Results The effect of high-dose chemotherapy on overall survival was not statistically different (median, 2.16 v 2.02 years; P = .08). A statistically significant advantage in progression-free survival (median, 0.91 v 0.69 years) did not translate into survival benefit. Subset analyses found little evidence that there are groups of patients who might benefit from high-dose chemotherapy with hematopoietic support. Conclusion Overall survival of patients with metastatic breast cancer in the six randomized trials was not significantly improved by high-dose chemotherapy; any benefit from high doses was small. No identifiable subset of patients seems to benefit from high-dose chemotherapy. PMID:21768454

Experience of micromultileaf collimator linear accelerator based single fraction stereotactic radiosurgery: Tumor dose inhomogeneity, conformity, and dose fall off

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

Hong, Linda X.; Garg, Madhur; Lasala, Patrick

2011-03-15

Purpose: Sharp dose fall off outside a tumor is essential for high dose single fraction stereotactic radiosurgery (SRS) plans. This study explores the relationship among tumor dose inhomogeneity, conformity, and dose fall off in normal tissues for micromultileaf collimator (mMLC) linear accelerator (LINAC) based cranial SRS plans. Methods: Between January 2007 and July 2009, 65 patients with single cranial lesions were treated with LINAC-based SRS. Among them, tumors had maximum diameters {<=}20 mm: 31; between 20 and 30 mm: 21; and >30 mm: 13. All patients were treated with 6 MV photons on a Trilogy linear accelerator (Varian Medical Systems,more » Palo Alto, CA) with a tertiary m3 high-resolution mMLC (Brainlab, Feldkirchen, Germany), using either noncoplanar conformal fixed fields or dynamic conformal arcs. The authors also created retrospective study plans with identical beam arrangement as the treated plan but with different tumor dose inhomogeneity by varying the beam margins around the planning target volume (PTV). All retrospective study plans were normalized so that the minimum PTV dose was the prescription dose (PD). Isocenter dose, mean PTV dose, RTOG conformity index (CI), RTOG homogeneity index (HI), dose gradient index R{sub 50}-R{sub 100} (defined as the difference between equivalent sphere radius of 50% isodose volume and prescription isodose volume), and normal tissue volume (as a ratio to PTV volume) receiving 50% prescription dose (NTV{sub 50}) were calculated. Results: HI was inversely related to the beam margins around the PTV. CI had a ''V'' shaped relationship with HI, reaching a minimum when HI was approximately 1.3. Isocenter dose and mean PTV dose (as percentage of PD) increased linearly with HI. R{sub 50}-R{sub 100} and NTV{sub 50} initially declined with HI and then reached a plateau when HI was approximately 1.3. These trends also held when tumors were grouped according to their maximum diameters. The smallest tumor group (maximum diameters {<=}20 mm) had the most HI dependence for dose fall off. For treated plans, CI averaged 2.55{+-}0.79 with HI 1.23{+-}0.06; the average R{sub 50}-R{sub 100} was 0.41{+-}0.08, 0.55{+-}0.10, and 0.65{+-}0.09 cm, respectively, for tumors {<=}20 mm, between 20 and 30 mm, and >30 mm. Conclusions: Tumor dose inhomogeneity can be used as an important and convenient parameter to evaluate mMLC LINAC-based SRS plans. Sharp dose fall off in the normal tissue is achieved with sufficiently high tumor dose inhomogeneity. By adjusting beam margins, a homogeneity index of approximately 1.3 would provide best conformity for the authors' SRS system.« less

Dedicated Linac for Radioneurosurgery at the National Institute of Neurology and Neurosurgery of Mexico

NASA Astrophysics Data System (ADS)

Celis-López, Miguel A.; Lárraga-Gutiérrez, José M.

2003-09-01

The objective is to present a description and the main clinical applications of this dedicated Linac for benign and malignant tumors in the central nervous system. The Novalis (BrainLab, Germany) is a 6 MV dedicated linac for a single high dose Radiosurgery (RS) and for fractionated doses in Stereotactic Radiotherapy with a high level of precision at the isocenter.

Single Low Dose Primaquine (0.25 mg/kg) Does Not Cause Clinically Significant Haemolysis in G6PD Deficient Subjects.

PubMed

Bancone, Germana; Chowwiwat, Nongnud; Somsakchaicharoen, Raweewan; Poodpanya, Lalita; Moo, Paw Khu; Gornsawun, Gornpan; Kajeechiwa, Ladda; Thwin, May Myo; Rakthinthong, Santisuk; Nosten, Suphak; Thinraow, Suradet; Nyo, Slight Naw; Ling, Clare L; Wiladphaingern, Jacher; Kiricharoen, Naw Lily; Moore, Kerryn A; White, Nicholas J; Nosten, Francois

2016-01-01

Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum. The transmission blocking dose of primaquine previously recommended was 0.75 mg/kg (adult dose 45 mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15-20%) in populations living in malarious areas. To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25 mg/kg (adult dose 15 mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing. Direct evidence of the safety of this low dose is lacking. Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%. The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects. Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration. G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females. Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models. No adverse events related to primaquine were reported during the trial. Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant. Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic. The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency. The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria. ClinicalTrials.gov NCT01872702.

Feasibility of a Single Contrast Bolus High-Pitch Pulmonary CT Angiography Protocol Followed by Low-Dose Retrospectively ECG-Gated Cardiac CT in Patients with Suspected Pulmonary Embolism.

PubMed

Schäfer, Julia Carmen; Haubenreisser, Holger; Meyer, Mathias; Grüttner, Joachim; Walter, Thomas; Borggrefe, Martin; Schoepf, Joseph U; Nance, John W; Schönberg, Stefan O; Henzler, Thomas

2018-06-01

 To prospectively evaluate the feasibility of single contrast bolus high-pitch CT pulmonary angiography (CTPA) subsequently followed by low-dose retrospectively ECG-gated cardiac CT (4D-cCT) in patients with suspected pulmonary embolism (PE) to accurately evaluate right ventricular (RV) function.  62 patients (33 female, age 65.1 ± 17.5 years) underwent high-pitch CTPA examination with 80cc of iodinated contrast material. 5 s after the end of the high-pitch CTPA study, a low-dose retrospectively ECG-gated cardiac CT examination was automatically started. The volume CT dose index (CTDI vol) and dose length product (DLP) were recorded in all patients and the effective dose was calculated. For the assessment of image quality, attenuation was measured as Hounsfield units (HUs) within various regions of interest (ROIs). These ROIs were used to calculate the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Subjective image quality was assessed using a five-point Likert scale. On 4D-cCT, the ejection fraction of both ventricles (RVEF, LVEF) as well as the ratio of RVEF and LVEF (RVEF/LVEF) was assessed. The statistical difference of all parameters between the PE and non-PE group was calculated.  The mean effective radiation dose was 4.22 ± 2.05 mSv. Attenuation measurements on CTPA showed the highest attenuation values in the main pulmonary artery (442.01 ± 187.64). On 4D-cCT attenuation values were highest in the descending aorta (560.59 ± 208.81). The CNR and SNR values on CTPA were highest within the main pulmonary artery (CNR = 12.43 ± 4.57; SNR = 15.14 ± 4.90). On 4D-cCT images, the highest SNR and CNR could be measured in the descending aorta (CNR = 10.26 ± 5.57; SNR = 10.86 ± 5.17). The mean LVEF was 60.73 %± 14.65 %, and the mean RVEF was 44.90 %± 9.54 %. The mean RVEF/LVEF was 0.79 ± 0.29. There was no significant difference between the PE and non-PE group for either of the parameters.  The investigated combined CTPA and 4D-cCT protocol is feasible using a single contrast bolus and allows the evaluation of RV function in patients with suspected PE. Further studies have to evaluate the additional value of this protocol regarding risk stratification in patients with PE.   · High-pitch CTPA is fast enough to leave sufficient contrast material within the heart that can be used for an additional low-dose functional cardiac CT examination.. · The tube current of the evaluated 4D-cCT is reduced over the entire cardiac cycle without any full dose peak.. · Low-dose cardiac CT subsequently performed after high-pitch CTPA allows for detailed analysis of RV function.. · Schäfer JC, Haubenreisser H, Meyer M et al. Feasibility of a Single Contrast Bolus High-Pitch Pulmonary CT Angiography Protocol Followed by Low-Dose Retrospectively ECG-Gated Cardiac CT in Patients with Suspected Pulmonary Embolism. Fortschr Röntgenstr 2018; 190: 542 - 550. © Georg Thieme Verlag KG Stuttgart · New York.

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.

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.

High-dose Versus Low-dose Tranexamic Acid to Reduce Transfusion Requirements in Pediatric Scoliosis Surgery.

PubMed

Johnson, Daniel J; Johnson, Christine C; Goobie, Susan M; Nami, Nina; Wetzler, Joshua A; Sponseller, Paul D; Frank, Steven M

2017-12-01

Our objective was to quantify blood loss and transfusion requirements for high-dose and low-dose tranexamic acid (TXA) dosing regimens in pediatric patients undergoing spinal fusion for correction of idiopathic scoliosis. Previous investigators have established the efficacy of TXA in pediatric scoliosis surgery; however, the dosing regimens vary widely and the optimal dose has not been established. We retrospectively analyzed electronic medical records for 116 patients who underwent spinal fusion surgery for idiopathic scoliosis by a single surgeon and were treated with TXA. In total, 72 patients received a 10 mg/kg loading dose with a 1 mg/kg/h maintenance dose (low-dose) and 44 patients received 50 mg/kg loading dose with a 5 mg/kg/h maintenance dose (high-dose). Estimated blood loss and transfusion requirements were compared between dosing groups. Patient characteristics were nearly identical between the 2 groups. Compared with the low-dose TXA group, the high-dose TXA group had decreased estimated blood loss (695 vs. 968 mL, P=0.01), and a decrease in both intraoperative (0.3 vs. 0.9 units, P=0.01) and whole hospitalization (0.4 vs. 1.0 units, P=0.04) red blood cell transfusion requirements. The higher-dose TXA was associated with decreased intraoperative (P=0.01), and whole hospital transfusion (P=0.01) requirements, even after risk-adjustment for potential confounding variables. High-dose TXA is more effective than low-dose TXA in reducing blood loss and transfusion requirements in pediatric idiopathic scoliosis patients undergoing surgery. Level-III, retrospective cohort study.

Unrestricted Hepatocyte Transduction with Adeno-Associated Virus Serotype 8 Vectors in Mice

PubMed Central

Nakai, Hiroyuki; Fuess, Sally; Storm, Theresa A.; Muramatsu, Shin-ichi; Nara, Yuko; Kay, Mark A.

2005-01-01

Recombinant adeno-associated virus (rAAV) vectors can mediate long-term stable transduction in various target tissues. However, with rAAV serotype 2 (rAAV2) vectors, liver transduction is confined to only a small portion of hepatocytes even after administration of extremely high vector doses. In order to investigate whether rAAV vectors of other serotypes exhibit similar restricted liver transduction, we performed a dose-response study by injecting mice with β-galactosidase-expressing rAAV1 and rAAV8 vectors via the portal vein. The rAAV1 vector showed a blunted dose-response similar to that of rAAV2 at high doses, while the rAAV8 vector dose-response remained unchanged at any dose and ultimately could transduce all the hepatocytes at a dose of 7.2 × 1012 vector genomes/mouse without toxicity. This indicates that all hepatocytes have the ability to process incoming single-stranded vector genomes into duplex DNA. A single tail vein injection of the rAAV8 vector was as efficient as portal vein injection at any dose. In addition, intravascular administration of the rAAV8 vector at a high dose transduced all the skeletal muscles throughout the body, including the diaphragm, the entire cardiac muscle, and substantial numbers of cells in the pancreas, smooth muscles, and brain. Thus, rAAV8 is a robust vector for gene transfer to the liver and provides a promising research tool for delivering genes to various target organs. In addition, the rAAV8 vector may offer a potential therapeutic agent for various diseases affecting nonhepatic tissues, but great caution is required for vector spillover and tight control of tissue-specific gene expression. PMID:15596817

Alteration in behavioral sensitivity to amphetamine after treatment with oxotremorine. Effect of dose and test environment.

PubMed

Gralewicz, Sławomir; Lutz, Piotr; Wiaderna, Dorota; Tomas, Tadeusz

2003-12-17

Our earlier experiment revealed that rats pretreated once with an anticholinesterase develop hyposensitivity to amphetamine (AMPH). One of the likely causes of this effect might be a transient hyperexcitation of the central muscarinic receptors. It has appeared, however, that rats pretreated with oxotremorine (OX), a muscarinic agonist, show an augmented behavioral response to AMPH weeks later. The present experiments were performed in order to obtain more information on the relationship between the OX-induced sensitization to AMPH and the OX dose and dosing regime (single or repeated), and to find out whether the environment associated with the acute effects of OX could affect the response to AMPH. In experiment 1, adult male rats were given a single i.p. injection of OX in home cages at a moderate (0.5 mg/kg) or high (1.0 mg/kg) dose. In experiment 2, the rats received eight 1.0 mg/kg doses of OX in the course of three days. After each injection, some animals returned to their home cages, and some were placed in the test cages for 30 min. In both experiments, the response to AMPH was assessed on day 21 after the treatment. The obtained results indicate that: (i) a single i.p. exposure to OX results in an increase of the rat's behavioral sensitivity to AMPH but the moderate dose is more effective in inducing this effect; (ii) repeated exposure to OX at high doses, in a regime enabling development of tolerance to the acute OX effects, does not alter the rat sensitivity to AMPH, and (iii) expression of the AMPH response is suppressed in environment which has been associated with acute effects of OX.

High-dose, single-bolus eptifibatide: a safe and cost-effective alternative to conventional glycoprotein IIb/IIIa inhibitor use for elective coronary interventions.

PubMed

Fischell, Tim A; Attia, Tamer; Rane, Santosh; Salman, Waddah

2006-10-01

Adjunctive pharmacotherapy with eptifibatide, a glycoprotein (GP) IIb/IIIa inhibitor, as an intravenous bolus followed by infusion has been shown to improve outcomes in elective coronary interventions (PCI). However, bleeding complications and costs have limited the routine adoption of this regimen. The goal of this study was to examine the safety, efficacy and cost-effectiveness of high-dose, single-bolus eptifibatide, without post-intervention infusion, in "real-world" patients undergoing elective PCI. We studied 401 patients with stable and unstable angina who were treated with a high-dose (20 mg), single bolus of eptifibatide plus heparin prior to the start of elective PCI. Exclusion criteria included recent MI, stenting of bypass graft(s), rotational atherectomy and/or brachytherapy. The primary study endpoints were major adverse clinical events (MACE), defined as the in-hospital and 30-day incidence of death from any cause, Q-wave or non-Q-wave MI, repeat target vessel revascularization and/or major bleeding complications. Relevant demographic and procedural characteristics included mean age: 66.4 +/- 11.2; male gender: 242/401 (61%); number of vessels treated per patient: 1.46 +/- 0.42; and number of stents deployed per patient: 1.82 +/- 0.65. In-hospital non-Q-wave MI (CPK and/or CPK-MB > 3 times the upper limit of normal) occurred in 7/401 patients (1.75%) and MACE was 2.25%. Major bleeding complications were seen in 2/401 patients (0.49%). There were 4 additional MACE events at 30-day follow up (total MACE and bleeding = 3.25%). The average anticoagulation cost was 66 dollars/patient. Intravenous eptifibatide, administered as a high-dose (20 mg) single-vial bolus, is a safe, effective and highly cost-effective alternative to the conventional regimens of bolus plus prolonged intravenous GP IIb/IIIa inhibitor infusion for patients undergoing elective PCI.

Evaluation of a 3D diamond detector for medical radiation dosimetry

NASA Astrophysics Data System (ADS)

Kanxheri, K.; Servoli, L.; Oh, A.; Munoz Sanchez, F.; Forcolin, G. T.; Murphy, S. A.; Aitkenhead, A.; Moore, C. J.; Morozzi, A.; Passeri, D.; Bellini, M.; Corsi, C.; Lagomarsino, S.; Sciortino, S.

2017-01-01

Synthetic diamond has several properties that are particularly suited to applications in medical radiation dosimetry. It is tissue equivalent, not toxic and shows a high resistance to radiation damage, low leakage current and stability of response. It is an electrical insulator, robust and realizable in small size; due to these features there are several examples of diamond devices, mainly planar single-crystalline chemical vapor depositation (sCVD) diamond, used for relative dose measurement in photon beams. Thanks to a new emerging technology, diamond devices with 3-dimensional structures are produced by using laser pulses to create graphitic paths in the diamond bulk. The necessary bias voltage to operate such detector decreases considerably while the signal response and radiation resistance increase. In order to evaluate the suitability of this new technology for measuring the dose delivered by radiotherapy beams in oncology a 3D polycrystalline (pCVD) diamond detector designed for single charged particle detection has been tested and the photon beam profile has been studied. The good linearity and high sensitivity to the dose observed in the 3D diamond, opens the way to the possibility of realizing a finely segmented device with the potential for dose distribution measurement in a single exposure for small field dosimetry that nowadays is still extremely challenging.

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).

A novel self-micro-emulsifying delivery system (SMEDS) formulation significantly improves the fasting absorption of EPA and DHA from a single dose of an omega-3 ethyl ester concentrate.

PubMed

Qin, Yan; Nyheim, Hilde; Haram, Else Marie; Moritz, Joseph M; Hustvedt, Svein Olaf

2017-10-16

Absorption of EPA and DHA from Omega-3-acid ethyl ester (EE) concentrate supplements occurs most efficiently when taken in context of a fatty meal; adequate fat intake is required to release bile salts that emulsify and pancreatic enzymes that digest omega-3-containing lipids in the intestine. Current guidelines recommend reduction in fat intake and therefore there is a need to optimize the absorption of Omega-3 in those consuming low-fat or no-fat meals. To this end, BASF has developed an Absorption Acceleration Technology, a novel self-micro-emulsifying delivery system (SMEDS) formulation of highly concentrated Omega-3-acid EE which enables rapid emulsification and microdroplet formation upon entering the aqueous environment of the gut therefore enhances the absorption. Two separate single dose, crossover studies were conducted to determine the relative bioavailability of omega-3-acid EE concentrate, either as a novel SMEDS formulation (PRF-021) or as control, in healthy fasted male and female adults at two dose levels (Study 1 "low dose": 630 mg EPA + DHA in PRF-021 vs. 840 mg EPA + DHA in control; Study 2 "high dose": 1680 mg EPA + DHA in PRF-021 vs. 3360 mg EPA + DHA in control). Blood samples were collected immediately before supplementation and at defined time intervals for 48 h. Plasma concentration of total EPA and DHA were determined for pharmacokinetic analysis, area under the curve (AUC) and maximum observed concentration (C max ) was determined. Total EPA plus DHA absorption from SMEDS formulation PRF-021 were 6.4 and 11.5 times higher compared to control in low- and high-dose studies respectively, determined as the ratio of baseline corrected, dose normalized AUC 0-24h of PRF-021 over that of control. EPA and DHA individually showed differing levels of enhancement: the AUC 0-24h ratio for EPA was 23.8 and 25.7 in low and high dose studies, respectively, and the AUC 0-24h ratio for DHA was 3.6 and 5.6 in low and high dose studies, respectively. C max was also increased for both EPA and DHA 2.7- to 9.2-fold. PRF-021 is a novel SMEDS formulation of Omega-3-acid EE demonstrating a marked improvement in absorption of a single dose of EPA and DHA EE under fasted conditions. This allows adequate absorption of Omega-3 from the supplement without the requirement of a high-fat meal.

Interference experiment with asymmetric double slit by using 1.2-MV field emission transmission electron microscope.

PubMed

Harada, Ken; Akashi, Tetsuya; Niitsu, Kodai; Shimada, Keiko; Ono, Yoshimasa A; Shindo, Daisuke; Shinada, Hiroyuki; Mori, Shigeo

2018-01-17

Advanced electron microscopy technologies have made it possible to perform precise double-slit interference experiments. We used a 1.2-MV field emission electron microscope providing coherent electron waves and a direct detection camera system enabling single-electron detections at a sub-second exposure time. We developed a method to perform the interference experiment by using an asymmetric double-slit fabricated by a focused ion beam instrument and by operating the microscope under a "pre-Fraunhofer" condition, different from the Fraunhofer condition of conventional double-slit experiments. Here, pre-Fraunhofer condition means that each single-slit observation was performed under the Fraunhofer condition, while the double-slit observations were performed under the Fresnel condition. The interference experiments with each single slit and with the asymmetric double slit were carried out under two different electron dose conditions: high-dose for calculation of electron probability distribution and low-dose for each single electron distribution. Finally, we exemplified the distribution of single electrons by color-coding according to the above three types of experiments as a composite image.

ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria.

PubMed

Miley, Galen P; Pou, Sovitj; Winter, Rolf; Nilsen, Aaron; Li, Yuexin; Kelly, Jane X; Stickles, Allison M; Mather, Michael W; Forquer, Isaac P; Pershing, April M; White, Karen; Shackleford, David; Saunders, Jessica; Chen, Gong; Ting, Li-Min; Kim, Kami; Zakharov, Lev N; Donini, Cristina; Burrows, Jeremy N; Vaidya, Akhil B; Charman, Susan A; Riscoe, Michael K

2015-09-01

ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300 from ELQ-337 is enhanced by 3- to 4-fold, reaching a maximum concentration of drug in serum (C max) of 5.9 μM by 6 h after oral administration, and unlike ELQ-300 at any dose, ELQ-337 provides single-dose cures of patent malaria infections in mice at low-single-digit milligram per kilogram doses. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Comparison of CREME (cosmic-ray effects on microelectronics) model LET (linear energy transfer) spaceflight dosimetry data

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

Letaw, J.R.; Adams, J.H.

The galactic cosmic radiation (GCR) component of space radiation is the dominant cause of single-event phenomena in microelectronic circuits when Earth's magnetic shielding is low. Spaceflights outside the magnetosphere and in high inclination orbits are examples of such circumstances. In high-inclination orbits, low-energy (high LET) particles are transmitted through the field only at extreme latitudes, but can dominate the orbit-averaged dose. GCR is an important part of the radiation dose to astronauts under the same conditions. As a test of the CREME environmental model and particle transport codes used to estimate single event upsets, we have compiled existing measurements ofmore » HZE doses were compiled where GCR is expected to be important: Apollo 16 and 17, Skylab, Apollo Soyuz Test Project, and Kosmos 782. The LET spectra, due to direct ionization from GCR, for each of these missions has been estimated. The resulting comparisons with data validate the CREME model predictions of high-LET galactic cosmic-ray fluxes to within a factor of two. Some systematic differences between the model and data are identified.« less

The comparative performance of the single intradermal test and the single intradermal comparative tuberculin test in Irish cattle, using tuberculin PPD combinations of differing potencies.

PubMed

Good, M; Clegg, T A; Costello, E; More, S J

2011-11-01

In national bovine tuberculosis (BTB) control programmes, testing is generally conducted using a single source of bovine purified protein derivative (PPD) tuberculin. Alternative tuberculin sources should be identified as part of a broad risk management strategy as problems of supply or quality cannot be discounted. This study was conducted to compare the impact of different potencies of a single bovine PPD tuberculin on the field performance of the single intradermal comparative tuberculin test (SICTT) and single intradermal test (SIT). Three trial potencies of bovine PPD tuberculin, as assayed in naturally infected bovines, namely, low (1192IU/dose), normal (6184IU/dose) and high (12,554IU/dose) were used. Three SICTTs (using) were conducted on 2102 animals. Test results were compared based on reactor-status and changes in skin-thickness at the bovine tuberculin injection site. There was a significant difference in the number of reactors detected using the high and low potency tuberculins. In the SICTT, high and low potency tuberculin detected 40% more and 50% fewer reactors, respectively, than normal potency tuberculin. Furthermore, use of the low potency tuberculin in the SICTT failed to detect 20% of 35 animals with visible lesions, and in the SIT 11% of the visible lesion animals would have been classified as negative. Tuberculin potency is critical to the performance of both the SICTT and SIT. Tuberculin of different potencies will affect reactor disclosure rates, confounding between-year or between-country comparisons. Independent checks of tuberculin potency are an important aspect of quality control in national BTB control programmes. Copyright © 2011 Elsevier Ltd. All rights reserved.

The protective effects of ascorbic acid, cimetidine, and nifedipine on diethyldithiocarbamate-induced hepatic toxicity in albino rats.

PubMed

Gaafa, Khadiga Mohammed; Badawy, Mohammed M; Hamza, Alaaeldin A

2011-10-01

The aim of the present work was to clarify the involvement of free radicals, cytochrome P450 toxic metabolites, and deregulation of calcium homeostasis in the mechanism of diethyldithiocarbamate (DDC) hepatotoxicity. This was elucidated through the preadministration of ascorbic acid (a free radical scavenger), cimetidine (an inhibitor of cytochrome P450 enzymes), or nifedipine (a calcium-blocking agent) before DDC treatment to male albino rats. DDC was administered either as a single dose [800 mg/kg body weight (b.w.), subcutaneously, s.c.] or daily repeated doses for 30 days (400 mg/kg b.w., s.c.). Oxidative stress indicators [e.g., malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase enzyme (SOD)] showed that single or repeated DDC doses induce an increase in MDA level and a decrease in SOD activity in the liver, whereas it causes depletion in hepatic GSH after a single dose and an elevation in its value after repeated doses. Severe histopathological changes were also observed in the livers of rats treated with single or repeated DDC doses. Ascorbic acid, cimetidine, and nifedipine pretreatments were found to induce highly protective effects against the evinced DDC hepatotoxicity, manifesting that free radical, cytochrome P450, and calcium-dependent processes contribute to DDC liver toxicity. Finally, although multiple mechanisms may be involved in the hepatotoxic changes induced by DDC, calcium disarrangement and free radical formation play a more critical role than cytochrome P450 in metabolic events leading to toxic effects of DDC.

Comparison of image quality, myocardial perfusion, and LV function between standard imaging and single-injection ultra-low-dose imaging using a high-efficiency SPECT camera: the MILLISIEVERT study

PubMed Central

Einstein, Andrew J.; Blankstein, Ron; Andrews, Howard; Fish, Mathews; Padgett, Richard; Hayes, Sean W.; Friedman, John D.; Qureshi, Mehreen; Rakotoarivelo, Harivony; Slomka, Piotr; Nakazato, Ryo; Bokhari, Sabahat; Di Carli, Marcello; Berman, Daniel S.

2015-01-01

SPECT myocardial perfusion imaging (MPI) plays a central role in coronary artery disease diagnosis; but concerns exist regarding its radiation burden. Compared to standard Anger-SPECT (A-SPECT) cameras, new high-efficiency (HE) cameras with specialized collimators and solid-state cadmium-zinc-telluride detectors offer potential to maintain image quality (IQ), while reducing administered activity and thus radiation dose to patients. No previous study has compared IQ, interpretation, total perfusion deficit (TPD), or ejection fraction (EF) in patients receiving both ultra-low-dose (ULD) imaging on a HE-SPECT camera and standard low-dose (SLD) A-SPECT imaging. Methods We compared ULD-HE-SPECT to SLD-A-SPECT imaging by dividing the rest dose in 101 patients at 3 sites scheduled to undergo clinical A-SPECT MPI using a same day rest/stress Tc-99m protocol. Patients received HE-SPECT imaging following an initial ~130 MBq (3.5mCi) dose, and SLD-A-SPECT imaging following the remainder of the planned dose. Images were scored visually by 2 blinded readers for IQ and summed rest score (SRS). TPD and EF were assessed quantitatively. Results Mean activity was 134 MBq (3.62 mCi) for ULD-HE-SPECT (effective dose 1.15 mSv) and 278 MBq (7.50 mCi, 2.39 mSv) for SLD-A-SPECT. Overall IQ was superior for ULD-HE-SPECT (p<0.0001), with twice as many studies graded excellent quality. Extracardiac activity and overall perfusion assessment were similar. Between-method correlations were high for SRS (r=0.87), TPD (r=0.91), and EF (r=0.88). Conclusion ULD-HE-SPECT rest imaging correlates highly with SLD-A-SPECT. It has improved image quality, comparable extracardiac activity, and achieves radiation dose reduction to 1 mSv for a single injection. PMID:24982439

Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents

PubMed Central

Rocha, Luis B.; Schaberle, Fábio; Dąbrowski, Janusz M.; Simões, Sérgio; Arnaut, Luis G.

2015-01-01

We assessed the tolerability and safety in rodents of a single intravenous (i.v.) dose of redaporfin, a novel photosensitizer for Photodynamic Therapy (PDT) of cancer. Two approaches were used to evaluate acute toxicity: (i) a dose escalation study in BALB/c mice to evaluate the maximum tolerated dose of redaporfin; and (ii) a safety toxicology study in Wistar rats, of a single dose of redaporfin, with or without illumination, to evaluate possible signs of systemic toxicity. Redaporfin formulation was well tolerated by mice, with no signs of adverse reactions up to 75 mg/kg. In rats, there were no relevant changes, except for a significant, but transient, increase in the blood serum markers for hepatic function and muscle integrity, and also on neutrophil counts, observed after the application of light. The overall results showed that redaporfin-PDT is very well tolerated. No abnormalities were observed, including reactions at the injection site or skin phototoxicity, although the animals were maintained in normal indoor lighting. Redaporfin also showed a high efficacy in the treatment of male BALB/c mice with subcutaneously implanted colon (CT26) tumours. Vascular-PDT with 1.5 mg/kg redaporfin and a light dose of 74 J/cm2 led to the complete tumour regression in 83% of the mice. PMID:26670231

Modeling Rabbit Responses to Single and Multiple Aerosol ...

EPA Pesticide Factsheets

Journal Article Survival models are developed here to predict response and time-to-response for mortality in rabbits following exposures to single or multiple aerosol doses of Bacillus anthracis spores. Hazard function models were developed for a multiple dose dataset to predict the probability of death through specifying dose-response functions and the time between exposure and the time-to-death (TTD). Among the models developed, the best-fitting survival model (baseline model) has an exponential dose-response model with a Weibull TTD distribution. Alternative models assessed employ different underlying dose-response functions and use the assumption that, in a multiple dose scenario, earlier doses affect the hazard functions of each subsequent dose. In addition, published mechanistic models are analyzed and compared with models developed in this paper. None of the alternative models that were assessed provided a statistically significant improvement in fit over the baseline model. The general approach utilizes simple empirical data analysis to develop parsimonious models with limited reliance on mechanistic assumptions. The baseline model predicts TTDs consistent with reported results from three independent high-dose rabbit datasets. More accurate survival models depend upon future development of dose-response datasets specifically designed to assess potential multiple dose effects on response and time-to-response. The process used in this paper to dev

Dosimetric response for crystalline and nanostructured aluminium oxide to a high-current pulse electron beam.

PubMed

Nikiforov, S V; Kortov, V S

2014-11-01

The main thermoluminescent (TL) and dosimetric properties of the detectors based on anion-defective crystalline and nanostructured aluminium oxide after exposure to a high-current pulse electron beam are studied. TL peaks associated with deep-trapping centres are registered. It is shown that the use of deep-trap TL at 200-600°С allows registering absorbed doses up to 750 kGy for single-crystalline detectors and those up to 6 kGy for nanostructured ones. A wide range of the doses registered, high reproducibility of the TL signal and low fading contribute to a possibility of using single-crystalline and nanostructured aluminium oxide for the dosimetry of high-current pulse electron beams. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Singlet oxygen and ROS in a new light: low-dose subcellular photodynamic treatment enhances proliferation at the single cell level.

PubMed

Blázquez-Castro, Alfonso; Breitenbach, Thomas; Ogilby, Peter R

2014-09-01

Two-photon excitation of a sensitizer with a focused laser beam was used to create a spatially-localized subcellular population of reactive oxygen species, ROS, in single HeLa cells. The sensitizer used was protoporphyrin IX, PpIX, endogenously derived from 5-aminolevulinic acid delivered to the cells. Although we infer that singlet oxygen, O2(a(1)Δg), is one ROS produced upon irradiation of PpIX under these conditions, it is possible that the superoxide ion, O2(-˙), may also play a role in this system. With a "high" dose of PpIX-sensitized ROS, the expected death of the cell was observed. However, under "low dose" conditions, clear signs of cell proliferation were observed. The present results facilitate studies of ROS-mediated signalling in imaging-based single cell experiments.

[Safety Evaluation of Rare Sugar Syrup: Single-dose Oral Toxicity in Rats, Reverse Mutation Assay, Chromosome Aberration Assay, and Acute Non-Effect Level for Diarrhea of a Single Dose in Humans].

PubMed

Yamada, Takako; Iida, Tetsuo; Takamine, Satoshi; Hayashi, Noriko; Okuma, Kazuhiro

2015-01-01

The safety of rare sugar syrup obtained from high-fructose corn syrup under slightly alkaline conditions was studied. Mutagenicity of rare sugar syrup was assessed by a reverse mutation assay using Salmonella typhimurium and Escherichia coli, and an in vitro chromosomal aberration assay using Chinese hamster lung cell line (CHL/IU). No mutagenicity of rare sugar syrup was detected under these experimental conditions. Oral administration of single dose (15,000 mg/kg) of rare sugar syrup to rats caused no abnormalities, suggesting no adverse effect of rare sugar syrup. In humans, the acute non-effect level of rare sugar syrup for causing diarrhea was estimated as 0.9 g/kg body weight as dry solid base in both males and females.

Single dose treatment of malaria - current status and perspectives.

PubMed

Mischlinger, Johannes; Agnandji, Selidji T; Ramharter, Michael

2016-07-01

Despite increased international efforts for control and ultimate elimination, malaria remains a major health problem. Currently, artemisinin-based combination therapies are the treatment of choice for uncomplicated malaria exhibiting high efficacy in clinical trial settings in sub-Saharan Africa. However, their administration over a three-day period is associated with important problems of treatment adherence resulting in markedly reduced effectiveness of currently recommended antimalarials under real world settings. Antimalarial drug candidates and antimalarial drug combinations currently under advanced clinical development for the indication as single dose antimalarial therapy. Expert commentary: Several new drug candidates and combinations are currently undergoing pivotal proof-of-concept studies or clinical development programmes. The development of a single dose combination therapy would constitute a breakthrough in the control of malaria. Such an innovative treatment approach would simultaneously close the effectiveness gap of current three-day therapies and revolutionize population based interventions in the context of malaria elimination campaigns.

Aluminum surface modification by a non-mass-analyzed nitrogen ion beam

NASA Astrophysics Data System (ADS)

Ohira, Shigeo; Iwaki, Masaya

Non-mass-analyzed nitrogen ion implantation into polycrystal and single crystal aluminum sheets has been carried out at an accelerating voltage of 90 kV and a dose of 1 × 10 18 N ions/cm 2 using a Zymet implanter model Z-100. The pressure during implantation rose to 10 -3 Pa due to the influence of N gas feeding into the ion source. The characteristics of the surface layers were investigated by means of Auger electron spectroscopy (AES), X-ray diffraction (XRD), transmission electron diffraction (TED), and microscopy (TEM). The AES depth profiling shows a rectangular-like distribution of N atoms and little migration of O atoms near the surface. The high dose N-implantation forms c-axis oriented aluminum nitride (AIN) crystallines, and especially irradiation of Al single crystals with N ions leads to the formation of a hcp AlN single crystal. It is concluded that the high dose N-implantation in Al can result in the formation of AlN at room temperature without any thermal annealing. Furthermore, non-mass-analyzed N-implantation at a pressure of 10 -3 Pa of the nitrogen atmosphere causes the formation of pure AlN single crystals in the Al surface layer and consequently it can be practically used for AlN production.

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

Effect of vaccination with recombinant canine distemper virus vaccine immediately before exposure under shelter-like conditions.

PubMed

Larson, L J; Schultz, R D

2006-01-01

Vaccination with modified-live virus (MLV) canine distemper virus (CDV) vaccine has historically been recommended for animals in high-risk environments because of the rapid onset of immunity following vaccination. Recombinant CDV (rCDV) vaccine was deemed a suitable alternative to MLV-CDV vaccination in pet dogs, but insufficient data precluded its use where CDV was a serious threat to puppies, such as in shelters, kennels, and pet stores. In this study, dogs experimentally challenged hours after a single dose of rCDV or MLV vaccine became sick but recovered, whereas unvaccinated dogs became sick and died. Dogs vaccinated with a single dose of rCDV or MLV vaccine 1 week before being experimentally challenged remained healthy and showed no clinical signs. Dogs given one dose of rCDV vaccine hours before being placed in a CDV-contaminated environment did not become sick. These findings support the hypothesis that rCDV vaccine has a similar time-to-immunity as MLV-CDV vaccines and can likewise protect dogs in high-risk environments after one dose.

Efficient production of therapeutic doses of [131I]-metaiodobenzylguanidine for clinical use.

PubMed

Prabhakar, G; Mathur, Anupam; Shunmugam, G; Teje, Y D; Sachdev, S S; Sivaprasad, N

2011-01-01

[(131)I]-metaiodobenzylguanidine (mIBG) is a known radiopharmaceutical used for the treatment of neuroendocrine tumors. The development of therapeutic [(131)I]-mIBG doses at production level is highly challenging due to rapid product degradation and high radiation exposures to the production plant personnel. In the present work, a working module for the production of 10 doses (100 mCi each) in a single operation was developed following copper (I) assisted isotope exchange. The labeled product complies with the pharmaceutical specifications suitable for in-vivo patient use. Copyright © 2010 Elsevier Ltd. All rights reserved.

Safety and Pharmacokinetics of Multiple 750-Milligram Doses of Intravenous Levofloxacin in Healthy Volunteers

PubMed Central

Chow, Andrew T.; Fowler, Cynthia; Williams, R. Rex; Morgan, Nancy; Kaminski, Susan; Natarajan, Jaya

2001-01-01

The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation. PMID:11408234

Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers.

PubMed

Chow, A T; Fowler, C; Williams, R R; Morgan, N; Kaminski, S; Natarajan, J

2001-07-01

The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation.

Influence of nonylphenol and octylphenol exposure on 5-HT, 5-HT transporter, and 5-HT2A receptor.

PubMed

Liu, Chunhong; Lai, Yuting; Ouyang, Junyan; Yang, Tongwang; Guo, Youting; Yang, Jie; Huang, Shaowen

2017-03-01

Nonylphenol (NP) and octylphenol (OP) are priority environmental contaminants that have a potential role as endocrine disruptors. They can be biomagnified in the food chain and pose an estrogenic health risk to human health. A 28-day oral toxicity study was performed to observe the impact of single and combined exposure to NP and OP on 5-HT transporter (SERT) as well as 5-HT 2A receptor. Results showed that the 5-HT levels in rat plasma increased with exposure to middle-dose and high-dose NP, to high-dose OP, and to low, middle, and high doses of combined NP and OP (P < 0.05), while the 5-HT levels in rat platelets increased when exposed to NP/OP or combined NP and OP of middle or high dose (P < 0.05). The expression levels of SERT in rat platelets decreased when exposed to high-dose NP/OP or high dose of combined NP and OP (P < 0.05). Meanwhile, the expression levels of 5-HT 2A in rat platelets decreased when exposed to high-dose NP/OP as well as combined NP and OP (P < 0.05). These findings suggested that exposure to NP and OP could influence the metabolic network of 5-hydroxytryptamine via transportation and receptor binding pathways.

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

PubMed

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

2008-01-01

To determine the pharmacokinetics and safety of orally administered voriconazole in African grey parrots. 20 clinically normal Timneh African grey parrots (Psittacus erithacus timneh). In single-dose trials, 12 parrots were each administered 6, 12, and 18 mg of voriconazole/kg orally and plasma concentrations of voriconazole were determined via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) was administered orally to 6 birds every 12 hours for 9 days; a control group (2 birds) received tap water. Treatment effects were assessed via observation, clinicopathologic analyses (3 assessments), and measurement of trough plasma voriconazole concentrations (2 assessments). Voriconazole's elimination half-life was short (1.1 to 1.6 hours). Higher doses resulted in disproportional increases in the maximum plasma voriconazole concentration and area under the curve. Trough plasma voriconazole concentrations achieved in the multiple-dose trial were lower than those achieved after administration of single doses. Polyuria (the only adverse treatment effect) developed in treated and control birds but was more severe in the treatment group. In African grey parrots, voriconazole has dose-dependent pharmacokinetics and may induce its own metabolism. Oral administration of 12 to 18 mg of voriconazole/kg twice daily is a rational starting dose for treatment of African grey parrots infected with Aspergillus or other fungal organisms that have a minimal inhibitory concentration for voriconazole < or = 0.4 microg/mL. Higher doses may be needed to maintain plasma voriconazole concentrations during long-term treatment. Safety and efficacy of various voriconazole treatment regimens in this species require investigation.

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.

Testing the effects of long-acting steroids in edema and ecchymosis after closed rhinoplasty

PubMed Central

Gutierrez, Santiago; Wuesthoff, Carolina

2014-01-01

BACKGROUND: Steroids have proven to be of some benefit in rhinoplasty edema and ecchymosis when administered at a high and repeated dose. OBJECTIVE: To evaluate the effects of single-dose, long-acting intramuscular steroids on postoperative edema and ecchymosis after closed rhinoplasty with osteotomies compared with placebo. METHODS: A randomized, double-blinded, placebo-controlled trial was performed. Fifty-four patients were randomly assigned to two groups: 28 received a single dose of long-acting dexamethasone (mean [± SD] dose 16±4 mg) immediately before anesthetic induction; the remaining 26 received an intramuscular injection of saline solution. The same surgeon performed all surgeries, with patients under general anesthesia. Acetaminophen was the only analgesic used to control postoperative pain. High-resolution digital photographs were taken on postoperative days 1, 3, 7 and 14. Scoring was performed separately for eyelid swelling and ecchymosis by an independent observer using a graded scale (0 to 5) for edema and a scoring system (0 to 13) for ecchymosis. RESULTS: No statistically significant differences in terms of age, sex or amount of bleeding during surgery were found between the two groups. No statistically significant difference was observed in the decrease of both ecchymosis and edema between placebo and high-dose, long-acting dexamethasone. A statistically significant difference in operation time was found, favouring the steroid group. No severe complications were observed due to steroid use. DISCUSSION: Osteotomies are basically a form of (controlled) trauma, with considerable disruption of the abundant blood vessels in this facial region and, therefore, are associated with with undesirable effects. A recent meta-analysis failed to show benefits of the use of steroids after postoperative day 3. Only a trend toward reduction in edema and ecchymosis with the use of long-acting steroids compared with placebo was demonstrated in the present study. CONCLUSION: There was no benefit in administering single-dose, long-acting steroids in patients undergoing closed rhinoplasty with osteotomies. PMID:25114618

Single Low Dose Primaquine (0.25mg/kg) Does Not Cause Clinically Significant Haemolysis in G6PD Deficient Subjects

PubMed Central

Bancone, Germana; Chowwiwat, Nongnud; Somsakchaicharoen, Raweewan; Poodpanya, Lalita; Moo, Paw Khu; Gornsawun, Gornpan; Kajeechiwa, Ladda; Thwin, May Myo; Rakthinthong, Santisuk; Nosten, Suphak; Thinraow, Suradet; Nyo, Slight Naw; Ling, Clare L.; Wiladphaingern, Jacher; Kiricharoen, Naw Lily; Moore, Kerryn A.; White, Nicholas J.; Nosten, Francois

2016-01-01

Background Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum. The transmission blocking dose of primaquine previously recommended was 0.75mg/kg (adult dose 45mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15–20%) in populations living in malarious areas. To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25mg/kg (adult dose 15mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing. Direct evidence of the safety of this low dose is lacking. Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%. Methods and Findings The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects. Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration. G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females. Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models. No adverse events related to primaquine were reported during the trial. Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant. Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic. Conclusions The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency. The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria. Trial Registration ClinicalTrials.gov NCT01872702 PMID:27010542

A Long-Acting Human Growth Hormone With Delayed Clearance (VRS-317): Results of a Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Growth Hormone–Deficient Adults

PubMed Central

Yuen, Kevin C. J.; Conway, Gerard S.; Popovic, Vera; Merriam, George R.; Bailey, Timothy; Hamrahian, Amir H.; Biller, Beverly M. K.; Kipnes, Mark; Moore, Jerome A.; Humphriss, Eric; Cleland, Jeffrey L.

2013-01-01

Background: Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes. Objectives: This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317. Design: This was a randomized, double-blind, placebo-controlled, single ascending dose study. Patients: Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo). Setting: The study was conducted in 17 adult endocrinology centers in North America and Europe. Main Outcome Measures: Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed. Results: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3–5.0 μg/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between −1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed. Conclusions: The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing. PMID:23585663

Corticosteroid injection for the treatment of carpal tunnel syndrome

PubMed Central

O'Gradaigh, D; Merry, P

2000-01-01

OBJECTIVE—To compare low and high dose, and short and long acting corticosteroids in the treatment of carpal tunnel syndrome.
METHODS—A randomised, controlled, single blind trial with electromyographic and subjective outcome measures.
RESULTS—25 mg hydrocortisone is as effective as higher doses or long acting triamcinolone at a six week and six month follow up.
CONCLUSION—As low dose steroid is as effective, and potentially less toxic, this should be the recommended dose for injection of carpal tunnel syndrome.

 PMID:11053073

Absolute bioavailability and pharmacokinetics of avosentan in man.

PubMed

Dieterle, W; Hengelage, T

2009-09-01

Avosentan is a potent, selective endothelin A receptor blocker. The pharmacokinetics of avosentan were investigated in healthy male and female volunteers, following oral and i.v. administration of single doses of avosentan and its absolute bioavailability was determined. In a randomized, balanced open-label, three-period oral crossover study, 26 healthy subjects (19 males and 7 females) received Treatments A, B and C. Treatment A consisted of a single dose of a 25 mg film-coated tablet of avosentan, Treatment B of a single dose of a 50 mg film-coated tablet of avosentan and Treatment C of 10 mg avosentan in 20 ml solution for infusion for 20 minutes (10 mg avosentan in 20 ml phosphate buffer pH 9.0 containing 1% polysorbate 20). Plasma concentrations of avosentan and its hydroxymethyl metabolite Ro 68-5925 were measured by liquid chromatography-tandem mass spectrometry. The absolute bioavailability values (compared with i.v. infusion) for the 25 and 50 mg film-coated tablets were 81% and 72%, respectively. The extent of absorption, as measured by partial and total AUC, increased almost proportionally with the dose. The estimated proportionality coefficient for AUC0- yen was 1.12 (90% CI 1.06, 1.18). For the rate of absorption (Cmax) strict dose-proportionality was not demonstrated (proportionality coefficient 1.13 (90% CI 1.0, 1.28)). No relevant gender differences in the pharmacokinetic characteristics were evident after a single i.v. dose and at an oral dose of 25 mg, whereas after oral administration of 50 mg of avosentan differences were seen in Cmax and t1/2. The absolute bioavailability of avosentan film-coated tablets is high, i.e. 70 - 80%.

Optimal timing and frequency of bone marrow soup therapy for functional restoration of salivary glands injured by single-dose or fractionated irradiation.

PubMed

Fang, Dongdong; Shang, Sixia; Liu, Younan; Bakkar, Mohammed; Sumita, Yoshinori; Seuntjens, Jan; Tran, Simon D

2018-02-01

Injections of bone marrow (BM) cell extract, known as 'BM soup', were previously reported to mitigate ionizing radiation (IR) injury to salivary glands (SGs). However, the optimal starting time and frequency to maintain BM soup therapeutic efficacy remains unknown. This study tested the optimal starting time and frequency of BM soup injections in mice radiated with either a single dose or a fractionated dose. First, BM soup treatment was started at 1, 3 or 7 weeks post-IR; positive (non-IR) and negative (IR) control mice received injections of saline (vehicle control). Second, BM soup-treated mice received injections at different frequencies (1, 2, 3 and 5 weekly injections). Third, a 'fractionated-dose radiation' model to injure mouse SGs was developed (5 Gy × 5 days) and compared with the single high dose radiation model. All mice (n = 65) were followed for 16 weeks post-IR. The results showed that starting injections of BM soup between 1 and 3 weeks mitigated the effect of IR-induced injury to SGs and improved the restoration of salivary function. Although the therapeutic effect of BM soup lessens after 8 weeks, it can be sustained by increasing the frequency of weekly injections. Moreover, both single-dose and fractionated-dose radiation models are efficient and comparable in inducing SG injury and BM soup treatments are effective in restoring salivary function in both radiation models. In conclusion, starting injections of BM soup within 3 weeks post-radiation, with 5 weekly injections, maintains 90-100% of saliva flow in radiated mice. Copyright © 2017 John Wiley & Sons, Ltd.

Time-course study of different innate immune mediators produced by UV-irradiated skin: comparative effects of short and daily versus a single harmful UV exposure.

PubMed

Cela, Eliana M; Friedrich, Adrian; Paz, Mariela L; Vanzulli, Silvia I; Leoni, Juliana; González Maglio, Daniel H

2015-05-01

The modulatory effects of solar UV radiation on the immune system have been widely studied. As the skin is the main target of UV radiation, our purpose was to compare the impact on skin innate immunity of two contrasting ways to be exposed to sunlight. Hairless mice were UV irradiated with a single high UV dose simulating a harmful exposure, or with repetitive low UV doses simulating short occasional daily exposures. Skin samples were taken at different times after UV irradiation to evaluate skin histology, inflammatory cell recruitment, epidermal T-cell population and the mitochondrial function of epidermal cells. The transcriptional profiles of pro-inflammatory cytokines, chemokines, antimicrobial peptides and Toll-like receptors were evaluated by RT-PCR and ELISA in tissue homogenates. Finally, a lymphangiography was performed to assess modification in the lymphatic vessel system. A single high UV dose produces a deep inflammatory state characterized by the production of pro-inflammatory cytokines and chemokines that, in turn, induces the recruitment of neutrophils and macrophages into the irradiated area. On the other hand, repetitive low UV doses drive the skin to a photo-induced alert state in which there is no sign of inflammation, but the epithelium undergoes changes in thickness, the lymphatic circulation increases, and the transcription of antimicrobial peptides is induced. © 2014 John Wiley & Sons Ltd.

Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study.

PubMed

Huttner, Angela; Agnandji, Selidji Todagbe; Combescure, Christophe; Fernandes, José F; Bache, Emmanuel Bache; Kabwende, Lumeka; Ndungu, Francis Maina; Brosnahan, Jessica; Monath, Thomas P; Lemaître, Barbara; Grillet, Stéphane; Botto, Miriam; Engler, Olivier; Portmann, Jasmine; Siegrist, Denise; Bejon, Philip; Silvera, Peter; Kremsner, Peter; Siegrist, Claire-Anne

2018-04-04

The recombinant vesicular stomatitis virus (rVSV) vaccine expressing the Zaire Ebola virus (ZEBOV) glycoprotein is efficacious in the weeks following single-dose injection, but duration of immunity is unknown. We aimed to assess antibody persistence at 1 and 2 years in volunteers who received single-dose rVSV-ZEBOV in three previous trials. In this observational cohort study, we prospectively followed-up participants from the African and European phase 1 rVSV-ZEBOV trials, who were vaccinated once in 2014-15 with 300 000 (low dose) or 10-50 million (high dose) plaque-forming units (pfu) of rVSV-ZEBOV vaccine to assess ZEBOV glycoprotein (IgG) antibody persistence. The primary outcome was ZEBOV glycoprotein-specific IgG geometric mean concentrations (GMCs) measured yearly by ELISA compared with 1 month (ie, 28 days) after immunisation. We report GMCs up to 2 years (Geneva, Switzerland, including neutralising antibodies up to 6 months) and 1 year (Lambaréné, Gabon; Kilifi, Kenya) after vaccination and factors associated with higher antibody persistence beyond 6 months, according to multivariable analyses. Trials and the observational study were registered at ClinicalTrials.gov (Geneva: NCT02287480 and NCT02933931; Kilifi: NCT02296983) and the Pan-African Clinical Trials Registry (Lambaréné PACTR201411000919191). Of 217 vaccinees from the original studies (102 from the Geneva study, 75 from the Lambaréné study, and 40 from the Kilifi study), 197 returned and provided samples at 1 year (95 from the Geneva study, 63 from the Lambaréné, and 39 from the Kilifi study) and 90 at 2 years (all from the Geneva study). In the Geneva group, 44 (100%) of 44 participants who had been given a high dose (ie, 10-50 million pfu) of vaccine and who were seropositive at day 28 remained seropositive at 2 years, whereas 33 (89%) of 37 who had been given the low dose (ie, 300 000 pfu) remained seropositive for 2 years (p=0·042). In participants who had received a high dose, ZEBOV glycoprotein IgG GMCs decreased significantly between their peak (at 1-3 months) and month 6 after vaccination in Geneva (p<0·0001) and Lambaréné (p=0·0298) but not in Kilifi (p=0·5833) and subsequently remained stable at all sites apart from Geneva, where GMC in those given a high dose of vaccine increased significantly between 6 months and 1 year (p=0·0264). Antibody persistence was similar at 1 year and at 6 months in those who had received a low dose of vaccine, with lower titres among participants from the Geneva study at 2 years than at 1 year after vaccination (GMC ratio 0·61, 95% CI 0·49-0·77; p<0·0001). In multivariable analyses, predictors of increased IgG GMCs beyond 6 months included high-dose versus low-dose vaccination (Geneva p=0·0133; Lambaréné p=0·008) and vaccine-related arthritis (p=0·0176), but not sex, age, or baseline seropositivity (all p>0·05). Neutralising antibodies seem to be less durable, with seropositivity dropping from 64-71% at 28 days to 27-31% at 6 months in participants from the Geneva study. Antibody responses to single-dose rVSV-ZEBOV vaccination are sustained across dose ranges and settings, a key criterion in countries where booster vaccinations would be impractical. The Wellcome Trust and Innovative Medicines Initiative 2 Joint Undertaking. Copyright © 2018 Elsevier Ltd. All rights reserved.

Accelerated heavy particles and the lens. VII: The cataractogenic potential of 450 MeV/amu iron ions

NASA Technical Reports Server (NTRS)

Worgul, B. V.; Brenner, D. J.; Medvedovsky, C.; Merriam, G. R. Jr; Huang, Y.

1993-01-01

PURPOSE. To determine the cataractogenic potential dose of high velocity iron ions as a fixation of dose administered singly or fractionated. The dose is critical to risk assessment and to theories of radiation action and cataractogenesis. METHODS. Twenty-eight-day-old rats were examined by slit-lamp biomicroscopy on a weekly-bi-weekly basis for more than 2 yr after radiation exposure. For the acute exposure study doses of 1, 2, 5, 25, and 50 cGy were evaluated. The fractionated regimens involved total doses of 2, 25, and 50 cGy. The reference radiation consisted of 50, 100, 200, or 700 cGy of 250 kilovolt (peak) x-rays. RESULTS. In accordance with previous findings in the rat using 570 MeV/amu 40Ar ions, the relative biologic effectiveness increased rapidly with decreasing dose, reaching values as high as 100. Unlike 40Ar ions, fractionation of the 56Fe doses did not produce a consistent enhancement at any of the doses examined. CONCLUSIONS. The data support the previous findings of a high cataractogenic potential for high linear energy transfer (LET) radiation. The effectiveness for the production of cataracts increases with decreasing dose relative to x-rays and is independent of dose protraction. Although the present study did not reveal a consistent enhancement of effect when the ions were applied in fractions, the results are consistent with at least one theory of the inverse dose-rate effect observed for high-LET radiation.

Evaluation of volumetric modulated arc therapy for cranial radiosurgery using multiple noncoplanar arcs

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

Audet, Chantal; Poffenbarger, Brett A.; Chang, Pauling

2011-11-15

Purpose: To evaluate a commercial volumetric modulated arc therapy (VMAT), using multiple noncoplanar arcs, for linac-based cranial radiosurgery, as well as evaluate the combined accuracy of the VMAT dose calculations and delivery. Methods: Twelve patients with cranial lesions of variable size (0.1-29 cc) and two multiple metastases patients were planned (Eclipse RapidArc AAA algorithm, v8.6.15) using VMAT (1-6 noncoplanar arcs), dynamic conformal arc (DCA, {approx}4 arcs), and IMRT (nine static fields). All plans were evaluated according to a conformity index (CI), healthy brain tissue doses and volumes, and the dose to organs at risk. A 2D dose distribution was measuredmore » (Varian Novalis Tx, HD120 MLC, 1000 MU/min, 6 MV beam) for the {approx}4 arc VMAT treatment plans using calibrated film dosimetry. Results: The CI (0-1 best) average for all plans was best for {approx}4 noncoplanar arc VMAT at 0.86 compared with {approx}0.78 for IMRT and a single arc VMAT and 0.68 for DCA. The volumes of healthy brain receiving 50% of the prescribed target coverage dose or more (V{sub 50%}) were lowest for the four arc VMAT [RA(4)] and DCA plans. The average ratio of the V{sub 50%} for the other plans to the RA(4) V{sub 50%} were 1.9 for a single noncoplanar arc VMAT [RA(1nc)], 1.4 for single full coplanar arc VMAT [RA(1f)] and 1.3 for IMRT. The V{sub 50%} improved significantly for single isocenter multiple metastases plan when two noncoplanar VMAT arcs were added to a full single coplanar one. The maximum dose to 5 cc of the outer 1 cm rim of healthy brain which one may want to keep below nonconsequential doses of 300-400 cGy, was 2-3 times greater for IMRT, RA(1nc) and RA(1f) plans compared with the multiple noncoplanar arc DCA and RA(4) techniques. Organs at risk near (0-4 mm) to targets were best spared by (i) single noncoplanar arcs when the targets are lateral to the organ at risk and (ii) by skewed nonvertical planes of IMRT fields when the targets are not lateral to the organ at risk. The highest dose gradient observed between an organ at risk and a target at the edge of a VMAT arc plane or plane of IMRT fields was 17%/mm. The average absolute percent difference between the measured and calculated central axis dose for all the VMAT plans was 3.6 {+-} 2.2%. The measured perpendicular profile widths and shifts were on average within 0.5 mm of planned values. The average total MUs for VMAT plans was double the DCA average and similar to the IMRT average. Conclusions: For the aforementioned planning and delivery system and cranial lesions greater than 7 mm in diameter, multiple noncoplanar arc VMAT consistently provides accurate and high quality cranial radiosurgery dose distributions with low doses to healthy brain tissue and high dose conformity to the target. These qualities may make multiple noncoplanar arc VMAT suitable for a greater range of prescription doses or larger and more irregular lesions. For smaller and/or rounder lesions there are other clinically acceptable treatment techniques that may involve fewer couch angles or arcs and reduce treatment times.« less

Dosimetric evaluation of two treatment planning systems for high dose rate brachytherapy applications

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

Shwetha, Bondel; Ravikumar, Manickam, E-mail: drravikumarm@gmail.com; Supe, Sanjay S.

2012-04-01

Various treatment planning systems are used to design plans for the treatment of cervical cancer using high-dose-rate brachytherapy. The purpose of this study was to make a dosimetric comparison of the 2 treatment planning systems from Varian medical systems, namely ABACUS and BrachyVision. The dose distribution of Ir-192 source generated with a single dwell position was compared using ABACUS (version 3.1) and BrachyVision (version 6.5) planning systems. Ten patients with intracavitary applications were planned on both systems using orthogonal radiographs. Doses were calculated at the prescription points (point A, right and left) and reference points RU, LU, RM, LM, bladder,more » and rectum. For single dwell position, little difference was observed in the doses to points along the perpendicular bisector. The mean difference between ABACUS and BrachyVision for these points was 1.88%. The mean difference in the dose calculated toward the distal end of the cable by ABACUS and BrachyVision was 3.78%, whereas along the proximal end the difference was 19.82%. For the patient case there was approximately 2% difference between ABACUS and BrachyVision planning for dose to the prescription points. The dose difference for the reference points ranged from 0.4-1.5%. For bladder and rectum, the differences were 5.2% and 13.5%, respectively. The dose difference between the rectum points was statistically significant. There is considerable difference between the dose calculations performed by the 2 treatment planning systems. It is seen that these discrepancies are caused by the differences in the calculation methodology adopted by the 2 systems.« less

Intraoperative irradiation: precision medicine for quality cancer control promotion.

PubMed

Calvo, Felipe A

2017-02-02

Intraoperative irradiation was implemented 4 decades ago, pioneering the efforts to improve precision in local cancer therapy by combining real-time surgical exploration/resection with high single dose radiotherapy (Gunderson et al., Intraoperative irradiation: techniques and results, 2011). Clinical and technical developments have led to very precise radiation dose deposit. The ability to deliver a very precise dose of radiation is an essential element of contemporary multidisciplinary individualized oncology.This issue of Radiation Oncology contains a collection of expert review articles and updates with relevant data regarding intraoperative radiotherapy. Technology, physics, biology of single dose and clinical results in a variety of cancer sites and histologies are described and analyzed. The state of the art for advanced cancer care through medical innovation opens a significant opportunity for individualize cancer management across a broad spectrum of clinical practice. The advantage for tailoring diagnostic and treatment decisions in an individualized fashion will translate into precise medical treatment.

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.

PubMed

Trammell, Samuel A J; Schmidt, Mark S; Weidemann, Benjamin J; Redpath, Philip; Jaksch, Frank; Dellinger, Ryan W; Li, Zhonggang; Abel, E Dale; Migaud, Marie E; Brenner, Charles

2016-10-10

Nicotinamide riboside (NR) is in wide use as an NAD + precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD + metabolism in humans. We report that human blood NAD + can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD + with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD + metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD + , is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD + repletion.

Tumor Induction in Mice After Localized Single- or Fractionated-Dose Irradiation: Differences in Tumor Histotype and Genetic Susceptibility Based on Dose Scheduling

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

Edmondson, Elijah F., E-mail: elijah.edmondson@colostate.edu; Hunter, Nancy R.; Weil, Michael M.

2015-07-15

Purpose: To investigate differences in tumor histotype, incidence, latency, and strain susceptibility in mice exposed to single-dose or clinically relevant, fractioned-dose γ-ray radiation. Methods and Materials: C3Hf/Kam and C57BL/6J mice were locally irradiated to the right hindlimb with either single large doses between 10 and 70 Gy or fractionated doses totaling 40 to 80 Gy delivered at 2-Gy/d fractions, 5 d/wk, for 4 to 8 weeks. The mice were closely evaluated for tumor development in the irradiated field for 800 days after irradiation, and all tumors were characterized histologically. Results: A total of 210 tumors were induced within the radiation field in 788 mice. Anmore » overall decrease in tumor incidence was observed after fractionated irradiation (16.4%) in comparison with single-dose irradiation (36.1%). Sarcomas were the predominant postirradiation tumor observed (n=201), with carcinomas occurring less frequently (n=9). The proportion of mice developing tumors increased significantly with total dose for both single-dose and fractionated schedules, and latencies were significantly decreased in mice exposed to larger total doses. C3Hf/Kam mice were more susceptible to tumor induction than C57BL/6J mice after single-dose irradiation; however, significant differences in tumor susceptibilities after fractionated radiation were not observed. For both strains of mice, osteosarcomas and hemangiosarcomas were significantly more common after fractionated irradiation, whereas fibrosarcomas and malignant fibrous histiocytomas were significantly more common after single-dose irradiation. Conclusions: This study investigated the tumorigenic effect of acute large doses in comparison with fractionated radiation in which both the dose and delivery schedule were similar to those used in clinical radiation therapy. Differences in tumor histotype after single-dose or fractionated radiation exposures provide novel in vivo evidence for differences in tumor susceptibility among stromal cell populations.« less

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.

Disposition and pharmacokinetics in rats of McN-5707, a potential antidepressant drug

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

Ng, K.T.; Holland, M.L.; Hills, J.F.

1986-03-01

A single 80 mg/kg oral solution dose of McN-5707-/sup 14/C x HBr (trans-6-(2-chlorophenyl)-1,2,3,5,6,10b-hexahydropyrrolo(2,1-a)isoquinoline hydrobromide (1:1)) was administered orally to 40 Wistar rats. Total /sup 14/C concentrations in plasma were high (> 4.5 ..mu..g x equiv/mL) for at least 24 hours after dosing. Unchanged McN-5707 represented < 10% of the total /sup 14/C concs in plasma at 45 min and < 1% at 24 hours after dosing. In the 8 days following dose administration, 23% of the dose was excreted in urine and 70% of the dose was excreted in feces. Analysis (HPLC and TLC) of glusulase treated urine, plasma andmore » fecal samples revealed the presence of multiple metabolites of McN-5707. Unchanged McN-5707 was found only in fecal extracts (2-7% of dose). Single solution doses of McN-5707 x HBr were administered p.o. (20 mg/kg) and i.v. (4 mg/kg) to 39 Wistar rats. Plasma samples were analyzed for McN-5707 using a capillary GC assay. These studies indicated that McN-5707 was well absorbed and extensively metabolized in rats following oral doses.« less

Meal frequency of pre-exercise carbohydrate feedings.

PubMed

Chryssanthopoulos, C; Petridou, A; Maridaki, M; Mougios, V

2008-04-01

This study compared the effect of single and multiple carbohydrate feedings before exercise on biochemical and physiological responses during exercise. Eight males performed 3 runs for 1 h at 70 % VO(2max) after consuming a meal containing 2.5 g carbohydrate per kg body mass in a single dose 3 h before exercise (SF), the same meal in 5 equal doses at 3, 2.5, 2, 1.5, and 1 h before exercise (MF), or a liquid placebo 3 h before exercise (P). RER and carbohydrate oxidation rates were higher in SF and MF compared to P trials, but there was no difference between SF and MF trials. Pre-exercise insulin was 2.0- and 3.4- fold higher in SF and MF, respectively, compared to P, and 1.7-fold higher in MF compared to SF. Glycerol and NEFA were higher in P compared to SF and MF trials before and at the end of exercise. In conclusion, a carbohydrate meal containing 2.5 g . kg(-1) ingested in doses over 3 h before running produced higher hyperinsulinemia pre-exercise than that produced when the meal was consumed in a single dose. Nevertheless, estimated carbohydrate utilization and adipose tissue lipolysis during exercise after multiple feedings seemed to be as high as after a single feeding.

The biological fate of decabromodiphenyl ethane following ...

EPA Pesticide Factsheets

1. The disposition of decabromodiphenyl ethane (DBDPE) was investigated based on concerns over its structural similarities to decaBDE, high potential for environmental persistence & bioaccumulation, and high production volume. 2. In the present study, female Sprague Dawley rats were administered a single dose of [14C]-DBDPE by oral, topical, or IV routes. Another set of rats were administered 10 daily oral doses of 14C]-DBDPE. Male B6C3F1/Tac mice were administered a single oral dose.3. DBDPE was poorly absorbed following oral dosing, with 95% of administered [14C]-radioactivity recovered in the feces, 1% recovered in the urine and less than 3% in the tissues at 72 h. DBDPE excretion was similar in male mice and female rats. Accumulation of [14C]-DBDPE was observed in liver and the adrenal gland after 10 daily oral doses.4. The dermis acted as a depot for dermally applied DBDPE; conservative estimates predict approx. 14 ± 8% of DBDPE may be absorbed into human skin in vivo; approx. 7 ± 4% of the parent chemical is expected to reach systemic circulation following continuous exposure (24 h). 5. Following intravenous administration, 6% of the dose was recovered in urine and 28% in the feces, while ~70% of the dose remained in tissues after 72 hours, with the highest concentrations found in the liver (42%) and lung (17%). Decabromodiphenyl ethane (DBDPE) is an additive brominated flame retardant used in a variety commercial products. It has been detected in indo

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.

PubMed

Ray, Kausik K; Landmesser, Ulf; Leiter, Lawrence A; Kallend, David; Dufour, Robert; Karakas, Mahir; Hall, Tim; Troquay, Roland P T; Turner, Traci; Visseren, Frank L J; Wijngaard, Peter; Wright, R Scott; Kastelein, John J P

2017-04-13

In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).

Azithromycin in the treatment of uncomplicated genital chlamydial infections.

PubMed

Stamm, W E

1991-09-12

Chlamydia trachomatis is among the most prevalent of sexually transmitted diseases and causes serious sequelae, especially in women. A major difficulty facing the clinician has been the effective treatment of patients with chlamydial infections, since existing drugs require 7 or more days of multidose therapy, and hence considerable commitment from the patient. Many patients, especially those who are minimally symptomatic or asymptomatic, are likely to be noncompliant when given such multiple day regimens and thus may fail therapy. Azithromycin is an azalide antibiotic that has a minimum inhibitory concentration against C. trachomatis of between 0.03 and 0.25 mg/L, as well as good in vitro activity against other sexually transmitted pathogens that are often present concurrently. Azithromycin also achieves high intracellular concentrations, which may be beneficial in eradicating Chlamydia, an obligate intracellular pathogen. More importantly, azithromycin has high tissue bioavailability and a tissue half-life of between 2 and 4 days. These pharmacokinetic properties imply that the dosing period for azithromycin can be greatly reduced while still achieving high antimicrobial activity at sites of infection. Clinical experience to date shows that a single 1 g oral dose of azithromycin is as effective as a standard 7-day twice daily regimen of doxycycline and more effective than 7 days of ciprofloxacin in eradicating uncomplicated chlamydial genital infections. As such, azithromycin is the first single-dose therapy for the treatment of urethritis and cervicitis due to C. trachomatis. Single-dose therapy for chlamydial infection, which could be administered under supervision in the clinic, would be a significant advance in the management and public health control of chlamydial infections.

SU-F-19A-03: Dosimetric Advantages in Critical Structure Dose Sparing by Using a Multichannel Cylinder in High Dose Rate Brachytherapy to Treat Vaginal Cuff Cancer

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

Syh, J; Syh, J; Patel, B

2014-06-15

Purpose: The multichannel cylindrical vaginal applicator is a variation of traditional single channel cylindrical vaginal applicator. The multichannel applicator has additional peripheral channels that provide more flexibility in the planning process. The dosimetric advantage is to reduce dose to adjacent organ at risk (OAR) such as bladder and rectum while maintaining target coverage with the dose optimization from additional channels. Methods: Vaginal HDR brachytherapy plans are all CT based. CT images were acquired in 2 mm thickness to keep integrity of cylinder contouring. The CTV of 5mm Rind with prescribed treatment length was reconstructed from 5mm expansion of inserted cylinder.more » The goal was 95% of CTV covered by 95% of prescribed dose in both single channel planning (SCP)and multichannel planning (MCP) before proceeding any further optimization for dose reduction to critical structures with emphasis on D2cc and V2Gy . Results: This study demonstrated noticeable dose reduction to OAR was apparent in multichannel plans. The D2cc of the rectum and bladder were showing the reduced dose for multichannel versus single channel. The V2Gy of the rectum was 93.72% and 83.79% (p=0.007) for single channel and multichannel respectively (Figure 1 and Table 1). To assure adequate coverage to target while reducing the dose to the OAR without any compromise is the main goal in using multichannel vaginal applicator in HDR brachytherapy. Conclusion: Multichannel plans were optimized using anatomical based inverse optimization algorithm of inverse planning simulation annealing. The optimization solution of the algorithm was to improve the clinical target volume dose coverage while reducing the dose to critical organs such as bladder, rectum and bowels. The comparison between SCP and MCP demonstrated MCP is superior to SCP where the dwell positions were based on geometric array only. It concluded that MCP is preferable and is able to provide certain features superior to SCP.« less

Detecting structural variances of Co 3O 4 catalysts by controlling beam-induced sample alterations in the vacuum of a transmission electron microscope

DOE PAGES

Kisielowski, C.; Frei, H.; Specht, P.; ...

2016-11-02

This article summarizes core aspects of beam-sample interactions in research that aims at exploiting the ability to detect single atoms at atomic resolution by mid-voltage transmission electron microscopy. Investigating the atomic structure of catalytic Co 3O 4 nanocrystals underscores how indispensable it is to rigorously control electron dose rates and total doses to understand native material properties on this scale. We apply in-line holography with variable dose rates to achieve this goal. Genuine object structures can be maintained if dose rates below ~100 e/Å 2s are used and the contrast required for detection of single atoms is generated by capturing largemore » image series. Threshold doses for the detection of single atoms are estimated. An increase of electron dose rates and total doses to common values for high resolution imaging of solids stimulates object excitations that restructure surfaces, interfaces, and defects and cause grain reorientation or growth. We observe a variety of previously unknown atom configurations in surface proximity of the Co 3O 4 spinel structure. These are hidden behind broadened diffraction patterns in reciprocal space but become visible in real space by solving the phase problem. Finallly, an exposure of the Co 3O 4 spinel structure to water vapor or other gases induces drastic structure alterations that can be captured in this manner.« less

Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice.

PubMed

Chang, Meng-Ya; Shiau, Ai-Li; Chen, Yu-Hung; Chang, Chih-Jui; Chen, Helen H-W; Wu, Chao-Liang

2008-07-01

High atomic number material, such as gold, may be used in conjunction with radiation to provide dose enhancement in tumors. In the current study, we investigated the dose-enhancing effect and apoptotic potential of gold nanoparticles in combination with single-dose clinical electron beams on B16F10 melanoma tumor-bearing mice. We revealed that the accumulation of gold nanoparticles was detected inside B16F10 culture cells after 18 h of incubation, and moreover, the gold nanoparticles were shown to be colocalized with endoplasmic reticulum and Golgi apparatus in cells. Furthermore, gold nanoparticles radiosensitized melanoma cells in the colony formation assay (P = 0.02). Using a B16F10 tumor-bearing mouse model, we further demonstrated that gold nanoparticles in conjunction with ionizing radiation significantly retarded tumor growth and prolonged survival compared to the radiation alone controls (P < 0.05). Importantly, an increase of apoptotic signals was detected inside tumors in the combined treatment group (P < 0.05). Knowing that radiation-induced apoptosis has been considered a determinant of tumor responses to radiation therapy, and the length of tumor regrowth delay correlated with the extent of apoptosis after single-dose radiotherapy, these results may suggest the clinical potential of gold nanoparticles in improving the outcome of melanoma radiotherapy.

A double-blind, randomized, placebo-controlled, single-dose study of the cyclooxygenase-2 inhibitor, GW406381, as a treatment for acute migraine.

PubMed

Wentz, A L; Jimenez, T B; Dixon, R M; Aurora, S K; Gold, M

2008-04-01

The objective of the present study was to explore the clinical efficacy and tolerability of GW406381, a cyclooxygenase-2 (COX-2) inhibitor with relatively high CNS penetration, in acute migraine. This was a double-blind, single-dose study of GW406381 compared with placebo and naproxen sodium compared with placebo (protocol number CXA20008). Three hundred and thirty-seven subjects were randomized 1:1:1 to GW406381 (70 mg), naproxen sodium (825 mg), or placebo for the treatment of one migraine headache of moderate or severe intensity in a potential 8-week period. The primary end-point was the proportion of subjects with headache relief [reduction in headache severity score from pre-dose 2 (moderate) or 3 (severe) to 0 (no pain) or 1 (mild)] at 2 h post-dose for GW406381 compared with placebo. Significantly higher proportions of subjects treated with GW406381 (50%, P = 0.032) or naproxen sodium (56%, P = 0.005) than with placebo (35%) reported headache relief at 2 h post-dose. Additional significant benefits were observed on many secondary outcomes, including proportions of subjects pain-free, for both GW406381 and naproxen sodium treatment compared with placebo. Both active treatments were well tolerated. Single-dose GW406381 (70 mg) and naproxen sodium (825 mg) were effective and well tolerated in the treatment of acute migraine.

PaxVax CVD 103-HgR single-dose live oral cholera vaccine.

PubMed

Levine, Myron M; Chen, Wilbur H; Kaper, James B; Lock, Michael; Danzig, Lisa; Gurwith, Marc

2017-03-01

Cholera remains a problem in developing countries and a risk for travelers. Hypochlorhydria, blood group O, cardiac and renal disease increase the risk of developing cholera gravis. Oral vaccines containing inactivated Vibrio cholerae and requiring two doses are available in some countries. No cholera vaccine had been available for U.S. travelers for decades until 2016 when CVD 103-HgR (VAXCHORA™), an oral live attenuated vaccine, was licensed by the U.S. FDA. Areas covered: Enduring protection following wild-type cholera provided the rationale to develop a single-dose live oral vaccine. CVD 103-HgR is well-tolerated and protects against cholera caused by V. cholerae O1 of either serotype (Inaba, Ogawa) and biotype (El Tor, Classical). Since 90% vaccine efficacy is evident 10 days post-ingestion of a single dose, CVD 103-HgR can rapidly protect travelers. Vibriocidal antibody seroconversion correlates with protection; >90% of U.S. adult (including elderly) vaccinees seroconvert. The U.S. Public Health Service's Advisory Committee on Immunization Practices recommends CVD 103-HgR for U.S. travelers to areas of ongoing cholera transmission. Expert commentary: Next steps include evaluations in children, post-licensure safety and effectiveness monitoring, diminishing cold chain constraints, optimizing a 'high-dose' formulation for developing countries, and diminishing/eliminating the need for water to administer a dose.

Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies

PubMed Central

Gomes, Melba; Ribeiro, Isabela; Warsame, Marian; Karunajeewa, Harin; Petzold, Max

2008-01-01

Background Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria. Methods Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success. Results Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether. Conclusion Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy. PMID:18373841

Urinary bactericidal activity of single doses (250, 500, 750 and 1000 mg) of levofloxacin against fluoroquinolone-resistant strains of Escherichia coli.

PubMed

Stein, Gary E; Schooley, Sharon L; Nicolau, David P

2008-10-01

Increasing resistance to fluoroquinolones in uropathogens has become a clinical concern. The purpose of this study was to analyse the urinary bactericidal activity (UBA) of levofloxacin against fluoroquinolone-resistant strains of Escherichia coli. Ten healthy adult subjects (aged 23-60 years) received single doses of levofloxacin (250, 500, 750 and 1000 mg) and then blood and urine samples were collected in intervals (0-1.5, 1.5-4, 4-8, 8-12 and 12-24h) over 24h. Both serum and urine concentrations were measured by a validated high-performance liquid chromatography assay. Bactericidal titres in urine were determined against E. coli isolates with minimum inhibitory concentrations of 0.125, 4, 8, 16, 32 and 64microg/mL for levofloxacin. The mean serum pharmacokinetic parameters for these doses of levofloxacin were similar to previously published values. The mean peak urinary concentrations (0-1.5h) were 210, 347, 620 and 536microg/mL for the 250, 500, 750 and 1000 mg dose, respectively. Each dose of levofloxacin exhibited early (0-1.5h time period) bactericidal activity in urine in virtually all subjects against E. coli strains with MICs

Chromosomal instability induced by heavy ion irradiation

NASA Technical Reports Server (NTRS)

Limoli, C. L.; Ponnaiya, B.; Corcoran, J. J.; Giedzinski, E.; Morgan, W. F.

2000-01-01

PURPOSE: To establish the dose-response relationship for the induction of chromosomal instability in GM10115 cells exposed to high-energy iron ions (1 GeV/nucleon, mean LET 146 keV/microm) and gold ions (11 GeV/nucleon, mean LET 1450 keV/microm). Past work has established that sparsely ionizing X-rays can induce a long-lived destabilization of chromosomes in a dose-dependent manner at an incidence of approximately 3% per gray. The present investigation assesses the capacity of High-Z and High-energy (HZE) particles to elicit this same endpoint. MATERIALS AND METHODS: Clonal populations derived from single progenitor cells surviving heavy-ion irradiation were analyzed cytogenetically to identify those clones showing a persistent destablization of chromosomes. RESULTS: Dose-response data, with a particular emphasis at low dose (< 1.0 Gy), indicate a frequency of approximately 4% per gray for the induction of chromosomal instability in clones derived from single progenitor cells surviving exposure to iron ions. The induction of chromosomal instability by gold ions was, however, less responsive to applied dose, as the observed incidence of this phenotype varied from 0 to 10% over 1-8 Gy. Both iron and gold ions gave dose-dependent increases in the yield of chromosomal aberrations (both chromosome- and chromatid-type) measured at the first mitosis following irradiation, as well as shoulderless survival curves having D0=0.87 and 1.1 Gy respectively. CONCLUSIONS: Based on the present dose-response data, the relative biological effectiveness of iron ions is 1.3 for the induction of chromosomal instability, and this indicates that heavy ions are only slightly more efficient than X-rays at eliciting this delayed phenotype.

Effects of TD-5108 on Gastrointestinal Transit and Bowel Function in Health and Pharmacokinetics in Health and Constipation

PubMed Central

Manini, Mhd Louai; Camilleri, Michael; Goldberg, Michael; Sweetser, Seth; McKinzie, Sanna; Burton, Duane; Wong, Shekman; Kitt, Michael M.; Li, Yu-Ping; Zinsmeister, Alan R.

2010-01-01

Background TD-5108 is a potent, selective high intrinsic activity serotonin 5-HT4 receptor agonist. Aim To assess effects of TD-5108 on gastrointestinal transit and compare its pharmacokinetics (PK) in healthy volunteers (HV) and chronic constipation (CC) patients. Methods 60 HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg TD-5108 (single and 6-day dosing). Primary endpoints were colonic transit (geometric center at 24 hours, GC24) and ascending colon emptying (ACE) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Results Single dose TD-5108 significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50°mg TD-5108 accelerated all 3 endpoints. With multiple doses, TD-5108 30 mg accelerated GC24, and overall accelerated GE T1/2 at 15–50 mg. PK studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of TD-5108. Stimulation of bowel function after15 mg TD-5108 were similar in CC and controls. There were no serious adverse events; notable adverse were the predictable GI effects such as diarrhea or altered bowel movements. Conclusions TD-5108 significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted. PMID:19691492

Correlation between the single, high dose of ingested baclofen and clinical symptoms.

PubMed

Anand, Jacek Sein; Zając, Maciej; Waldman, Wojciech; Wojtyła, Andrzej; Biliński, Przemysław; Jaworska-Łuczak, Barbara

2017-12-23

Baclofen is a drug used mainly to treat muscle spasticity. Its overdose can lead to life-threatening clinical symptoms, including acute respiratory failure requiring mechanical ventilation. The aim of this study was to assess the prevalence of selected clinical symptoms associated with baclofen poisoning comparing to an ingested dose. 60 cases of oral baclofen poisoning were analyzed. Gender, age distribution, and correlation between the dose of ingested baclofen were studied, as well as and following clinical parameters: degree of altered consciousness, heart rate, blood pressure, presence of acute respiratory failure, duration of mechanical ventilation, and presence of psychotic symptoms. The study found statistically significant correlations between dosage of ingested baclofen and presence of acute respiratory failure, as well as duration of mechanical ventilation. No statistically significant correlations were found between the dose of ingested baclofen and presence of hypertension, bradycardia, acute psychotic symptoms, or level of consciousness disturbance. However, it was found that patients who suffered from hypertension, bradycardia, and altered mental status ingested a larger dose of baclofen. There is a statistically significant correlation between the dose of ingested baclofen and the presence of acute respiratory failure, and duration of mechanical ventilation. Patients who have taken a single dose of baclofen of 200 mg, or higher, should be managed in centres able to provide continuous monitoring of life functions. Those with a higher level of a single dose of baclofen ingestion (>500 mg), should be hospitalized in a Toxicology Unit or Intensive Care Unit able to provide airway support and mechanical ventilation.

Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases.

PubMed

Frey, Benjamin; Hehlgans, Stephanie; Rödel, Franz; Gaipl, Udo S

2015-11-28

Inflammation is a homeostatic mechanism aiming to maintain tissue integrity. The underlying immunological mechanisms and the interrelationship between ionizing radiation and inflammation are complex and multifactorial on cellular and chemical levels. On the one hand, radiation with single doses exceeding 1 Gy might initiate inflammatory reactions and thereby impact on tumor development. On the other hand, radiation is capable of attenuating an established inflammatory process, which is clinically used for the treatment of inflammatory and degenerative diseases with low-dose radiotherapy (single dose <1 Gy). At higher doses, ionizing radiation, especially in combination with additional immune stimulation, fosters the induction of immunogenic forms of tumor cell death and shifts the tumor microenvironment as well as the infiltration of immune cells from an anti- to a pro-inflammatory state. Distinct tumor infiltrating immune cells predict the response to radiochemotherapy in a multitude of tumor entities. While a high tumor infiltration of these adaptive immune cells mostly predicts a favorable disease outcome, a high infiltration of tumor-associated macrophages predicts an unfavorable response. Pro-inflammatory events should dominate over anti-inflammatory ones in this scenario. This review focuses on how ionizing radiation modulates inflammatory events in benign inflammatory and in malign diseases. A special focus is set on the role of tumor infiltrating lymphocytes and macrophages as biomarkers to predict treatment response and anti-tumor immunity and on mechanisms implicated in the anti-inflammatory effects of low-dose radiation therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Durable antibody responses following one dose of the bivalent human papillomavirus L1 virus-like particle vaccine in the Costa Rica Vaccine Trial.

PubMed

Safaeian, Mahboobeh; Porras, Carolina; Pan, Yuanji; Kreimer, Aimee; Schiller, John T; Gonzalez, Paula; Lowy, Douglas R; Wacholder, Sholom; Schiffman, Mark; Rodriguez, Ana C; Herrero, Rolando; Kemp, Troy; Shelton, Gloriana; Quint, Wim; van Doorn, Leen-Jan; Hildesheim, Allan; Pinto, Ligia A

2013-11-01

The Costa Rica HPV16/18 Vaccine Trial (CVT) showed that four-year vaccine efficacy against 12-month HPV16/18 persistent infection was similarly high among women who received one, two, or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle (VLP) vaccine. Live-attenuated viral vaccines, but not simple-subunit vaccines, usually induce durable lifelong antibody responses after a single dose. It is unclear whether noninfectious VLP vaccines behave more like live-virus or simple-subunit vaccines in this regard. To explore the likelihood that efficacy will persist longer term, we investigated the magnitude and durability of antibodies to this vaccine by measuring HPV16- and HPV18-specific antibodies by VLP-ELISA using serum from enrollment, vaccination, and annual visits through four years in four vaccinated groups; one-dose (n = 78), two-doses separated by one month (n = 140), two doses separated by six months (n = 52), and three scheduled doses (n = 120, randomly selected). We also tested enrollment sera from n = 113 HPV16- or HPV18 L1-seropositive women prevaccination, presumably from natural infection. At four years, 100% of women in all groups remained HPV16/18 seropositive; both HPV16/18 geometric mean titers (GMT) among the extended two-dose group were non-inferior to the three-dose group, and ELISA titers were highly correlated with neutralization titers in all groups. Compared with the natural infection group, HPV16/18 GMTs were, respectively, at least 24 and 14 times higher among the two-dose and 9 and 5 times higher among one-dose vaccinees. Antibody levels following one-dose remained stable from month 6 through month 48. Results raise the possibility that even a single dose of HPV VLPs will induce long-term protection. ©2013 AACR.

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

PubMed

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

2013-06-01

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

Faecal egg counts and expulsion dynamics of the whipworm, Trichuris trichiura following self-infection.

PubMed

Hansen, E P; Tejedor, A M; Thamsborg, S M; Alstrup Hansen, T V; Dahlerup, J F; Nejsum, P

2016-05-01

More than 400 million humans are estimated to be infected with the intestinal helminth parasite, Trichuris trichiura. The infection is chronic in nature and high-intensity infection can lead to colitis, anaemia, Trichuris Dysentery Syndrome and reduced cognitive performance. Single doses of 400 mg albendazole or 500 mg mebendazole (MBZ) are used in mass drug administration programmes, but this has been shown to be insufficient. In this study, worm expulsion dynamics are described after MBZ treatment, given as a multi-dose and single-dose treatment in two separate T. trichiura self-infection studies. Worm expulsion dynamics post-treatment showed a similar pattern regardless of the dose regime, with the first worms observed on day 2 and the last worms expelled on days 9 and 13 post-treatment. Establishment of a chronic infection was observed following the inefficient single-dose treatment. The prepatent period was 13-16 weeks in both studies and worms were found to have a lifespan of at least 1 year and 10 months. These self-infection studies provide key information on the chronicity of T. trichiura infections, expulsion dynamics after anthelmintic treatment and the prepatent period, as well as the fecundity of female worms, which was around 18,000 eggs/female per day.

Three-dimensional visualization of endolymphatic hydrops after intravenous administration of single-dose gadodiamide.

PubMed

Naganawa, Shinji; Yamazaki, Masahiro; Kawai, Hisashi; Bokura, Kiminori; Sone, Michihiko; Nakashima, Tsutomu

2013-01-01

Endolymphatic hydrops can be visualized with high contrast-to-noise ratio even after intravenous injection of single-dose gadolinium-based contrast material (IV-SD-GBCM) using HYDROPS-Mi2 images. We applied 3-dimensional rendering software to process HYDROPS-Mi2 images of 15 ears with and without suspected Ménière's disease and separately visualized the volumes of endo- and perilymph in patients with Ménière's disease even after IV-SD-GBCM. Such dimensional visualization will aid understanding of the pathophysiology of Ménière's disease.

Palonosetron as an anti-emetic and anti-nausea agent in oncology.

PubMed

Aapro, Matti S

2007-12-01

Palonosetron (Aloxi(®), Onicit(®), Paloxi(®)) is a second-generation 5-HT(3) receptor antagonist (RA) with an extended half-life of ~40 hours and high binding affinity for the 5-HT₃ receptor that is markedly different from other 5-HT(3) RAs. Phase III trials demonstrate that a single dose of palonosetron compared with traditional 5-HT₃ RAs is more effective in preventing chemotherapy-induced nausea and vomiting (CINV) during the first 24 hours following chemotherapy (acute CINV), and also exhibits prolonged efficacy to provide significantly better protection from CINV in the delayed and overall phases. This superior and extended protection from CINV conferred by palonosetron following a single intravenous dose before chemotherapy simplifies dosing schedules. Recent research has focused on optimization of palonosetron-based antiemetic regimens, particularly in combination with steroids and neurokinin-1 RAs. The available clinical data indicate high control rates for palonosetron, suggesting a synergistic potential for protection in patients scheduled to receive emetogenic drug regimens.

Long-term Pulmonary Responses to Quadweekly Intermittent Intratracheal Spray Instillations of Magnetite (Fe3O4) Nanoparticles for 52 Weeks in Fischer 344 Rats.

PubMed

Tada, Yukie; Yano, Norio; Takahashi, Hiroshi; Yuzawa, Katsuhiro; Ando, Hiroshi; Kubo, Yoshikazu; Nagasawa, Akemichi; Inomata, Akiko; Ogata, Akio; Nakae, Dai

2013-12-01

Information about potential risks of iron nanomaterials is still limited, while a wide variety of applications are expected. We recently reported acute phase responses of male and female Fischer 344 rats after a single intratracheal spray instillation of Fe3O4 nanoparticles (magnetite), clearly showing dose-dependent pulmonary inflammatory changes (Tada et al., J Toxicol Pathol 25, 233-239, 2012). The present study assessed long-term responses of male and female Fischer 344 rats to multiple administrations of magnetite. Ten-week-old male and female Fischer 344 rats (n=20/group) were exposed to a total of 13 quadweekly intermittent intratracheal spray instillations of magnetite during the experimental period of 52 weeks, at doses of 0, 0.2 (low), 1.0 (medium) and 5.0 (high-dose) mg/kg body weight per administration. Absolute and relative lung weights of the high-dose group were significantly higher than those of the control group. Macroscopically, slight enlargement and scattered black patches were recognized in the lungs and the lung-associated lymph nodes of the high-dose group. Histopathologically, infiltration of macrophages phagocytosing magnetite (all dose groups) and of chronic inflammatory cells (medium- and high-dose males and high-dose females), alveolar bronchiolization and granuloma (high-dose group) were observed. In addition, alveolar hyperplasias were observed in some rats of the high-dose group, and cytoplasmic overexpression of β-catenin protein was immunohistochemically found in such lesions. The present results clearly show that instilled magnetite causes chronic inflammatory responses in the lung. These responses occur in a dose-dependent manner without apparent differences among sexes.

Long-term mesalamine maintenance in ulcerative colitis: which is more important? Adherence or daily dose.

PubMed

Khan, Nabeel; Abbas, Ali M; Koleva, Yordanka N; Bazzano, Lydia A

2013-05-01

There are limited data about the long-term follow-up of patients with ulcerative colitis (UC) maintained on high versus low doses of mesalamine. We evaluated the best long-term average daily dose that would keep the disease in remission. Nationwide ulcerative colitis data were obtained from the Veterans Affairs health care system for the period 2001 to 2011. Those who started mesalamine maintenance during this period were included. Average daily dose and the level of adherence were assessed for the period between the first mesalamine dispense and the date of first flare defined as the first filling of 40 mg/day or more of oral prednisone or any dose of intravenous steroids. Patients with ulcerative colitis maintained on an average daily dose 2.4 to 2.8 g/day (low dose) were compared with 4.4 to 4.8 g/day (high dose). Adherence was assessed using continuous single interval medication availability indicator. We included 4452 patients with a median follow-up of 6 years. There was no significant reduction in the risk of flares when comparing high versus low average mesalamine dose among patients with high [hazard ratio = 0.96, P = 0.8)] and medium (hazard ratio = 0.74, P = 0.17) adherence. However, there was a significant reduction in the risk of flares with high dose of mesalamine among patients with low adherence (hazard ratio = 0.28, P = 0.003). Our data show that when starting a patient on mesalamine, there is no difference in the long-term flare risk between low versus high average daily dose as long as the patients have a high to moderate level of adherence.

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.

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.

Poster - 08: Preliminary Investigation into Collapsed-Cone based Dose Calculations for COMS Eye Plaques

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

Morrison, Hali; Menon, Geetha; Sloboda, Ron

Purpose: To investigate the accuracy of model-based dose calculations using a collapsed-cone algorithm for COMS eye plaques loaded with I-125 seeds. Methods: The Nucletron SelectSeed 130.002 I-125 seed and the 12 mm COMS eye plaque were incorporated into a research version of the Oncentra® Brachy v4.5 treatment planning system which uses the Advanced Collapsed-cone Engine (ACE) algorithm. Comparisons of TG-43 and high-accuracy ACE doses were performed for a single seed in a 30×30×30 cm{sup 3} water box, as well as with one seed in the central slot of the 12 mm COMS eye plaque. The doses along the plaque centralmore » axis (CAX) were used to calculate the carrier correction factor, T(r), and were compared to tabulated and MCNP6 simulated doses for both the SelectSeed and IsoAid IAI-125A seeds. Results: The ACE calculated dose for the single seed in water was on average within 0.62 ± 2.2% of the TG-43 dose, with the largest differences occurring near the end-welds. The ratio of ACE to TG-43 calculated doses along the CAX (T(r)) of the 12 mm COMS plaque for the SelectSeed was on average within 3.0% of previously tabulated data, and within 2.9% of the MCNP6 simulated values. The IsoAid and SelectSeed T(r) values agreed within 0.3%. Conclusions: Initial comparisons show good agreement between ACE and MC doses for a single seed in a 12 mm COMS eye plaque; more complicated scenarios are being investigated to determine the accuracy of this calculation method.« less

Primaquine or other 8-aminoquinoline for reducing Plasmodium falciparum transmission

PubMed Central

Graves, Patricia M; Gelband, Hellen; Garner, Paul

2015-01-01

Background Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person's blood. Plasmodium falciparum gametocytes are sensitive to the drug primaquine (PQ) and other 8-aminoquinolines (8AQ); these drugs could prevent parasite transmission from infected people to mosquitoes, and consequently reduce the incidence of malaria. However, PQ will not directly benefit the individual, and could be harmful to those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In 2010, The World Health Organization (WHO) recommended a single dose of PQ at 0.75 mg/kg, alongside treatment for P. falciparum malaria to reduce transmission in areas approaching malaria elimination. In 2013 the WHO revised this to 0.25 mg/kg due to concerns about safety. Objectives To assess whether giving PQ or an alternative 8AQ alongside treatment for P. falciparum malaria reduces malaria transmission, and to estimate the frequency of severe or haematological adverse events when PQ is given for this purpose. Search methods We searched the following databases up to 10 Feb 2014 for trials: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; metaRegister of Controlled Trials (mRCT); and the WHO trials search portal using 'malaria*', 'falciparum', and 'primaquine' as search terms. In addition, we searched conference proceedings and reference lists of included studies, and contacted researchers and organizations. Selection criteria Randomized controlled trials (RCTs) or quasi-RCTs comparing PQ (or alternative 8AQ) given as a single dose or short course alongside treatment for P. falciparum malaria with malaria treatment given without PQ/8AQ in adults or children. Data collection and analysis Two authors independently screened all abstracts, applied inclusion criteria, and extracted data. We sought evidence of an impact on transmission (community incidence), infectiousness (mosquitoes infected from humans) and potential infectiousness (gametocyte measures). We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available. We sought data on haematological and other adverse effects, as well as secondary outcomes of asexual clearance time and recrudescence. We stratified by whether the malaria treatment regimen included an artemisinin derivative or not; by PQ dose category (low < 0.4 mg/kg; medium ≥ 0.4 to < 0.6 mg/kg; high ≥ 0.6 mg/kg); and by PQ schedules. We used the GRADE approach to assess evidence quality. Main results We included 17 RCTs and one quasi-RCT. Eight studies tested for G6PD status: six then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and one included all irrespective of status. The remaining ten trials either did not report on whether they tested (8), or reported that they did not test (2). Nine trials included study arms with artemisinin-based malaria treatment regimens, and eleven included study arms with non-artemisinin-based treatments. Only two trials evaluated PQ given at low doses (0.25 mg/kg in one and 0.1 mg/kg in the other). PQ with artemisinin-based treatments: No trials evaluated effects on malaria transmission directly (incidence, prevalence, or entomological inoculation rate), and none evaluated infectiousness to mosquitoes. For potential infectiousness, the proportion of people with detectable gametocytaemia on day eight was reduced by around two thirds with high dose PQ category (RR 0.29, 95% CI 0.22 to 0.37, seven trials, 1380 participants, high quality evidence), and with medium dose PQ category (RR 0.34, 95% CI 0.19 to 0.59, two trials, 269 participants, high quality evidence), but the trial evaluating low dose PQ category (0.1 mg/kg) did not demonstrate an effect (RR 0.67, 95% CI 0.44 to 1.02, one trial, 223 participants, low quality evidence). Reductions in log(10)AUC estimates for gametocytaemia on days 1 to 43 with medium and high doses ranged from 24.3% to 87.5%. For haemolysis, one trial reported percent change in mean haemoglobin against baseline, and did not detect a difference between the two arms (very low quality evidence). PQ with non-artemisinin treatments: No trials assessed effects on malaria transmission directly. Two small trials from the same laboratory evaluated infectiousness to mosquitoes, and report that infectivity was eliminated on day 8 in 15/15 patients receiving high dose PQ compared to 1/15 in the control group (low quality evidence). For potential infectiousness, the proportion of people with detectable gametocytaemia on day 8 was reduced by around half with high dose PQ category (RR 0.44, 95% CI 0.27 to 0.70, three trials, 206 participants, high quality evidence), and by around a third with medium dose category (RR 0.62, 0.50 to 0.76, two trials, 283 participants, high quality evidence), but the single trial using low dose PQ category did not demonstrate a difference between groups (one trial, 59 participants, very low quality evidence). Reduction in log(10)AUC for gametocytaemia days 1 to 43 were 24.3% and 27.1% for two arms in one trial giving medium dose PQ. No trials systematically sought evidence of haemolysis. Two trials evaluated the 8AQ bulaquine, and suggest the effects may be greater than PQ, but the small number of participants (n = 112) preclude a definite conclusion. Authors' conclusions In individual patients, PQ added to malaria treatments reduces gametocyte prevalence when given in doses greater than 0.4 mg/kg. Whether this translates into preventing people transmitting malaria to mosquitoes has rarely been tested in controlled trials, but there appeared to be a strong reduction in infectiousness in the two small studies that evaluated this. No included trials evaluated whether this policy has an impact on community malaria transmission either in low-endemic settings approaching elimination, or in highly-endemic settings where many people are infected but have no symptoms and are unlikely to be treated. For the currently recommended low dose regimen, there is little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved. Most trials excluded people with G6PD deficiency, and thus there is little reliable evidence from controlled trials of the safety of PQ in single dose or short course. PLAIN LANGUAGE SUMMARY A single dose of primaquine added to malaria treatment to prevent malaria transmission We conducted a review of the effects of adding a single dose (or short course) of primaquine to malaria treatment with the aim of reducing the transmission of malaria. We included 17 randomized controlled trials and one quasi-randomized controlled trial. What is primaquine and how might it reduce transmission Primaquine is an antimalarial drug which does not cure malaria illness, but is known to kill the gametocyte stage of the malaria parasite which infects mosquitoes when they bite humans. Primaquine is also known to have potentially serious side effects in people with an enzyme deficiency common in many malaria endemic settings (glucose-6-phosphate dehydrogenase (G6PD) deficiency). In these people, high doses of primaquine given over several days sometimes destroys red blood cells, causing anaemia and, in some cases, possibly life-threatening effects. The World Health Organization (WHO) recommends adding a single dose of primaquine to malaria treatment with the intention of reducing malaria transmission and to contribute to malaria elimination. This recommendation was made in 2010, but in 2013 the WHO amended its recommendation from a dose of 0.75 mg/kg to 0.25 mg/kg due to concerns about safety, and indirect evidence suggesting this was as effective as the higher dose.This review examines the evidence of benefits and harms of using primaquine in this way, and looks for evidence that primaquine will reduce malaria transmission in communities. What the research says We did not find any studies that tested whether primaquine added to malaria treatment reduces the community transmission of malaria. When added to current treatments for malaria (artemisinin-based combination therapy), we found no studies evaluating the effects of primaquine on the number of mosquitoes infected. However, primaquine does reduce the duration of infectiousness (the period that gametocytes are detected circulating in the blood) when given at doses of 0.4 mg/kg or above (high quality evidence). We only found one study using 0.1 mg/kg but this study did not conclusively show that primaquine was still effective at this dose (low quality evidence). When added to older treatments for malaria, two studies showed that primaquine at doses of 0.75 mg/kg reduced the number of mosquitoes infected after biting humans (low quality evidence). Doses above 0.4 mg/kg reduced the duration of detectable gametocytes (high quality evidence), but in a single study of the currently recommended 0.25 mg/kg no effect was demonstrated (very low quality evidence). Some studies excluded patients with G6PD deficiency, some included them, and some did not comment. Overall the safety of PQ given as a single dose was poorly evaluated across all studies, so these data do not demonstrate whether the drug is safe or potentially harmful at this dosing level. PMID:25693791

Primaquine or other 8-aminoquinoline for reducing P. falciparum transmission

PubMed Central

Graves, Patricia M; Gelband, Hellen; Garner, Paul

2014-01-01

Background Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person's blood. Plasmodium falciparum gametocytes are sensitive to the drug primaquine (PQ) and other 8-aminoquinolines (8AQ); these drugs could prevent parasite transmission from infected people to mosquitoes, and consequently reduce the incidence of malaria. However, PQ will not directly benefit the individual, and could be harmful to those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In 2010, The World Health Organization (WHO) recommended a single dose of PQ at 0.75 mg/kg, alongside treatment for P. falciparum malaria to reduce transmission in areas approaching malaria elimination. In 2013 the WHO revised this to 0.25 mg/kg due to concerns about safety. Objectives To assess whether giving PQ or an alternative 8AQ alongside treatment for P. falciparum malaria reduces malaria transmission, and to estimate the frequency of severe or haematological adverse events when PQ is given for this purpose. Search methods We searched the following databases up to 10 Feb 2014 for trials: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; metaRegister of Controlled Trials (mRCT); and the WHO trials search portal using 'malaria*', 'falciparum', and 'primaquine' as search terms. In addition, we searched conference proceedings and reference lists of included studies, and contacted researchers and organizations. Selection criteria Randomized controlled trials (RCTs) or quasi-RCTs comparing PQ (or alternative 8AQ) given as a single dose or short course alongside treatment for P. falciparum malaria with malaria treatment given without PQ/8AQ in adults or children. Data collection and analysis Two authors independently screened all abstracts, applied inclusion criteria, and extracted data. We sought evidence of an impact on transmission (community incidence), infectiousness (mosquitoes infected from humans) and potential infectiousness (gametocyte measures). We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available. We sought data on haematological and other adverse effects, as well as secondary outcomes of asexual clearance time and recrudescence. We stratified by whether the malaria treatment regimen included an artemisinin derivative or not; by PQ dose category (low < 0.4 mg/kg; medium ≥ 0.4 to < 0.6 mg/kg; high ≥ 0.6 mg/kg); and by PQ schedules. We used the GRADE approach to assess evidence quality. Main results We included 17 RCTs and one quasi-RCT. Eight studies tested for G6PD status: six then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and one included all irrespective of status. The remaining ten trials either did not report on whether they tested (8), or reported that they did not test (2). Nine trials included study arms with artemisinin-based malaria treatment regimens, and eleven included study arms with non-artemisinin-based treatments. Only two trials evaluated PQ given at low doses (0.25 mg/kg in one and 0.1 mg/kg in the other). PQ with artemisinin-based treatments: No trials evaluated effects on malaria transmission directly (incidence, prevalence, or entomological inoculation rate), and none evaluated infectiousness to mosquitoes. For potential infectiousness, the proportion of people with detectable gametocytaemia on day eight was reduced by around two thirds with high dose PQ category (RR 0.29, 95% CI 0.22 to 0.37, seven trials, 1380 participants, high quality evidence), and with medium dose PQ category (RR 0.34, 95% CI 0.19 to 0.59, two trials, 269 participants, high quality evidence), but the trial evaluating low dose PQ category (0.1 mg/kg) did not demonstrate an effect (RR 0.67, 95% CI 0.44 to 1.02, one trial, 223 participants, low quality evidence). Reductions in log(10)AUC estimates for gametocytaemia on days 1 to 43 with medium and high doses ranged from 24.3% to 87.5%. For haemolysis, one trial reported percent change in mean haemoglobin against baseline, and did not detect a difference between the two arms (very low quality evidence). PQ with non-artemisinin treatments: No trials assessed effects on malaria transmission directly. Two small trials from the same laboratory evaluated infectiousness to mosquitoes, and report that infectivity was eliminated on day 8 in 15/15 patients receiving high dose PQ compared to 1/15 in the control group (low quality evidence). For potential infectiousness, the proportion of people with detectable gametocytaemia on day 8 was reduced by around half with high dose PQ category (RR 0.44, 95% CI 0.27 to 0.70, three trials, 206 participants, high quality evidence), and by around a third with medium dose category (RR 0.62, 0.50 to 0.76, two trials, 283 participants, high quality evidence), but the single trial using low dose PQ category did not demonstrate a difference between groups (one trial, 59 participants, very low quality evidence). Reduction in log(10)AUC for gametocytaemia days 1 to 43 were 24.3% and 27.1% for two arms in one trial giving medium dose PQ. No trials systematically sought evidence of haemolysis. Two trials evaluated the 8AQ bulaquine, and suggest the effects may be greater than PQ, but the small number of participants (n = 112) preclude a definite conclusion. Authors' conclusions In individual patients, PQ added to malaria treatments reduces gametocyte prevalence when given in doses greater than 0.4 mg/kg. Whether this translates into preventing people transmitting malaria to mosquitoes has rarely been tested in controlled trials, but there appeared to be a strong reduction in infectiousness in the two small studies that evaluated this. No included trials evaluated whether this policy has an impact on community malaria transmission either in low-endemic settings approaching elimination, or in highly-endemic settings where many people are infected but have no symptoms and are unlikely to be treated. For the currently recommended low dose regimen, there is little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved. Most trials excluded people with G6PD deficiency, and thus there is little reliable evidence from controlled trials of the safety of PQ in single dose or short course. PLAIN LANGUAGE SUMMARY A single dose of primaquine added to malaria treatment to prevent malaria transmission We conducted a review of the effects of adding a single dose (or short course) of primaquine to malaria treatment with the aim of reducing the transmission of malaria. We included 17 randomized controlled trials and one quasi-randomized controlled trial. What is primaquine and how might it reduce transmission Primaquine is an antimalarial drug which does not cure malaria illness, but is known to kill the gametocyte stage of the malaria parasite which infects mosquitoes when they bite humans. Primaquine is also known to have potentially serious side effects in people with an enzyme deficiency common in many malaria endemic settings (glucose-6-phosphate dehydrogenase (G6PD) deficiency). In these people, high doses of primaquine given over several days sometimes destroys red blood cells, causing anaemia and, in some cases, possibly life-threatening effects. The World Health Organization (WHO) recommends adding a single dose of primaquine to malaria treatment with the intention of reducing malaria transmission and to contribute to malaria elimination. This recommendation was made in 2010, but in 2013 the WHO amended its recommendation from a dose of 0.75 mg/kg to 0.25 mg/kg due to concerns about safety, and indirect evidence suggesting this was as effective as the higher dose.This review examines the evidence of benefits and harms of using primaquine in this way, and looks for evidence that primaquine will reduce malaria transmission in communities. What the research says We did not find any studies that tested whether primaquine added to malaria treatment reduces the community transmission of malaria. When added to current treatments for malaria (artemisinin-based combination therapy), we found no studies evaluating the effects of primaquine on the number of mosquitoes infected. However, primaquine does reduce the duration of infectiousness (the period that gametocytes are detected circulating in the blood) when given at doses of 0.4 mg/kg or above (high quality evidence). We only found one study using 0.1 mg/kg but this study did not conclusively show that primaquine was still effective at this dose (low quality evidence). When added to older treatments for malaria, two studies showed that primaquine at doses of 0.75 mg/kg reduced the number of mosquitoes infected after biting humans (low quality evidence). Doses above 0.4 mg/kg reduced the duration of detectable gametocytes (high quality evidence), but in a single study of the currently recommended 0.25 mg/kg no effect was demonstrated (very low quality evidence). Some studies excluded patients with G6PD deficiency, some included them, and some did not comment. Overall the safety of PQ given as a single dose was poorly evaluated across all studies, so these data do not demonstrate whether the drug is safe or potentially harmful at this dosing level. PMID:24979199

Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization

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

Song, Changhoon; Hong, Beom-Ju; Bok, Seoyeon

Purpose: To investigate the serial changes of tumor hypoxia in response to single high-dose irradiation by various clinical and preclinical methods to propose an optimal fractionation schedule for stereotactic ablative radiation therapy. Methods and Materials: Syngeneic Lewis lung carcinomas were grown either orthotopically or subcutaneously in C57BL/6 mice and irradiated with a single dose of 15 Gy to mimic stereotactic ablative radiation therapy used in the clinic. Serial [{sup 18}F]-misonidazole (F-MISO) positron emission tomography (PET) imaging, pimonidazole fluorescence-activated cell sorting analyses, hypoxia-responsive element-driven bioluminescence, and Hoechst 33342 perfusion were performed before irradiation (day −1), at 6 hours (day 0), and 2 (daymore » 2) and 6 (day 6) days after irradiation for both subcutaneous and orthotopic lung tumors. For F-MISO, the tumor/brain ratio was analyzed. Results: Hypoxic signals were too low to quantitate for orthotopic tumors using F-MISO PET or hypoxia-responsive element-driven bioluminescence imaging. In subcutaneous tumors, the maximum tumor/brain ratio was 2.87 ± 0.483 at day −1, 1.67 ± 0.116 at day 0, 2.92 ± 0.334 at day 2, and 2.13 ± 0.385 at day 6, indicating that tumor hypoxia was decreased immediately after irradiation and had returned to the pretreatment levels at day 2, followed by a slight decrease by day 6 after radiation. Pimonidazole analysis also revealed similar patterns. Using Hoechst 33342 vascular perfusion dye, CD31, and cleaved caspase 3 co-immunostaining, we found a rapid and transient vascular collapse, which might have resulted in poor intratumor perfusion of F-MISO PET tracer or pimonidazole delivered at day 0, leading to decreased hypoxic signals at day 0 by PET or pimonidazole analyses. Conclusions: We found tumor hypoxia levels decreased immediately after delivery of a single dose of 15 Gy and had returned to the pretreatment levels 2 days after irradiation and had decreased slightly by day 6. Our results indicate that single high-dose irradiation can produce a rapid, but reversible, vascular collapse in tumors.« less

Long-term evaluation of mucosal and systemic immunity and protection conferred by different polio booster vaccines.

PubMed

Xiao, Yuhong; Daniell, Henry

2017-09-25

Oral polio vaccine (OPV) and Inactivated Polio Vaccine (IPV) have distinct advantages and limitations. IPV does not provide mucosal immunity and introduction of IPV to mitigate consequences of circulating vaccine-derived polio virus from OPV has very limited effect on transmission and OPV campaigns are essential for interrupting wild polio virus transmission, even in developed countries with a high coverage of IPV and protected sewer systems. The problem is magnified in many countries with limited resources. Requirement of refrigeration for storage and transportation for both IPV and OPV is also a major challenge in developing countries. Therefore, we present here long-term studies on comparison of a plant-based booster vaccine, which is free of virus and cold chain with IPV boosters and provide data on mucosal and systemic immunity and protection conferred by neutralizing antibodies. Mice were primed subcutaneously with IPV and boosted orally with lyophilized plant cells containing 1μg or 25μg polio viral protein 1 (VP1), once a month for three months or a single booster one year after the first prime. Our results show that VP1-IgG1 titers in single or double dose IPV dropped to background levels after one year of immunization. This decrease correlated with >50% reduction in seropositivity in double dose and <10% seropositivity in single dose IPV against serotype 1. Single dose IPV offered no or minimal protection against serotype 1 and 2 but conferred protection against serotype 3. VP1-IgA titers were negligible in IPV single or double dose vaccinated mice. VP1 antigen with two plant-derived adjuvants induced significantly high level and long lasting VP1-IgG1, IgA and neutralizing antibody titers (average 4.3-6.8 log2 titers). Plant boosters with VP1 and plant derived adjuvants maintained the same level titers from 29 to 400days and conferred the same level of protection against all three serotypes throughout the duration of this study. Even during period, when no plant booster was given (∼260days), VP1-IgG1 titers were maintained at high levels. Lyophilized plant cells expressing VP1 can be stored without losing efficacy, eliminating cold chain. Virus-free, cold-chain free vaccine is ready for further clinical development. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

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.

A 0.18 micrometer CMOS Thermopile Readout ASIC Immune to 50 MRAD Total Ionizing Dose (SI) and Single Event Latchup to 174MeV-cm(exp 2)/mg

NASA Technical Reports Server (NTRS)

Quilligan, Gerard T.; Aslam, Shahid; Lakew, Brook; DuMonthier, Jeffery J.; Katz, Richard B.; Kleyner, Igor

2014-01-01

Radiation hardened by design (RHBD) techniques allow commercial CMOS circuits to operate in high total ionizing dose and particle fluence environments. Our radiation hard multi-channel digitizer (MCD) ASIC (Figure 1) is a versatile analog system on a chip (SoC) fabricated in 180nm CMOS. It provides 18 chopper stabilized amplifier channels, a 16- bit sigma-delta analog-digital converter (SDADC) and an on-chip controller. The MCD was evaluated at Goddard Space Flight Center and Texas A&M University's radiation effects facilities and found to be immune to single event latchup (SEL) and total ionizing dose (TID) at 174 MeV-cm(exp 2)/mg and 50 Mrad (Si) respectively.

Single Event Effects and Total Dose Testing of the Intersil ISL 70003SEH Integrated Point of Load Converter

NASA Astrophysics Data System (ADS)

van Vonno, N. W.; White, J. D.; Pearce, L. G.; Thomson, E. J.; Gill, J. S.; Mansilla, O. E.

2014-08-01

Single-event transient (SET) phenomena in power management applications has evolved into a key issue, particularly in point of load (POL) buck regulators, as the loads driven by these devices are sensitive to even short-term overvoltage conditions. We preface this paper by a discussion of earlier destructive and nondestructive SEE testing of Intersil integrated point of load regulators, with emphasis on SET phenomena and some of the lessons learned in this work. We then report recent results of SET and destructive SEE testing of the ISL70003SEH POL converter, together with a brief discussion of the part's electrical and radiation hardness specifications. We conclude with a brief overview of low and high dose rate total dose testing of the part.

A review of immunogenicity and tolerability of live attenuated Hepatitis A vaccine in children.

PubMed

Rao, Sameer; Mao, J S; Motlekar, Salman; Fangcheng, Zhuang; Kadhe, Ganesh

2016-12-01

Changing epidemiology of Hepatitis A virus (HAV) has led to an increased susceptibility of adolescents and adults to the infection. Vaccination can remarkably reduce the incidence and associated morbidity of HAV infection. This review is focused on the safety and efficacy of H2 strain derived live attenuated Hepatitis A vaccine. We found the vaccine to be highly immunogenic with minimal or negligible safety issues. Moreover, a single dose of live attenuated vaccine persists a long term immune response and can be a preferred option for developing countries. In 2014, Indian Academy of Paediatrics (IAP) also updated their recommendations for H2 vaccine as a single dose as against the previous 2 dose schedule. A focused approach to include the vaccine in national immunization program should be explored.

Fast, high-resolution 3D dosimetry utilizing a novel optical-CT scanner incorporating tertiary telecentric collimation

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

Sakhalkar, H. S.; Oldham, M.

2008-01-15

This study introduces a charge coupled device (CCD) area detector based optical-computed tomography (optical-CT) scanner for comprehensive verification of radiation dose distributions recorded in nonscattering radiochromic dosimeters. Defining characteristics include: (i) a very fast scanning time of {approx}5 min to acquire a complete three-dimensional (3D) dataset, (ii) improved image formation through the use of custom telecentric optics, which ensures accurate projection images and minimizes artifacts from scattered and stray-light sources, and (iii) high resolution (potentially 50 {mu}m) isotropic 3D dose readout. The performance of the CCD scanner for 3D dose readout was evaluated by comparison with independent 3D readout frommore » the single laser beam OCTOPUS-scanner for the same PRESAGE dosimeters. The OCTOPUS scanner was considered the 'gold standard' technique in light of prior studies demonstrating its accuracy. Additional comparisons were made against calculated dose distributions from the ECLIPSE treatment-planning system. Dose readout for the following treatments were investigated: (i) a single rectangular beam irradiation to investigate small field and very steep dose gradient dosimetry away from edge effects, (ii) a 2-field open beam parallel-opposed irradiation to investigate dosimetry along steep dose gradients, and (iii) a 7-field intensity modulated radiation therapy (IMRT) irradiation to investigate dosimetry for complex treatment delivery involving modulation of fluence and for dosimetry along moderate dose gradients. Dose profiles, dose-difference plots, and gamma maps were employed to evaluate quantitative estimates of agreement between independently measured and calculated dose distributions. Results indicated that dose readout from the CCD scanner was in agreement with independent gold-standard readout from the OCTOPUS-scanner as well as the calculated ECLIPSE dose distribution for all treatments, except in regions within a few millimeters of the edge of the dosimeter, where edge artifact is predominant. Agreement of line profiles was observed, even along steep dose gradients. Dose difference plots indicated that the CCD scanner dose readout differed from the OCTOPUSscanner readout and ECLIPSE calculations by {approx}10% along steep dose gradients and by {approx}5% along moderate dose gradients. Gamma maps (3% dose-difference and 3 mm distance-to-agreement acceptance criteria) revealed agreement, except for regions within 5 mm of the edge of the dosimeter where the edge artifact occurs. In summary, the data demonstrate feasibility of using the fast, high-resolution CCD scanner for comprehensive 3D dosimetry in all applications, except where dose readout is required close to the edges of the dosimeter. Further work is ongoing to reduce this artifact.« less

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…

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial

PubMed Central

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-01-01

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD. PMID:27552585

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial.

PubMed

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-08-23

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

SU-E-T-10: A Clinical Implementation and the Dosimetric Evidence in High Dose Rate Vaginal Multichannel Applicator Brachytherapy

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

Syh, J; Syh, J; Patel, B

2015-06-15

Purpose: The multichannel cylindrical applicator has a distinctive modification of the traditional single channel cylindrical applicator. The novel multichannel applicator has additional peripheral channels that provide more flexibility both in treatment planning process and outcomes. To protect by reducing doses to adjacent organ at risk (OAR) while maintaining target coverage with inverse plan optimization are the goals for such novel Brachytherapy device. Through a series of comparison and analysis of reults in more than forty patients who received HDR Brachytherapy using multichannel vaginal applicator, this procedure has been implemented in our institution. Methods: Multichannel planning was CT image based. Themore » CTV of 5mm vaginal cuff rind with prescribed length was well reconstructed as well as bladder and rectum. At least D95 of CTV coverage is 95% of prescribed dose. Multichannel inverse plan optimization algorithm not only shapes target dose cloud but set dose avoids to OAR’s exclusively. The doses of D2cc, D5cc and D5; volume of V2Gy in OAR’s were selected to compare with single channel results when sole central channel is only possibility. Results: Study demonstrates plan superiorly in OAR’s doe reduction in multi-channel plan. The D2cc of the rectum and bladder were showing a little lower for multichannel vs. single channel. The V2Gy of the rectum was 93.72% vs. 83.79% (p=0.007) for single channel vs. multichannel respectively. Absolute reduced mean dose of D5 by multichannel was 17 cGy (s.d.=6.4) and 44 cGy (s.d.=15.2) in bladder and rectum respectively. Conclusion: The optimization solution in multichannel was to maintain D95 CTV coverage while reducing the dose to OAR’s. Dosimetric advantage in sparing critical organs by using a multichannel applicator in HDR Brachytherapy treatment of the vaginal cuff is so promising and has been implemented clinically.« less

Single-dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection With Vibrio cholerae O1 El Tor.

PubMed

Chen, Wilbur H; Cohen, Mitchell B; Kirkpatrick, Beth D; Brady, Rebecca C; Galloway, David; Gurwith, Marc; Hall, Robert H; Kessler, Robert A; Lock, Michael; Haney, Douglas; Lyon, Caroline E; Pasetti, Marcela F; Simon, Jakub K; Szabo, Flora; Tennant, Sharon; Levine, Myron M

2016-06-01

No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance.PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model. Consenting healthy adult volunteers, 18-45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 × 10(8) colony-forming units [CFU]) or placebo in double-blind fashion. Volunteers ingested approximately 1 × 10(5) CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration. The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (≥3.0 L) to severe (≥5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P < .0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P < .0001). The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine. NCT01895855. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Absolute Bioavailability and Effect of Food on the Disposition of Safinamide Immediate Release Tablets in Healthy Adult Subjects.

PubMed

Seithel-Keuth, Annick; Johne, Andreas; Freisleben, Achim; Kupas, Katrin; Lissy, Michael; Krösser, Sonja

2013-01-01

The objectives of this study were to establish the basic intravenous (IV) single-dose PK of safinamide and its major human metabolites, the absolute bioavailability (BA) and food effect on safinamide tablets. Fourteen healthy adult male and female subjects received 50 mg safinamide single-dose treatments according to a randomized, 3-period, 2-sequence crossover design: immediate release (IR) tablets, administered after an overnight fast and after a standardized high-fat, high-calorie breakfast, and IV solution, administered over 30 minutes. Treatments were separated by wash-out intervals of at least 17 days. Serial blood samples were collected for 240 hours postdosing to evaluate safinamide parent drug and metabolite concentrations for the determination of PK parameters. The absolute BA of safinamide 50 mg IR tablets was high, with geoMean AUC0-∞ ratios of about 95% (90% CI: 90-99%) indicating that safinamide is virtually completely absorbed after oral administration. Safinamide IR tablets did not display a food effect on exposure parameters; both 90% CIs for the ratios fed/fasted of AUC0-∞ and Cmax were entirely within the bioequivalence acceptance margins of 80-125%. Only tmax was delayed by about 30% in the fed state. Oral and IV safinamide 50 mg single-dose administrations were generally well tolerated. © The Author(s) 2013.

A study of dose-proportionality in the pharmacokinetics of the oral direct renin inhibitor aliskiren in healthy subjects.

PubMed

Limoges, D; Dieterich, H A; Yeh, C-M; Vaidyanathan, S; Howard, D; Dole, W P

2008-05-01

To evaluate the dose-proportionality of the pharmacokinetics of aliskiren, the first in a new class of orally active direct renin inhibitors approved for the treatment of hypertension. This was an open-label, single-center, single-dose, randomized, 4-period crossover study. Following a 21-day screening period, 32 healthy male or female subjects (ages 18 - 45 years) were randomized to 1 of 4 aliskiren dosing sequence groups (8 subjects per group): 75, 150, 300 and 600 mg. Blood samples were obtained for determination of plasma aliskiren concentrations (HPLC/MS/MS) for 96 h post dose. Log-transformed pharmacokinetic parameters AUC and C(max) were analyzed to determine dose-proportionality using the power model, parameter = A*(Dose)(beta), where A = intercept and beta = dose-proportionality coefficient. The predefined dose-proportionality criteria over the dose range 75 â 600 mg were 90% confidence intervals (CI) for beta contained within the range 0.89 - 1.11. AUC and Cmax values increased with increasing doses of aliskiren. Both AUC and C(max) were associated with high variability (coefficient of variation 55 - 64% for AUC and 59 - 117% for C(max)). The estimated proportionality coefficients (beta) for AUC(0-infiniti), AUC(0-t) and C(max) were 1.18 (90% CI 1.10, 1.25), 1.29 (90% CI 1.22, 1.36) and 1.42 (90% CI 1.31, 1.52), respectively. Dose-proportionality was, therefore, not demonstrated across the entire 8-fold dose range. For the clinical dose range of 150 â 300 mg, increases of 2.3- and 2.6-fold were observed for AUC and C(max), respectively. All doses of aliskiren were well tolerated. Exposure to aliskiren was greater than proportional over the dose range of 75 - 600 mg. Over the therapeutic dose range of 150 â 300 mg approved for the treatment of hypertension, AUC and Cmax increased by 2.3- and 2.6-fold, respectively. The pharmacokinetics of aliskiren show relatively high intersubject variability.

SU-F-T-625: Optimal Treatment Planning Strategy Among Arc Arrangements for Prostate SBRT with VMAT Technique

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

Chung, J; Kim, J; Eom, K

Purpose: The purpose of this study is to determine the optimal treatment planning strategy among the different arc arrangements for prostate stereotactic body radiotherapy (SBRT) plans with volumetric modulated arc therapy (VMAT). Methods: Ten patients with prostate cancer were selected. The SBRT-VMAT plans for each patient were generated with single-full (181° to 179°; 1FA), single-partial (240° to 120°; 1PA), double-full (181° to 179° and 179° to 181°; 2FA), and double-partial (240° to 120° and 120° to 240°; 2PA) arc arrangements. The prescription dose was 42.7 Gy in 7 fractions. Dose distribution was calculated using a 10-MV flattening-filter-free beam and themore » Acuros XB algorithm. Dosimetric parameters of target volume and organs at risk (OARs) were evaluated from cumulative dose-volume histograms on prostate SBRT-VMAT plans between single-arc (1FA and 1PA) and double-arc (2FA and 2PA) arrangements. Results: All plans using four arc arrangements were highly conformal with conformity index (CI)<1.05 and conformation number (CN)=0.91, and the doses to target volume were homogeneous (homogeneity index (HI)= 0.09 0.12). Pertaining to the dose to the OARs, there were significant differences in the rectum, left and right femoral head doses while having no difference in the bladder dose. The partial-arc (1PA and 2PA) had relatively high reductions for the mean rectum dose compared to full-arc (1FA and 2FA). The near-to-maximum dose (D2%) and mean dose of the left and right femoral head were always lower on prostate SBRT-VMAT plan using the full-arc, when compared to the partial-arc arrangement. Conclusion: This study confirmed that prostate SBRT-VMAT using 1PA was feasible fast delivery time and produced equivalent target coverage and better rectum sparing, although the D2% and mean dose of the left and right femoral head increased slightly. Therefore, the results of this study suggest that the use of 1PA is an attractive choice for delivering prostate SBRT-VMAT.« less

Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings.

PubMed

Keyserling, Constance H; Barbaras, Ronald; Benghozi, Renee; Dasseux, Jean-Louis

2017-05-01

CER-001 comprises recombinant human apolipoprotein A-I complexed with phospholipids that mimics natural, nascent, pre-β high-density lipoprotein (HDL). We present animal model data showing dose-dependent increases in cholesterol efflux with CER-001 and its subsequent elimination by reverse lipid transport, together with inhibition of atherosclerotic plaque progression. We report the first phase I study results with CER-001 in humans, starting at 0.25 mg/kg, which is 1/80th of the safe dose (20 mg/kg) established in 4-week multiple-dose animal studies dosed every second day. Healthy volunteers, 18-55 years old with a low-density lipoprotein-cholesterol:HDL-cholesterol ratio greater than 3.0, received single intravenous escalating doses of CER-001 (0.25-45.0 mg/kg) and placebo in a double-blind randomised cross-over fashion. Subjects were followed up for 3 weeks post-dose. Assessments included adverse event monitoring, blood sampling, and clinical laboratory measurements. Thirty-two subjects were enrolled. All CER-001 doses (0.25-45 mg/kg) were safe and well tolerated, with an adverse event profile similar to placebo. Effects on clinical chemistry, haematology and coagulation parameters were comparable to placebo. No adverse effects of CER-001 on electrocardiograms were observed. No antibodies to apolipoprotein A-I were detected following single-dose administration of CER-001. Plasma apolipoprotein A-I levels increased in a dose-related manner and returned to baseline by 24 h post-dose for doses up to 10 mg/kg but remained in circulation for >72 h post-dose for doses >10 mg/kg. CER-001 caused elevations in plasma cholesterol and total and unesterified cholesterol in the HDL fraction. Mobilisation of unesterified cholesterol in the HDL fraction was seen with CER-001 at doses as low as 2 mg/kg. CER-001 is well tolerated when administered to humans as single doses up to 45 mg/kg and mobilises and eliminates cholesterol via reverse lipid transport.

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.

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.

Pharmacokinetics of doxylamine, a component of Bendectin, in the rhesus monkey.

PubMed

Slikker, W; Holder, C L; Lipe, G W; Bailey, J R; Young, J F

1989-01-01

The elimination of doxylamine and metabolites was determined after iv administration of [14C]doxylamine succinate at 0.7 and 13.3 mg/kg to the adult female rhesus monkey. Although the total recovery of radioactivity was the same for the low- and high-dose studies (90.2%), the rate of plasma elimination of doxylamine and its demethylated metabolite (desmethyldoxylamine) was slower for the high dose group. The 24 hr urinary excretion of doxylamine metabolites, desmethyl- and didesmethyldoxylamine, was significantly increased and the polar doxylamine metabolites were significantly decreased as the iv doxylamine succinate dose was increased. The plasma elimination of gas chromatograph (GC)-detected doxylamine was determined after oral administration of Bendectin (doxylamine succinate and pyridoxine hydrochloride) at 7, 13.3, and 27 mg/kg to adult female rhesus monkeys. As the dose increased, the clearance of doxylamine decreased. A statistically evaluated fit of the oral data to a single-compartment, parallel first-order elimination model and a single-compartment, parallel first- and second-order (Michaelis-Menten) elimination model indicated that the more complex model containing the second-order process was most consistent with the observed elimination data.

Low- and high-dose laser irradiation effects on cell migration and destruction

NASA Astrophysics Data System (ADS)

Layton, Elivia; Gallagher, Kyra A.; Zukerman, Sara; Stevens, Brianna; Zhou, Feifan; Liu, Hong; Chen, Wei R.

2018-02-01

Metastases are the cause of more than 90 percent of cancer-related deaths. Current treatment methods, including chemotherapy, radiation, and surgery, fail to target the metastases effectively. One potential treatment for metastatic cancer is laser immunotherapy (LIT). LIT combines the use of a photothermal laser with an immunoadjuvant, Glycated Chitosan (GC). GC combined with single-walled carbon nanotubes (SWNTs) has proven to be a viable alternative to traditional cancer treatment methods, when under irradiation of laser with appropriate wavelength. In this study, the effects of low dose and high dose laser irradiation on metastatic pancreatic cancer cell migration were observed. It was found that low dose irradiation increased the migration rate, but the high dose irradiation significantly decreased the migration rate of the cancer cells. When using LIT, the goal is to kill tumor cells and to prompt the correct immune response. If the tumor were irradiated with a low dose, it would promote metastasis. If the dose of irradiation were too high, it would destroy the entire tumor and the immune response would not recognize the tumor. Therefore, the laser dose plays an important role in LIT, particularly when using SWNT as light absorbing agent. Our results from this study will delineate the optimal laser irradiation dose for destroying tumor cells and at the same time preserve and release tumor antigens as a precursor of antitumor immune response.

Efficacy of single-dose antibiotic against early-onset pneumonia in comatose patients who are ventilated.

PubMed

Vallés, Jordi; Peredo, Raquel; Burgueño, Maria Jose; Rodrigues de Freitas, A Patrícia; Millán, Susana; Espasa, Mateu; Martín-Loeches, Ignacio; Ferrer, Ricard; Suarez, David; Artigas, Antonio

2013-05-01

Comatose patients present a high risk of early-onset ventilator-associated pneumonia (EO-VAP) for which antibiotic prophylaxis has been proposed. Comatose patients were studied to evaluate the efficacy of a single-dose of antibiotic prophylaxis at intubation against EO-VAP. A prospective cohort of comatose patients (Glasgow Coma Score ≤ 8) who were admitted in 2009-2010 and administered a single-dose of antibiotic within 4 h of intubation was compared with comatose patients (admitted ≥ 4 h after intubation in 2009-2010 or admitted in 2007-2008) who did not receive antibiotic prophylaxis. We analyzed the incidence of EO-VAP, late-onset VAP, and ventilator-associated tracheobronchitis in both groups. Propensity scores for receiving antibiotic prophylaxis were derived on the basis of patients' characteristics (eg, age and severity) to assess its impact on EO-VAP development. We included 129 patients (71 in the prophylaxis group and 58 in the control group). The global incidence of VAP and incidence of EO-VAP were lower in the prophylaxis group: 10.8 vs 28.4 episodes/1,000 days on mechanical ventilation (P = .015) and 4.4 vs 23.1 episodes/1,000 days on mechanical ventilation (P = .02), respectively. The incidence of late-onset VAP did not differ. The prophylaxis group tended toward lower incidence of ventilator-associated tracheobronchitis (15.5% vs 25.9%, P = .14). No differences in mortality were found between groups. The propensity-score regression analysis confirmed that a single dose of antibiotic prophylaxis was independently associated with lower incidence of EO-VAP (OR, 0.11; 95% CI, 0.02-0.58; P = .009). A single dose of antibiotic prophylaxis at intubation might lower the incidence of EO-VAP. However, a randomized clinical trial should be conducted to confirm our findings.

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

PubMed Central

Todd, John A.; Porter, Linsey; Smyth, Deborah J.; Rainbow, Daniel B.; Ferreira, Ricardo C.; Yang, Jennie H.; Bell, Charles J. M.; Schuilenburg, Helen; Challis, Ben; Clarke, Pamela; Coleman, Gillian; Dawson, Sarah; Goymer, Donna; Kennet, Jane; Brown, Judy; Greatorex, Jane; Goodfellow, Ian; Evans, Mark; Mander, Adrian P.; Bond, Simon; Wicker, Linda S.

2016-01-01

Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = −0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015–0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%–48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%–85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. Conclusions The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2–3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%–50%, with the eventual goal of preventing T1D. Trial Registration ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735 PMID:27727279

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.

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

Two Formulations of Venlafaxine are Bioequivalent when Administered as Open Capsule Mixed with Applesauce to Healthy Subjects.

PubMed

Jain, Renu T; Panda, J; Srivastava, A

2011-09-01

Venlafaxine is a unique antidepressant approved for treatment of various depressive disorders. A single dose, cross-over bioequivalence study was performed with two different formulations of venlafaxine 150 mg extended-release capsules in which the contents of capsule were mixed with applesauce and administered to healthy subjects under fed condition. A total of 24 healthy adult male subjects participated in this randomized, single-dose, non-blinded, two-way crossover study conducted at a single centre and 23 subjects completed the study as per the study protocol. After an overnight fast of 10 h, a high-fat and high-calorie breakfast was served 30 min before dosing. The subjects then received a single dose of either formulation administered with apple sauce followed by 240 ml of water as per randomized schedule in each period separated by a washout period of 7 days. A series of blood samples were collected upto 72 h for estimation of venlafaxine and its active metabolite, O-desmethylvenlafaxine. The quantification of venlafaxine and O-desmethylvenlafaxine was done by LC-MS/MS method and pharmacokinetic and statistical analysis by WinNonlin(®) 5.2 and SAS(®) 9.1.3. The results of the study demonstrated bioequivalence of two formulations as the 90% confidence interval for the intra-individual mean ratio of log-transformed C(max), AUC(0-t) and AUC(0-inf) of the test to the reference formulation were found within the defined bioequivalence range of 80.00%-125.00%. Both the formulations were well tolerated. This alternative mode of administration may provide benefits to patients who have difficulty in swallowing the capsule as a whole.

Two Formulations of Venlafaxine are Bioequivalent when Administered as Open Capsule Mixed with Applesauce to Healthy Subjects

PubMed Central

Jain, Renu T.; Panda, J.; Srivastava, A.

2011-01-01

Venlafaxine is a unique antidepressant approved for treatment of various depressive disorders. A single dose, cross-over bioequivalence study was performed with two different formulations of venlafaxine 150 mg extended-release capsules in which the contents of capsule were mixed with applesauce and administered to healthy subjects under fed condition. A total of 24 healthy adult male subjects participated in this randomized, single-dose, non-blinded, two-way crossover study conducted at a single centre and 23 subjects completed the study as per the study protocol. After an overnight fast of 10 h, a high-fat and high-calorie breakfast was served 30 min before dosing. The subjects then received a single dose of either formulation administered with apple sauce followed by 240 ml of water as per randomized schedule in each period separated by a washout period of 7 days. A series of blood samples were collected upto 72 h for estimation of venlafaxine and its active metabolite, O-desmethylvenlafaxine. The quantification of venlafaxine and O-desmethylvenlafaxine was done by LC-MS/MS method and pharmacokinetic and statistical analysis by WinNonlin® 5.2 and SAS® 9.1.3. The results of the study demonstrated bioequivalence of two formulations as the 90% confidence interval for the intra-individual mean ratio of log-transformed Cmax, AUC0-t and AUC0-inf of the test to the reference formulation were found within the defined bioequivalence range of 80.00%-125.00%. Both the formulations were well tolerated. This alternative mode of administration may provide benefits to patients who have difficulty in swallowing the capsule as a whole. PMID:22923863

Local noise reduction for emphysema scoring in low-dose CT images

NASA Astrophysics Data System (ADS)

Schilham, Arnold; Prokop, Mathias; Gietema, Hester; van Ginneken, Bram

2005-04-01

Computed Tomography (CT) has become the new reference standard for quantification of emphysema. The most popular measure for emphysema derived from CT is the Pixel Index (PI), which expresses the fraction of the lung volume with abnormally low intensity values. As PI is calculated from a single, fixed threshold on intensity, this measure is strongly influenced by noise. This effect shows up clearly when comparing the PI score for a high-dose scan to the PI score for a low-dose (i.e. noisy) scan of the same subject. This paper presents a class of noise filters that make use of a local noise estimate to specify the filtering strength: Local Noise Variance Weighted Averaging (LNVWA). The performance of the filter is assessed by comparing high-dose and low-dose PI scores for 11 subjects. LNVWA improves the reproducibility of high-dose PI scores: For an emphysema threshold of -910 HU, the root-mean-square difference in PI score drops from 10% of the lung volume to 3.3% of the lung volume if LNVWA is used.

The effect of prolonged ethanol administration on central alpha 2-adrenoceptors sensitivity.

PubMed

Szmigielski, A; Szmigielska, H; Wejman, I

1989-01-01

The response of an endogenous inhibitor of protein kinases (type II inhibitor) to clonidine was used as an index of sensitivity of central alpha 2-adrenoceptors. Low doses of clonidine (20-50 micrograms/kg) induced an increase in type II inhibitor activity in the nucleus accumbens, hippocampus and in the anterior and posterior hypothalamus by stimulating presynaptic alpha 2-adrenoceptors. Stimulation of postsynaptic alpha 2-adrenoceptors by high doses of clonidine 0.5-1.0 mg/kg resulted in a dose-dependent decrease in type II inhibitor activity. Prolonged treatment with ethanol (5 g/kg/day po for 21 days) greatly reduced the action of high doses of clonidine in all the examined brain areas, suggesting subsensitivity of postsynaptic alpha 2-adrenoceptors lasting for at least 48 h after the last ethanol administration. A single dose of ethanol induced a short lasting subsensitivity of postsynaptic alpha 2-adrenoceptors in the anterior hypothalamus. 12 h after administration of alcohol the response of type II inhibitor to high doses of clonidine in this brain area was the same as in untreated rats.

Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model

NASA Astrophysics Data System (ADS)

Cekanova, Maria; Uddin, Md. Jashim; Legendre, Alfred M.; Galyon, Gina; Bartges, Joseph W.; Callens, Amanda; Martin-Jimenez, Tomas; Marnett, Lawrence J.

2012-11-01

We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1 mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1 mg/kg showed a peak of fluorocoxib A (92±28 ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.

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

SU-E-CAMPUS-T-05: Validation of High-Resolution 3D Patient QA for Proton Pencil Beam Scanning and IMPT by Polymer Gel Dosimetry

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

Cardin, A; Avery, S; Ding, X

2014-06-15

Purpose: Validation of high-resolution 3D patient QA for proton pencil beam scanning and IMPT by polymer gel dosimetry. Methods: Four BANG3Pro polymer gel dosimeters (manufactured by MGS Research Inc, Madison, CT) were used for patient QA at the Robert's Proton Therapy Center (RPTC, Philadelphia, PA). All dosimeters were sealed in identical thin-wall Pyrex glass spheres. Each dosimeter contained a set of markers for 3D registration purposes. The dosimeters were mounted in a consistent and reproducible manner using a custom build holder. Two proton pencil beam scanning plans were designed using Varian Eclipse™ treatment planning system: 1) A two-field intensity modulatedmore » proton therapy (IMPT) plan and 2) one single field uniform dose (SFUD) plan. The IMPT fields were evaluated as a composite plan and individual fields, the SFUD plan was delivered as a single field plan.Laser CT scanning was performed using the manufacturer's OCTOPUS-IQ axial transmission laser CT scanner using a 1 mm slice thickness. 3D registration, analysis, and OD/cm to absorbed dose calibrations were perfomed using DICOM RT-Dose and CT files, and software developed by the manufacturer. 3D delta index, a metric equivalent to the gamma tool, was used for dose comparison. Results: Very good agreement with single IMPT fields and with SFUD was obtained. Composite IMPT fields had a less satisfactory agreement. The single fields had 3D delta index passing rates (3% dose difference, 3 mm DTA) of 98.98% and 94.91%. The composite 3D delta index passing rate was 80.80%. The SFUD passing rate was 93.77%. Required shifts of the dose distributions were less than 4 mm. Conclusion: A formulation of the BANG3Pro polymer gel dosimeter, suitable for 3D QA of proton patient plans is established and validated. Likewise, the mailed QA analysis service provided by the manufacturer is a practical option when required resources are unavailable. We fully disclose that the subject of this research regards a production of MGS Research, Inc.« less

Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings.

PubMed

Noel, Gary J; Goodman, Daniel B; Chien, Shuchean; Solanki, Bhavna; Padmanabhan, Mukund; Natarajan, Jaya

2004-05-01

A clinical trial was conducted in healthy volunteers using both periodic and continuous ECG recordings to assess the effect of increasing doses of levofloxacin on the QT and QTc interval. Periodic and continuous ECGs were recorded before and after subjects were dosed with placebo and increasing doses of levofloxacin (500 mg, 1000 mg, 1500 mg) that included doses twice the maximum recommended dose of 750 mg in a double-blind, randomized, four-period, four-sequence crossover trial. Mean heart rate (HR) and the QT and QTc interval after dosing with levofloxacin and placebo were compared, and HR-QT interval relationships defined by linear regression analysis were calculated. After single doses of 1000 and 1500 mg of levofloxacin, HR increased significantly, as measured by periodic and continuous ECG recordings. This transient increase occurred at times of peak plasma concentration and was without symptoms. Mean QT intervals after placebo and mean intervals after levofloxacin were indistinguishable. Using periodic ECG recordings, single doses of 1500 mg were associated with small increases in QTc that were statistically significant. In contrast, an effect on QTc was shown only using the Bazett formula with data obtained from continuous ECG recordings. Together with the finding that levofloxacin does not influence HR-QT relationships, these findings suggest that levofloxacin has little effect on prolonging ventricular repolarization and that small increases in HR associated with high doses of levofloxacin contribute to the drug's apparent effect on QTc. Single doses of 1000 or 1500 mg of levofloxacin transiently increase HR without affecting the uncorrected QT interval. Differences in mean QTc after levofloxacin compared to placebo vary depending on the correction formula used and whether the data analyzed are from periodic or continuous ECG recordings. This work suggests that using continuous ECG recordings in assessing QT/QTc effects of drugs may be of value, particularly with drugs that might influence HR.

Dose painting to treat single-lobe prostate cancer with hypofractionated high-dose radiation using targeted external beam radiation: Is it feasible?

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

Amini, Arya; Westerly, David C.; Waxweiler, Timothy V.

Targeted focal therapy strategies for treating single-lobe prostate cancer are under investigation. In this planning study, we investigate the feasibility of treating a portion of the prostate to full-dose external beam radiation with reduced dose to the opposite lobe, compared with full-dose radiation delivered to the entire gland using hypofractionated radiation. For 10 consecutive patients with low- to intermediate-risk prostate cancer, 2 hypofractionated, single-arc volumetric-modulated arc therapy (VMAT) plans were designed. The first plan (standard hypofractionation regimen [STD]) included the entire prostate gland, treated to 70 Gy delivered in 28 fractions. The second dose painting plan (DP) encompassed the involvedmore » lobe treated to 70 Gy delivered in 28 fractions, whereas the opposing, uninvolved lobe received 50.4 Gy in 28 fractions. Mean dose to the opposing neurovascular bundle (NVB) was considerably lower for DP vs STD, with a mean dose of 53.9 vs 72.3 Gy (p < 0.001). Mean penile bulb dose was 18.6 Gy for DP vs 19.2 Gy for STD (p = 0.880). Mean rectal dose was 21.0 Gy for DP vs 22.8 Gy for STD (p = 0.356). Rectum V{sub 70} (the volume receiving ≥70 Gy) was 2.01% for DP vs 2.74% for STD (p = 0.328). Bladder V{sub 70} was 1.69% for DP vs 2.78% for STD (p = 0.232). Planning target volume (PTV) maximum dose points were 76.5 and 76.3 Gy for DP and STD, respectively (p = 0.760). This study demonstrates the feasibility of using VMAT for partial-lobe prostate radiation in patients with prostate cancer involving 1 lobe. Partial-lobe prostate plans appeared to spare adjacent critical structures including the opposite NVB.« less

Comparison in vivo Study of Genotoxic Action of High- Versus Very Low Dose-Rate γ-Irradiation

PubMed Central

Osipov, A. N.; Klokov, D. Y.; Elakov, A. L.; Rozanova, O. M.; Zaichkina, S. I.; Aptikaeva, G. F.; Akhmadieva, A. Kh.

2004-01-01

The aim of the present study was to compare genotoxicity induced by high- versus very low dose-rate exposure of mice to γ-radiation within a dose range of 5 to 61 cGy using the single-cell gel electrophoresis (comet) assay and the micronucleus test. CBA/lac male mice were irradiated at a dose rate of 28.2 Gy/h (high dose rate) or 0.07 mGy/h (very low dose rate). The comet assay study on spleen lymphocytes showed that very low dose-rate irradiation resulted in a statistically significant increase in nucleoid relaxation (DNA breaks), starting from a dose of 20 cGy. Further prolongation of exposure time and, hence, increase of a total dose did not, however, lead to further increase in the extent of nucleoid relaxation. Doses of 20 and 61 cGy were equal in inducing DNA breaks in mouse spleen lymphocytes as assayed by the comet assay. Of note, the level of DNA damage by 20–61 cGy doses of chronic irradiation (0.07 mGy/h) was similar to that an induced by an acute (28.2 Gy/h) dose of 14 cGy. The bone marrow micronucleus test revealed that an increase in polychromatic erythrocytes with micronuclei over a background level was induced by very low-level γ-irradiation with a dose of 61 cGy only, with the extent of the cytogenetic effect being similar to that of 10 cGy high-dose-rate exposure. In summary, presented results support the hypothesis of the nonlinear threshold nature of mutagenic action of chronic low dose-rate irradiation. PMID:19330145

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.

The effect of single and repeated UVB radiation on rabbit cornea.

PubMed

Fris, Miroslav; Tessem, May-Britt; Cejková, Jitka; Midelfart, Anna

2006-12-01

Cumulative effect of ultraviolet radiation (UVR) is an important aspect of UV corneal damage. The purpose of this study was to apply high resolution magic angle spinning proton nuclear magnetic resonance (HR-MAS 1H NMR) spectroscopy to evaluate the effect of single and repeated UV radiation exposure of the same overall dose on the rabbit cornea. Corneal surfaces of 24 normal rabbit eyes were examined for the effects of UVB exposure (312 nm). In the first group (UVB1), animals were irradiated with a single dose (3.12 J/cm2; 21 min) of UVB radiation. The animals in the second group (UVB2) were irradiated three times for 7 min every other day (dose of 1.04 J/cm2; days 1, 3, 5) to give the same overall dose (3.12 J/cm2). The third group served as an untreated control group. One day after the last irradiation, the animals were sacrificed, and the corneas were removed and frozen. HR-MAS 1H NMR spectra from intact corneas were obtained. Special grouping patterns among the tissue samples and the relative percentage changes in particular metabolite concentrations were evaluated using modern statistical methods (multivariate analysis, one-way ANOVA). The metabolic profile of both groups of UVB-irradiated samples was significantly different from the control corneas. Substantial decreases in taurine, hypo-taurine and choline-derivatives concentrations and substantial elevation in glucose and betaine levels were observed following the UVR exposure. There was no significant difference between the effect of a single and repeated UVB irradiation of the same overall dose. For the first time, the effects of single and repeated UVR doses on the metabolic profile of the rabbit cornea were analysed and compared. The combination of HR-MAS 1H NMR spectroscopy and modern statistical methods (multivariate analysis, one-way ANOVA) proved suitable to assess the overall view of the metabolic alterations in the rabbit corneal tissue following UVB radiation exposure.

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.

Effect of a single intraoperative high-dose ATG-Fresenius on delayed graft function in donation after cardiac-death donor renal allograft recipients: a randomized study.

PubMed

van den Hoogen, Martijn W F; Kho, Marcia M L; Abrahams, Alferso C; van Zuilen, Arjan D; Sanders, Jan-Stephan; van Dijk, Marja; Hilbrands, Luuk B; Weimar, Willem; Hoitsma, Andries J

2013-04-01

Reducing the incidence of delayed graft function after transplant with donation after cardiac death donor renal allografts would facilitate managing recipients during their first weeks after a transplant. To reduce this incidence, in most studies, induction therapy with depleting anti-T-lymphocyte antibodies is coupled with a reduction of the dosage of the calcineurin inhibitor. The separate effect of anti-T-cell therapy on the incidence and duration of delayed graft function is therefore difficult to assess. We performed a randomized study to evaluate the effect of a single intraoperative high-dose of anti-T-lymphocyte immunoglobulin (ATG)-Fresenius (9 mg/kg body weight) on the incidence of delayed graft function. Eligible adult recipients of a first donation after cardiac death donor renal allograft were randomly assigned to ATG-Fresenius or no induction therapy. Maintenance immunosuppression consisted of tacrolimus, in an unadjusted dose, mycophenolate mofetil, and steroids. The study was prematurely terminated because of a lower-than-anticipated inclusion rate. Baseline characteristics were comparable in the ATG-Fresenius group (n=28) and the control group (n=24). Twenty-two patients in the ATG-Fresenius group (79%) had delayed graft function, compared with 13 in the control group (54%; P = .06). Allograft and patient survival were comparable in both groups. Serious adverse events occurred more frequently in the ATG-Fresenius group than they did in the control group (57% vs 29%; P < .05). Intraoperative administration of a single high-dose of ATG-Fresenius in donation after cardiac death donor renal allograft recipients, followed by triple immunosuppression with an unadjusted tacrolimus dose, seems ineffective to reduce the incidence of delayed graft function. Moreover, this was associated with a higher rate of serious adverse events (EudraCT-number, 2007-000210-36.).

High-temperature thermoluminescence of anion-deficient alumina and possibilities of its application in high-dose dosimetry

NASA Astrophysics Data System (ADS)

Surdo, A. I.; Milman, I. I.; Abashev, R. M.; Vlasov, M. I.

2014-12-01

Results of studies of the thermoluminescence (TL) of anion-deficient alumina (α-Al2O3 - δ) single crystals and based on them TLD-500 detectors exposed to pulsed X-ray and electron radiation in a wide range of doses D, pulsed dose rates P p , and temperatures are described. The TL responses of α-Al2O3 - δ for continuous and pulsed X-ray irradiation at D = 0.05-150 Gy are compared. Unlike continuous irradiation, in the case of pulsed irradiation at P p ≥ 6 × 106 Gy/s, a linear increase in the TL response as a function of D is registered in the main and "chromium" peaks at 450 and 580 K, respectively, with a decrease in the slope of the dose dependence at D > 2 Gy for the peak at 450 K. It is found that high-dose irradiation (>60 Gy) leads to the formation of a new TL peak at 830 K and the preferential redistribution of the stored light sums into this peak. The dose dependence for the TL peak at 830 K is studied. It is established that it is linear in a super-high dose range of 104 to 6 × 106 Gy at P p = 2.6 × 1011 Gy/s.

Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans

PubMed Central

Carter, Lawrence P.; Reissig, Chad J.; Johnson, Matthew W.; Klinedinst, Margaret A.; Griffiths, Roland R.

2012-01-01

BACKGROUND Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. METHODS Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg /70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 hours. RESULTS Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM. CONCLUSION The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse. PMID:22989498

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

PubMed

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

2014-03-01

The pharmacokinetic interaction of enrofloxacin and trimethoprim was evaluated after single-dose intraperitoneal or oral co-administration in rats. Plasma concentrations of the two drugs were determined by high-performance liquid chromatography. Following intraperitoneal combination, a significant (P < 0.05) increase in mean values of plasma half-life (t 1/2) and maximum plasma concentration (C max) was observed for enrofloxacin and trimethoprim, respectively. There was a significant (P < 0.05) increase in mean values of area under the plasma drug concentration versus time from time zero to infinity (AUC0-∞) and C max between combined oral doses (10, 30 and 100 mg/kg) of both antibacterial drugs. Also, after oral conjugation a significant difference in mean values of MRT0-∞ was observed between lower (10 mg/kg) and higher (100 mg/kg) doses of both drugs. A significant increase in pharmacokinetic parameters of both drugs in combined intraperitoneal and oral doses indicated pharmacokinetic interaction of enrofloxacin and trimethoprim. Further study is recommended in other species of animals.

Experimental validation of a deforming grid 4D dose calculation for PBS proton therapy.

PubMed

Krieger, Miriam; Klimpki, Grischa; Fattori, Giovanni; Hrbacek, Jan; Oxley, David; Safai, Sairos; Weber, Damien C; Lomax, Antony J; Zhang, Ye

2018-03-01

The aim of this study was to verify the temporal accuracy of the estimated dose distribution by a 4D dose calculation (4DDC) in comparison to measurements. A single-field plan (0.6 Gy), optimised for a liver patient case (CTV volume: 403cc), was delivered to a homogeneous PMMA phantom and measured by a high resolution scintillating-CCD system at two water equivalent depths. Various motion scenarios (no motion and motions with amplitude of 10 mm and two periods: 3.7 s and 4.4 s) were simulated using a 4D Quasar phantom and logged by an optical tracking system in real-time. Three motion mitigation approaches (single delivery, 6[Formula: see text] layered and volumetric rescanning) were applied, resulting in 10 individual measurements. 4D dose distributions were retrospectively calculated in water by taking into account the delivery log files (retrospective) containing information on the actually delivered spot positions, fluences, and time stamps. Moreover, in order to evaluate the sensitivity of the 4DDC inputs, the corresponding prospective 4DDCs were performed as a comparison, using the estimated time stamps of the spot delivery and repeated periodical motion patterns. 2D gamma analyses and dose-difference-histograms were used to quantify the agreement between measurements and calculations for all pixels with [Formula: see text]5% of the maximum calculated dose. The results show that a mean gamma score of 99.2% with standard deviation 1.0% can be achieved for 3%/3 mm criteria and all scenarios can reach a score of more than 95%. The average area with more than 5% dose difference was 6.2%. Deviations due to input uncertainties were obvious for single scan deliveries but could be smeared out once rescanning was applied. Thus, the deforming grid 4DDC has been demonstrated to be able to predict the complex patterns of 4D dose distributions for PBS proton therapy with high dosimetric and geometric accuracy, and it can be used as a valid clinical tool for 4D treatment planning, motion mitigation selection, and eventually 4D optimisation applications if the correct temporal information is available.

Experimental validation of a deforming grid 4D dose calculation for PBS proton therapy

NASA Astrophysics Data System (ADS)

Krieger, Miriam; Klimpki, Grischa; Fattori, Giovanni; Hrbacek, Jan; Oxley, David; Safai, Sairos; Weber, Damien C.; Lomax, Antony J.; Zhang, Ye

2018-03-01

The aim of this study was to verify the temporal accuracy of the estimated dose distribution by a 4D dose calculation (4DDC) in comparison to measurements. A single-field plan (0.6 Gy), optimised for a liver patient case (CTV volume: 403cc), was delivered to a homogeneous PMMA phantom and measured by a high resolution scintillating-CCD system at two water equivalent depths. Various motion scenarios (no motion and motions with amplitude of 10 mm and two periods: 3.7 s and 4.4 s) were simulated using a 4D Quasar phantom and logged by an optical tracking system in real-time. Three motion mitigation approaches (single delivery, 6× layered and volumetric rescanning) were applied, resulting in 10 individual measurements. 4D dose distributions were retrospectively calculated in water by taking into account the delivery log files (retrospective) containing information on the actually delivered spot positions, fluences, and time stamps. Moreover, in order to evaluate the sensitivity of the 4DDC inputs, the corresponding prospective 4DDCs were performed as a comparison, using the estimated time stamps of the spot delivery and repeated periodical motion patterns. 2D gamma analyses and dose-difference-histograms were used to quantify the agreement between measurements and calculations for all pixels with > 5% of the maximum calculated dose. The results show that a mean gamma score of 99.2% with standard deviation 1.0% can be achieved for 3%/3 mm criteria and all scenarios can reach a score of more than 95%. The average area with more than 5% dose difference was 6.2%. Deviations due to input uncertainties were obvious for single scan deliveries but could be smeared out once rescanning was applied. Thus, the deforming grid 4DDC has been demonstrated to be able to predict the complex patterns of 4D dose distributions for PBS proton therapy with high dosimetric and geometric accuracy, and it can be used as a valid clinical tool for 4D treatment planning, motion mitigation selection, and eventually 4D optimisation applications if the correct temporal information is available.

A model for treating avian aspergillosis: serum and lung tissue kinetics for Japanese quail (Coturnix japonica) following single and multiple aerosol exposures of a nanoparticulate itraconazole suspension.

PubMed

Rundfeldt, Chris; Wyska, Elżbieta; Steckel, Hartwig; Witkowski, Andrzej; Jeżewska-Witkowska, Grażyna; Wlaź, Piotr

2013-11-01

Aspergillosis is frequently reported in parrots, falcons and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but administration requires repeated oral dosing and the safety margin is narrow. We describe lung tissue and serum pharmacokinetics of a nanoparticulate ITRA suspension administered to Japanese quail by aerosol exposure. Aerosolized ITRA (1 and 10% suspension) administered over 30 min did not induce adverse clinical reactions in quail upon single or 5-day repeated doses. High lung concentrations, well above the inhibitory levels for A. fumigatus, of 4.14 ± 0.19 μg/g and 27.5 ± 4.58 μg/g (mean ± SEM, n = 3), were achieved following single-dose inhalation of 1% and 10% suspension, respectively. Upon multiple dose administration of 10% suspension, mean lung concentrations reached 104.9 ± 10.1 μg/g. Drug clearance from the lungs was slow with terminal half-lives of 19.7 h and 35.8 h following inhalation of 1% and 10% suspension, respectively. Data suggest that lung clearance is solubility driven. Lung concentrations of hydroxy-itraconazole reached 1-2% of the ITRA lung tissue concentration indicating metabolism in lung tissue. Steady, but low, serum concentrations of ITRA could be measured after multiple dose administration, reaching less than 0.1% of the lung tissue concentration. This formulation may represent a novel, easy to administer treatment modality for fungal lung infection, preventing high systemic exposure. It may also be useful as metaphylaxis to prevent the outbreak of aspergillosis in colonized animals.

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

PubMed

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

2018-05-01

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

Health-Related Quality of Life After Single-Fraction High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy for Prostate Cancer

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

Morton, Gerard C., E-mail: gerard.morton@sunnybrook.ca; Loblaw, D. Andrew; Chung, Hans

Purpose: To investigate the change in health-related quality of life for men after high-dose-rate brachytherapy and external beam radiotherapy for prostate cancer and the factors associated with this change. Methods and Materials: Eligible patients had clinically localized intermediate-risk prostate cancer. The patients received high-dose-rate brachytherapy as a single 15-Gy implant, followed by external beam radiotherapy to 37.5 Gy in 15 fractions. The patients were monitored prospectively for toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]). The proportion of patients developing a clinically significant difference in the EPIC domainmore » score (minimally important difference of >0.5 standard deviation) was determined and correlated with the baseline clinical and dosimetric factors. The study accrued 125 patients, with a median follow-up of 24 months. Results: By 24 months, 23% had Grade 2 urinary toxicity and only 5% had Grade 2 bowel toxicity, with no Grade 3 toxicity. The proportion of patients reporting a significant decrease in EPIC urinary, bowel, sexual, and hormonal domain scores was 53%, 51%, 45%, and 40% at 12 months and 57%, 65%, 51%, and 30% at 24 months, respectively. The proportion with a >1 standard deviation decrease in the EPIC urinary, bowel, sexual, and hormonal domain scores was 38%, 36%, 24%, and 20% at 12 months and 46%, 48%, 19%, and 8% at 24 months, respectively. On multivariate analysis, the dose to 10% of the urethra was associated with a decreasing EPIC urinary domain score (p = .0089) and, less strongly (p = .0312) with a decreasing hormonal domain score. No association was found between the prostate volume, bladder dose, or high-dose volume and urinary health-related quality of life. A high baseline International Index of Erectile Function score was associated (p = .0019) with a decreasing sexual domain score. The optimal maximal dose to 10% of the urethra cutpoint for urinary health-related quality of life was 120% of the prescription dose. Conclusion: EPIC was a more sensitive tool for detecting the effects on function and bother than were the generic toxicity scales. The urethral dose had the strongest association with a deteriorating urinary quality of life.« less

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

The role of single-shot metronidazole in the prevention of Clostridium difficile infection following ileostomy reversal surgery.

PubMed

Fernandes, Roland; Robinson, Paul; Rangarajan, Karan; Scott, Sophie; Angco, Laura

2017-05-01

Symptomatic infection with Clostridium difficile is strongly linked to antibiotic use and rates are higher for colorectal surgery. In February 2015, trust policy for antibiotic prophylaxis of ileostomy reversal surgery was changed from three doses of metronidazole plus cefuroxime to single-dose metronidazole, in a bid to reduce rates of Clostridium difficile infection. A retrospective cohort study was conducted at a single, large hospital trust between February 2014 and February 2016, before and after change in antimicrobial policy. Theatre data, clinical notes and pathology results were all reviewed. Outcome data, patient age, gender, length of operation and hospital stay were extracted. One hundred three patients underwent ileostomy reversal surgery between February 2014 and February 2015. All received cefuroxime together with metronidazole at induction of anaesthesia followed by two further post-operative doses as operative prophylaxis. Ninety-six patients underwent ileostomy reversal surgery between February 2015 and February 2016. All received single-dose metronidazole at induction as prophylaxis. Post-operative diarrhoea was significantly reduced in patients given single-dose metronidazole compared with patients managed with multiple dose, dual antibiotic therapy (32 vs 12.5%, P 0.001). Rates of CDI were also significantly reduced in patients given single-dose metronidazole (6.8 vs 1%, P 0.038). Single-dose, pre-operative metronidazole is effective at reducing post-operative diarrhoea and CDI in ileostomy reversal surgery compared with multiple-dose cefuroxime plus metronidazole. Metronidazole may be effective as a prophylactic antibiotic against CDI in colonic surgery.

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia.

PubMed

Azevedo, M C; Velloso, E D R P; Buccheri, V; Chamone, D A F; Dorlhiac-Llacer, P E

2015-02-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival.

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia

PubMed Central

Azevedo, M.C.; Velloso, E.D.R.P.; Buccheri, V.; Chamone, D.A.F.; Dorlhiac-Llacer, P.E.

2014-01-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival. PMID:25517921

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.

Production, PET performance and dosimetric considerations of 134Ce/134La, an Auger electron and positron-emitting generator for radionuclide therapy.

PubMed

Lubberink, Mark; Lundqvist, Hans; Tolmachev, Vladimir

2002-02-21

We propose the use of the Auger electron and positron-emitting generator 134Ce/134La (half-lives 3.16 d and 6.45 min) for radionuclide therapy. It combines emission of high-energy beta particles with Auger electrons. The high-energy beta particles have similar energies as those emitted by 90Y. Many cancer patients receiving radionuclide therapy have both bulk tumours, which are best treated with high-energy beta particles, and single spread cells or micrometastasis, which are preferably treated with low-energy electrons such as Auger and conversion electrons. Furthermore, the positron-emitting 134La can be used to study kinetics and dosimetry using PET. Production and PET performance were investigated and theoretical dosimetry calculations were made. PET resolution, recovery and quantitative accuracy were slightly degraded for 134La compared to 18F. 134Ce/134La absorbed doses to single cells were higher than absorbed doses from 90Y and 111In. Absorbed doses to spheres representing bulk tumours were almost as high as for 90Y, and a factor 10 higher than for 111In. Whole-body absorbed doses, based on kinetics of the somatostatin analogue octreotide, were higher for 134Ce/134La than for 90Y because of the 134La annihilation photons. This initial study of the therapeutic possibilities of 134Ce/134La is encouraging and justifies further investigations.

MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor.

PubMed

Tran, Hai-Quyen; Chung, Yoon Hee; Shin, Eun-Joo; Tran, The-Vinh; Jeong, Ji Hoon; Jang, Choon-Gon; Nah, Seung-Yeol; Yamada, Kiyofumi; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2017-11-01

Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1

Amorphization resistance of nano-engineered SiC under heavy ion irradiation

NASA Astrophysics Data System (ADS)

Imada, Kenta; Ishimaru, Manabu; Xue, Haizhou; Zhang, Yanwen; Shannon, Steven C.; Weber, William J.

2016-09-01

Silicon carbide (SiC) with a high-density of planar defects (hereafter, 'nano-engineered SiC') and epitaxially-grown single-crystalline 3C-SiC were simultaneously irradiated with Au ions at room temperature, in order to compare their relative resistance to radiation-induced amorphization. It was found that the local threshold dose for amorphization is comparable for both samples under 2 MeV Au ion irradiation; whereas, nano-engineered SiC exhibits slightly greater radiation tolerance than single crystalline SiC under 10 MeV Au irradiation. Under 10 MeV Au ion irradiation, the dose for amorphization increased by about a factor of two in both nano-engineered and single crystal SiC due to the local increase in electronic energy loss that enhanced dynamic recovery.

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

Conformity of commercial oral single solid unit dose packages in hospital pharmacy practice.

PubMed

Thibault, Maxime; Prot-Labarthe, Sonia; Bussières, Jean-François; Lebel, Denis

2008-06-01

There are limited published data on the labelling of single unit dose packages in hospitals. The study was conducted in three large hospitals (two adult and one paediatric) in the metropolitan Montreal area, Quebec, Canada. The objective is to evaluate the labelling of commercial oral single solid unit dose packages available in Canadian urban hospital pharmacy practice. The study endpoint was the labelling conformity of each unit dose package for each criterion and overall for each manufacturer. Complete labelling of unit dose packages should include the following information: (1) brand name, (2) international non-proprietary name or generic name, (3) dosage, (4) pharmaceutical form, (5) manufacturer's name, (6) expiry date, (7) batch number and (8) drug identification number. We also evaluated the ease with which a single unit dose package is detached from a multiple unit dose package for quick, easy and safe use by pharmacy staff. Conformity levels were compared between brand-name and generic packages. A total of 124 different unit dose packages were evaluated. The level of conformity of each criterion varied between 19 and 50%. Only 43% of unit dose packages provided an easy-to-detach system for single doses. Among the 14 manufacturers with three or more unit dose packages evaluated, eight (57%) had a conformity level less than 50%. This study describes the conformity of commercial oral single solid unit dose packages in hospital pharmacy practice in Quebec. A large proportion of unit dose packages do not conform to a set of nine criteria set out in the guidelines of the American Society of Health-System Pharmacists and the Canadian Society of Hospital Pharmacists.

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

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

Biological measure of compliance to Artesunate plus Amodiaquine association: interest in a Mono-Desethyl-Amodiaquine blood assay?

PubMed

Sarrassat, Sophie; Sakho, Madiagne; Le Hesran, Jean Yves

2009-04-01

The deployment of Artemisinin-based Combination Therapy for treating uncomplicated malaria poses problems in the patient compliance to these new treatments. The aim of our study was to investigate the relationship between compliance to 3 days treatment with Artesunate plus Amodiaquine (AS+AQ) and the Mono-Desethyl-Amodiaquine (MDA) blood concentration on the fourth day. A reference scale of mean MDA blood concentrations was constructed in 40 healthy adults. Each concentration corresponded to the MDA level on day 3 in a subject having one of the seven compliance degrees defined by the number and sequence of drug intakes from day 0 to day 2: one single dose on day 0, day 1 or day 2; two single doses separated by 24h, on day 0 and day 1 or on day 1 and day 2; two single doses separated by 48 h, on day 0 and day 2; three single doses, on day 0, day 1 and day 2. MDA was assayed in whole blood samples by HPLC. Non-parametric Mann and Whitney U tests were used for the comparison of two means. Our results demonstrated no clear relationship between the mean MDA blood concentrations on day 3 and compliance degrees, according to neither the number nor the sequence of doses taken. In particular, even though the differences were not significant, the mean concentration after three doses, expected to be the maximum, was unexpectedly lower than after two doses, on day 0 and day 1 or on day 1 and day 2. The high inter-individual variability of MDA concentrations attributed to the different rates of hepatic metabolism of each individual appears to have a greater effect on MDA levels than the number or timing of doses. Therefore, it seems that the role of a MDA blood assay is limited in use to discerning if none or one or more doses have been taken. A MDA assay do not allow to measure the compliance degree of one patient to AS+AQ association. Presently, interview and pill count following treatment seem to be the only tools available that may permit differentiation between degrees of compliance.

Tolerance to 3,4-Methylenedioxymethamphetamine (MDMA) in Rats Exposed to Single High-Dose Binges

PubMed Central

Baumann, Michael H.; Clark, Robert D.; Franken, Frederick H.; Rutter, John J.; Rothman, Richard B.

2008-01-01

3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) stimulates the transporter-mediated release of monoamines, including serotonin (5-HT). High-dose exposure to MDMA causes persistent 5-HT deficits (e.g., depletion of brain 5-HT) in animals, yet the functional and clinical relevance of such deficits are poorly defined. Here we examine functional consequences of MDMA-induced 5-HT depletions in rats. Male rats received binges of 3 ip injections of MDMA or saline, one injection every 2 h; MDMA was given at a threshold pharmacological dose (1.5 mg/kg × 3, low dose) or at a 5-fold higher amount (7.5 mg/kg × 3, high dose). One week later, jugular catheters and intracerebral guide cannulae were implanted. Two weeks after binges, rats received acute iv challenge injections of 1 and 3 mg/kg MDMA. Neuroendocrine effects evoked by iv MDMA (prolactin and corticosterone secretion) were assessed via serial blood sampling, while neurochemical effects (5-HT and dopamine release) were assessed via microdialysis in brain. MDMA binges elevated core temperatures only in the high-dose group, with these same rats exhibiting ~50% loss of forebrain 5-HT two weeks later. Prior exposure to MDMA did not alter baseline plasma hormones or dialysate monoamines, and effects of iv MDMA were similar in saline and low-dose groups. By contrast, rats pretreated with high-dose MDMA displayed significant reductions in evoked hormone secretion and 5-HT release when challenged with iv MDMA. As tolerance developed only in rats exposed to high-dose binges, hyperthermia and 5-HT depletion are implicated in this phenomenon. Our results suggest that MDMA tolerance in humans may reflect 5-HT deficits which could contribute to further dose escalation. PMID:18313226

Effect of PPARβ/δ agonist on the placentation and embryo-fetal development in rats.

PubMed

Nishimura, Kyohei; Nakano, Nao; Chowdhury, Vishwajit Sur; Kaneto, Masako; Torii, Mikinori; Hattori, Masa-aki; Yamauchi, Nobuhiko; Kawai, Motoyuki

2013-04-01

The present study was conducted to evaluate the developmental toxicity in the endometrium and placenta due to GW501516 administration by gavage to pregnant rats. GW501516 was orally administered repeatedly to pregnant rats from gestation day (GD) 6 to 17 at a dose of 0, 30, and 100 mg/kg/day. In next study, GW501516 was also orally administered to pregnant rats on GD 7, 8, 9, 10, or 11 at a single dose of 275 or 350 mg/kg. In these studies, caesarean section was performed to examine the pregnancy outcome on GD21. Additionally, GW501516 was orally administered to pregnant rats on GD 10 at a single dose of 275 mg/kg. Placentae were subjected for temporal histological examinations on GD 11, 13, 15, or 17. Placental malformation was induced by repeated administration of GW501516 at a dose of 100 mg/kg/day. Single oral administration of GW501516 at a dose of 275 and/or 350 mg/kg on GD 8, 9, 10, or 11 induced placental malformation, whereas GW501516 administered on GD 10 was the most effective for increasing placental malformation. Histopathologically, single oral administration of GW501516 on GD 10 induced cystic degeneration associated with cellular lysis of glycogen cells started from GD 15 in the basal zone. High frequency of placental malformation was observed by the administration of GW501516. From GD 8 to 11, especially GD 10, is more sensitive period to induce the placental malformation. © 2013 Wiley Periodicals, Inc.

Addition of High-Dose Cytarabine to Fludarabine-Based Conditioning for Hematopoietic Stem Cell Transplantation for Treating Fanconi Anemia Patients with Advanced Myeloid Malignancy: A Single-Center Experience and Literature Review.

PubMed

Aoki, Takahiro; Koh, Katsuyoshi; Ikeda, Yuhachi; Sekinaka, Yujin; Akiyama, Kosuke; Mori, Makiko; Arakawa, Yuki; Hanada, Ryoji

2016-09-01

The complication of Fanconi anemia (FA) with acute leukemia is rare and challenging to treat because of high relapse rates, despite the improved outcome of hematopoietic stem cell transplantation with fludarabine-based conditioning for treating FA patients with hematological abnormalities. We added high-dose cytarabine to fludarabine-based conditioning to promote an enhanced antitumor effect and successfully subjected 4 patients with FA, including 3 with acute leukemia, to hematopoietic stem cell transplantation. All patients remain alive without treatment-related mortality or evidence of disease. Adding high-dose cytarabine to fludarabine-based conditioning may be tolerable and effective for treating FA patients with acute leukemia. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

A review of immunogenicity and tolerability of live attenuated Hepatitis A vaccine in children

PubMed Central

Rao, Sameer; Mao, J. S.; Motlekar, Salman; Fangcheng, Zhuang; Kadhe, Ganesh

2016-01-01

ABSTRACT Changing epidemiology of Hepatitis A virus (HAV) has led to an increased susceptibility of adolescents and adults to the infection. Vaccination can remarkably reduce the incidence and associated morbidity of HAV infection. This review is focused on the safety and efficacy of H2 strain derived live attenuated Hepatitis A vaccine. We found the vaccine to be highly immunogenic with minimal or negligible safety issues. Moreover, a single dose of live attenuated vaccine persists a long term immune response and can be a preferred option for developing countries. In 2014, Indian Academy of Paediatrics (IAP) also updated their recommendations for H2 vaccine as a single dose as against the previous 2 dose schedule. A focused approach to include the vaccine in national immunization program should be explored. PMID:27532370

Once-daily high-dose pindolol for SSRI-refractory depression.

PubMed

Sokolski, Kenneth N; Conney, Janet C; Brown, Brenda J; DeMet, Edward M

2004-02-15

Selective serotonin reuptake inhibitor (SSRI) augmentation with the 5-HT1A antagonist pindolol has met with mixed results. Recent studies using positron emission tomography (PET) suggest that pindolol doses used in these studies were too low to effect 5-HT1A autoreceptor blockade. To test the hypothesis that a single higher dose of pindolol would effectively augment antidepressant responses in SSRI-refractory patients, nine subjects with major depression unresponsive to paroxetine 40 mg/day given for 2 months or more were randomized to AM pindolol 7.5 mg (n=4) or placebo (n=5). Subjects were administered the Hamilton Depression Scale (HAM-D), the Hamilton Anxiety Scale (HAM-A), the Bech-Rafaelsen Melancholia Scale, and the Zung Depression Inventory at baseline and weeks 1, 2, 3, and 4. Subjects receiving pindolol exhibited significant improvements in all ratings beginning at week 2 which continued through week 4. Aside from transient dizziness and a five-point decrease in systolic/diastolic blood pressure associated with pindolol, no adverse effects were reported. Although results must be verified in a larger sample, these findings support previous studies indicating that pindolol can accelerate antidepressant responses during SSRI therapy. In addition, results reported here suggest that a single high dose of pindolol (7.5 mg) is a more effective augmentation strategy in SSRI-refractory patients compared with the same total dose given at 2.5 mg tid.

Higher doses of (+)MK-801 (dizocilpine) induced mortality and procedural but not cognitive deficits in delayed testing in the active place avoidance with reversal on the Carousel.

PubMed

Lobellová, V; Brichtová, E; Petrásek, T; Valeš, K; Stuchlík, A

2015-01-01

Schizophrenia is a devastating disorder affecting 1 % of the world's population. An important role in the study of this disease is played by animal models. Since there is evidence that acute psychotic episodes can have consequences on later cognitive functioning, the present study has investigated the effects of a single systemic application of higher doses of (+)MK-801 (3 mg/kg and 5 mg/kg) to adult male Long-Evans rats from the Institute's breeding colony on delayed testing in the active place avoidance task with reversal on the Carousel (a rotating arena). Besides significant mortality due to the injections, a disruption of procedural functions in active place avoidance, after the dose 5 mg/kg was observed. It was concluded that Long-Evans rats from our breeding colony do not represent a suitable biomodel for studying the effects of single high-dose NMDA antagonists.

A single high dose of dexamethasone affects the phosphorylation state of glutamate AMPA receptors in the human limbic system

PubMed Central

Lopes, M W; Leal, R B; Guarnieri, R; Schwarzbold, M L; Hoeller, A; Diaz, A P; Boos, G L; Lin, K; Linhares, M N; Nunes, J C; Quevedo, J; Bortolotto, Z A; Markowitsch, H J; Lightman, S L; Walz, R

2016-01-01

Glucocorticoids (GC) released during stress response exert feedforward effects in the whole brain, but particularly in the limbic circuits that modulates cognition, emotion and behavior. GC are the most commonly prescribed anti-inflammatory and immunosuppressant medication worldwide and pharmacological GC treatment has been paralleled by the high incidence of acute and chronic neuropsychiatric side effects, which reinforces the brain sensitivity for GC. Synapses can be bi-directionally modifiable via potentiation (long-term potentiation, LTP) or depotentiation (long-term depression, LTD) of synaptic transmission efficacy, and the phosphorylation state of Ser831 and Ser845 sites, in the GluA1 subunit of the glutamate AMPA receptors, are a critical event for these synaptic neuroplasticity events. Through a quasi-randomized controlled study, we show that a single high dexamethasone dose significantly reduces in a dose-dependent manner the levels of GluA1-Ser831 phosphorylation in the amygdala resected during surgery for temporal lobe epilepsy. This is the first report demonstrating GC effects on key markers of synaptic neuroplasticity in the human limbic system. The results contribute to understanding how GC affects the human brain under physiologic and pharmacologic conditions. PMID:27959333

Analysis of clinical efficacy, side effects, and laboratory changes among patients with acne vulgaris receiving single versus twice daily dose of oral isotretinoin.

PubMed

Ahmad, Hesham M

2015-01-01

Acne vulgaris is a debilitating disorder and requires proper treatment. This work evaluates the clinical efficacy, side effects, and laboratory changes of serum lipids and liver function during oral isotretinoin therapy for acne vulgaris, comparing single versus twice daily dose. Fifty-eight patients with acne vulgaris were included and randomized into group I (26 patients), who received once daily dose, and group II (32 patients), who received twice daily dose of oral isotretinoin. Global acne scoring system was used to evaluate acne severity and post-treatment improvement. Both regimens resulted in highly significant clinical improvement of acne with no significant difference. However, side effects were significantly more common among patients of group I. Both regimens caused mild rise of serum cholesterol, alanine transaminase (ALT), and aspartate aminotransferase (AST) with more prominent rise of triglycerides especially with twice daily dose. Oral isotretinoin is a very effective treatment for acne vulgaris with no statistically significant difference in clinical efficacy between once and twice daily doses. However, dividing dose to twice per day might cause fewer incidence of side effects without reducing clinical efficacy. The drug causes mild clinically insignificant rise of serum cholesterol, triglycerides, AST, and ALT. © 2015 Wiley Periodicals, Inc.

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

Impact of Genomics Platform and Statistical Filtering on Transcriptional Benchmark Doses (BMD) and Multiple Approaches for Selection of Chemical Point of Departure (PoD)

PubMed Central

Webster, A. Francina; Chepelev, Nikolai; Gagné, Rémi; Kuo, Byron; Recio, Leslie; Williams, Andrew; Yauk, Carole L.

2015-01-01

Many regulatory agencies are exploring ways to integrate toxicogenomic data into their chemical risk assessments. The major challenge lies in determining how to distill the complex data produced by high-content, multi-dose gene expression studies into quantitative information. It has been proposed that benchmark dose (BMD) values derived from toxicogenomics data be used as point of departure (PoD) values in chemical risk assessments. However, there is limited information regarding which genomics platforms are most suitable and how to select appropriate PoD values. In this study, we compared BMD values modeled from RNA sequencing-, microarray-, and qPCR-derived gene expression data from a single study, and explored multiple approaches for selecting a single PoD from these data. The strategies evaluated include several that do not require prior mechanistic knowledge of the compound for selection of the PoD, thus providing approaches for assessing data-poor chemicals. We used RNA extracted from the livers of female mice exposed to non-carcinogenic (0, 2 mg/kg/day, mkd) and carcinogenic (4, 8 mkd) doses of furan for 21 days. We show that transcriptional BMD values were consistent across technologies and highly predictive of the two-year cancer bioassay-based PoD. We also demonstrate that filtering data based on statistically significant changes in gene expression prior to BMD modeling creates more conservative BMD values. Taken together, this case study on mice exposed to furan demonstrates that high-content toxicogenomics studies produce robust data for BMD modelling that are minimally affected by inter-technology variability and highly predictive of cancer-based PoD doses. PMID:26313361

Doses effects of zoledronic acid on mineral apatite and collagen quality of newly-formed bone in the rat's calvaria defect.

PubMed

Olejnik, Cécile; Falgayrac, Guillaume; During, Alexandrine; Cortet, Bernard; Penel, Guillaume

2016-08-01

Due to their inhibitory effects on resorption, bisphosphonates are widely used in the treatment of diseases associated to an extensive bone loss. Yet, little is known about bisphosphonates effects on newly-formed bone quality. In the present study, adult male Sprague-Dawley rats (n=80) with a bone defect calvaria area were used and short-term effects of zoledronic acid (ZA) were studied on the healing bone area. Three ZA treatments were tested by using either: 1°) a low single dose (120μgZA/kg, n=10; equivalent to human osteoporosis treatment), 2°) a low fractionated doses (20μgZA/kg daily for 6days either a total of 120μg/kg, n=15), and 3°) a high fractionated doses, (100μgZA/kg weekly for 6weeks, n=15; equivalent to 6months of human bone metastasis treatment). For each treatment, a control "vehicle" treatment was performed (with an identical number of rats). After ZA administration, the intrinsic bone material properties were evaluated by quantitative backscattered electron imaging (qBEI) and Raman microspectroscopy. Neither single nor fractionated low ZA doses modify the intrinsic bone material properties of the newly-formed bone compared to their respective control animals. On the opposite, the high ZA treatment resulted in a significant decrease of the crystallinity (-25%, P< 0.05) and of the hydroxyproline-to-proline ratio (-30%, P<0.05) in newly-formed bones. Moreover, with the high ZA treatment, the crystallinity was positively correlated with the hydroxyproline-to-proline ratio (ρ=0.78, P<0.0001). The present data highlight new properties for ZA on bone formation in a craniofacial defect model. As such, ZA at high doses disrupted the apatite crystal organization. In addition, we report here for the first time that high ZA doses decreased the hydroxyproline-to-proline ratio suggesting that ZA may affect the early collagen organization during the bone healing. Copyright © 2016 Elsevier Inc. All rights reserved.

Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram.

PubMed

Kasper, Siegfried; Sacher, Julia; Klein, Nikolas; Mossaheb, Nilufar; Attarbaschi-Steiner, Trawat; Lanzenberger, Rupert; Spindelegger, Christoph; Asenbaum, Susanne; Holik, Alexander; Dudczak, Robert

2009-05-01

Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than citalopram in the treatment of major depressive disorder. However, the precise mechanism by which escitalopram achieves superiority over citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at a low-affinity allosteric site on serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, high-affinity serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in citalopram-treated and escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of escitalopram compared with citalopram in major depressive disorder.

Radiation induced leakage due to stochastic charge trapping in isolation layers of nanoscale MOSFETs

NASA Astrophysics Data System (ADS)

Zebrev, G. I.; Gorbunov, M. S.; Pershenkov, V. S.

2008-03-01

The sensitivity of sub-100 nm devices to microdose effects, which can be considered as intermediate case between cumulative total dose and single event errors, is investigated. A detailed study of radiation-induced leakage due to stochastic charge trapping in irradiated planar and nonplanar devices is developed. The influence of High-K insulators on nanoscale ICs reliability is discussed. Low critical values of trapped charge demonstrate a high sensitivity to single event effect.

Differential effects of pair housing on voluntary nicotine consumption: a comparison between male and female adolescent rats.

PubMed

Lee, Hyunchan; Jang, Minji; Kim, Woonhee; Noh, Jihyun

2017-08-01

Tobacco smoking occurs in a wide array of social circumstances. Social support for quitting is generally used to stop smoking, while peer interactions may be a crucial factor in triggering tobacco use among adolescents. To determine the role of social factors on nicotine dependence, we compared single- and pair-housed rats subjected to voluntary oral nicotine consumption tests. Six-week-old adolescent rats were subjected to experimental procedures and assigned to one of the following groups: a male single group, a male pair group with a sibling, a female single group, and a female pair group with a sibling. To measure voluntary nicotine intake, we adopted a two-bottle free-choice paradigm for each two days using 25 μg/ml and 100 μg/ml nicotine solution. There were no differences in change in body weight or food intake between the two groups of either sex. Pair-housed female rats showed a reduction in nicotine consumption and preference for both low- and high-dose nicotine solution, while pair-housed male rats showed only reduced consumption and preference for high-dose nicotine solution, but not low-dose solution, as compared to single-housed male rats. Nicotine consumption is sex-dependently controlled by the social circumstances of rats. This study broadens our perspectives on the role of social interactions as a therapeutic strategy to treat nicotine addiction-related behaviors depending on sex.

Bioavailability of modified-release methylphenidate: influence of high-fat breakfast when administered intact and when capsule content sprinkled on applesauce.

PubMed

Lee, Lucy; Kepple, Joanne; Wang, Yibin; Freestone, Stephen; Bakhtiar, Ray; Wang, Yanfeng; Hossain, Mohammad

2003-09-01

Ritalin, an immediate release form of racemic methylphenidate hydrochloride, has been available in the USA since 1955 and is used for the treatment of ADHD. The objective of this study was to evaluate the pharmacokinetics of modified-release methylphenidate (highest single dose), Ritalin LA, when administered under fasting condition, with a high-fat breakfast, and when sprinkled on applesauce in healthy adult subjects. Blood samples were drawn for 24 h following a 40 mg oral administration. Most subjects appeared to produce a bimodal methylphenidate plasma concentration profile. In all three treatment groups, methylphenidate was rapidly absorbed with an initial average t(max(0-4)) of 1.3-2.4 h and an average peak plasma concentration [C(max(abs))] of 14.4-15.2 ng/ml. On average, both the rate [C(max(abs)) and t(max(abs))] and the extent of absorption (AUC(0- infinity)) of methylphenidate were similar when the capsule was given with a high fat breakfast and when the capsule contents were sprinkled onto applesauce, compared with the fasting state. No dose dumping was observed when the capsule was given with a high fat breakfast or when sprinkled onto applesauce. The dose was safe and generally well tolerated. Coadministration of a single oral dose of 40 mg methylphenidate capsule whether administered intact with a high-fat breakfast or sprinkled on applesauce did not affect the overall rate or extent of absorption of methylphenidate compared with the fasted condition. Copyright 2003 John Wiley & Sons, Ltd.

Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites.

PubMed

Mahipal, Amit; Klapman, Jason; Vignesh, Shivakumar; Yang, Chung S; Neuger, Anthony; Chen, Dung-Tsa; Malafa, Mokenge P

2016-07-01

Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects. Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC. No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4-9.3 and 4.7-7.3 h, maximum concentration of 795.6-3742.6 and 493.3-3746 ng/mL, half-life of 1.7-5.9 and 2.3-6.9 h, and 0-12 h area under the curve of 4518.7-20,781.4 and 1987.7-22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30-60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed. Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.

Blood phenylalanine concentrations in patients with PAH-deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: assessing responsiveness in a model of statistical process control.

PubMed

Lindner, M; Gramer, G; Garbade, S F; Burgard, P

2009-08-01

Tetrahydrobiopterin (BH(4)) cofactor loading is a standard procedure to differentiate defects of BH(4) metabolism from phenylalanine hydroxylase (PAH) deficiency. BH(4) responsiveness also exists in PAH-deficient patients with high residual PAH activity. Unexpectedly, single cases with presumed nil residual PAH activity have been reported to be BH(4) responsive, too. BH(4) responsiveness has been defined either by a >or=30% reduction of blood Phe concentration after a single BH(4) dose or by a decline greater than the individual circadian Phe level variation. Since both methods have methodological disadvantages, we present a model of statistical process control (SPC) to assess BH(4) responsiveness. Phe levels in 17 adult PKU patients of three phenotypic groups off diet were compared without and with three different single oral dosages of BH(4) applied in a double-blind randomized cross-over design. Results are compared for >or=30% reduction and SPC. The effect of BH(4) by >or=30% reduction was significant for groups (p < 0.01) but not for dose (p = 0.064), with no interaction of group with dose (p = 0.24). SPC revealed significant effects for group (p < 0.01) and the interaction for group with dose (p < 0.05) but not for dose alone (p = 0.87). After one or more loadings, seven patients would be judged to be BH(4) responsive either by the 30% criterion or by the SPC model, but only three by both. Results for patients with identical PAH genotype were not very consistent within (for different BH(4) doses) and between the two models. We conclude that a comparison of protein loadings without and with BH(4) combined with a standardized procedure for data analysis and decision would increase the reliability of diagnostic results.

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

Efficacy and safety of a single 2 mg dose or 4 mg double dose of alteplase for 50 occluded chest ports using a unique instillation technique.

PubMed

Sharma, Rajinder P; Ree, Chung Ja; Ree, Alexander

2008-01-01

To evaluate the effectiveness and safety of a single 2 mg dose or a 4 mg double dose of alteplase for restoring function in occluded chest ports. A prospective, open-label, nonblinded study was performed on 40 enrolled patients with a total of 50 chest ports at the Henry Ford Hospital Interventional Radiology Department (Detroid, Michigan, USA). Alteplase (Cathflo Activase; Genentech, USA), a recombinant tissue plasminogen activator produced by recombinant DNA technology, was used to restore the function of 50 occluded chest ports. Occlusion was defined as the inability to withdraw blood freely from the port, or the inability to flush the port easily. A 2 mg (2 mL) dose of alteplase was injected into the port through a Huber needle, using a gentle push and pull technique, and was left to dwell for 30 min. If the port remained occluded after the initial 2 mg alteplase treatment, an additional 2 mg alteplase treatment was administered with the same dwell time of 30 min. If a port had remained occluded despite the above regimen, this outcome would have been considered a failure and the chest port would have required surgical intervention. However, all ports were successfully treated, and no surgical intervention was required. The safety end points included minor or major hemorrhages, such as intracranial hemorrhages, or sepsis. Safety end points were determined by a 24 h follow-up telephone call. Of the 50 chest ports (30 single ports and 10 double ports) treated with alteplase, 36 required 2 mg (72%) and 14 required 4 mg (28%). The efficacy end point was 100% for all chest ports treated, without any adverse events. High efficacy and safety rates of restoring function in occluded chest ports were obtained with 2 mg or 4 mg doses of alteplase. Part of this high efficacy rate may be due to the gentle push and pull technique used in the present study.

Single Versus Customized Treatment Planning for Image-guided High-Dose-Rate Brachytherapy for Cervical Cancer: Dosimetric Comparison and Predicting Factor for Organs at Risk Overdose With Single Plan Approach

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

Chi, Alexander; Gao Mingcheng; Sinacore, James

2009-09-01

Purpose: To compare the dose distribution between customized planning (CP) and adopting a single plan (SP) in multifractionated high-dose-rate brachytherapy and to establish predictors for the necessity of CP in a given patient. Methods and Materials: A total of 50 computed tomography-based plans for 10 patients were evaluated. Each patient had received 6 Gy for five fractions. The clinical target volume and organs at risk (i.e., rectum, bladder, sigmoid, and small bowel) were delineated on each computed tomography scan. For the SP approach, the same dwell position and time was used for all fractions. For the CP approach, the dwellmore » position and time were reoptimized for each fraction. Applicator position variation was determined by measuring the distance between the posterior bladder wall and the tandem at the level of the vaginal fornices. Results: The organs at risk D{sub 2cc} (dose to 2 cc volume) was increased with the SP approach. The dose variation was statistically similar between the tandem and ring and tandem and ovoid groups. The bladder D{sub 2cc} dose was 81.95-105.42 Gy{sub 2} for CP and 82.11-122.49 Gy{sub 2} for SP. In 5 of the 10 patients, the bladder would have been significantly overdosed with the SP approach. The variation of the posterior bladder wall distance from that in the first fraction was correlated with the increase in the bladder D{sub 2cc} (SP/CP), with a correlation coefficient of -0.59. Conclusion: Our results support the use of CP instead of the SP approach to help avoid a significant overdose to the bladder. This is especially true for a decrease in the posterior wall distance of {>=}0.5 cm compared with that in the first fraction.« less

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.

Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD).

PubMed

Press, Neil J; Taylor, Roger J; Fullerton, Joseph D; Tranter, Pamela; McCarthy, Clive; Keller, Thomas H; Arnold, Nicola; Beer, David; Brown, Lyndon; Cheung, Robert; Christie, Julie; Denholm, Alastair; Haberthuer, Sandra; Hatto, Julia D I; Keenan, Mark; Mercer, Mark K; Oakman, Helen; Sahri, Helene; Tuffnell, Andrew R; Tweed, Morris; Trifilieff, Alexandre

2015-09-10

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.

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).

Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

PubMed

Glue, Paul; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, Cheung-Tak; Friedhoff, Lawrence

2015-02-01

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers. © 2014, The American College of Clinical Pharmacology.

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

Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis

PubMed Central

Gallardo, Carmen R; Rigau Comas, David; Valderrama Rodríguez, Angélica; Roqué i Figuls, Marta; Parker, Lucy Anne; Caylà, Joan; Bonfill Cosp, Xavier

2016-01-01

Background People who are newly diagnosed with pulmonary tuberculosis (TB) typically receive a standard first-line treatment regimen that consists of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by four months of isoniazid and rifampicin. Fixed-dose combinations (FDCs) of these drugs are widely recommended. Objectives To compare the efficacy, safety, and acceptability of anti-tuberculosis regimens given as fixed-dose combinations compared to single-drug formulations for treating people with newly diagnosed pulmonary tuberculosis. Search methods We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library, Issue 11 2015); MEDLINE (1966 to 20 November 2015); EMBASE (1980 to 20 November 2015); LILACS (1982 to 20 November 2015); the metaRegister of Controlled Trials; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), without language restrictions, up to 20 November 2015. Selection criteria Randomized controlled trials that compared the use of FDCs with single-drug formulations in adults (aged 15 years or more) newly diagnosed with pulmonary TB. Data collection and analysis Two review authors independently assessed studies for inclusion, and assessed the risk of bias and extracted data from the included trials. We used risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with 95% confidence intervals (CIs). We attempted to assess the effect of treatment for time-to-event measures with hazard ratios and their 95% CIs. We used the Cochrane 'Risk of bias' assessment tool to determine the risk of bias in included trials. We used the fixed-effect model when there was little heterogeneity and the random-effects model with moderate heterogeneity. We used an I² statistic value of 75% or greater to denote significant heterogeneity, in which case we did not perform a meta-analysis. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results We included 13 randomized controlled trials (RCTs) in the review, which enrolled 5824 participants. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants. Overall there is little or no difference detected between FDCs and single-drug formulations for most outcomes reported. We did not detect a difference in treatment failure between FDCs compared with single-drug formulations (RR 1.28, 95% CI 0.82 to 2.00; 3606 participants, seven trials, moderate quality evidence). Relapse may be more frequent in people treated with FDCs compared to single-drug formulations, although the confidence interval (CI) includes no difference (RR 1.28, 95% CI 1.00 to 1.64; 3621 participants, 10 trials, low quality evidence). We did not detect any difference in death between fixed-dose and single-drug formulation groups (RR 0.96, 95% CI 0.67 to 1.39; 4800 participants, 11 trials, moderate quality evidence). When we compared FDCs with single-drug formulations we found little or no difference for sputum smear or culture conversion at the end of treatment (RR 0.99, 95% CI 0.96 to 1.02; 2319 participants, seven trials, high quality evidence), for serious adverse events (RR 1.45, 95% CI 0.90 to 2.33; 3388 participants, six trials, moderate quality evidence), and for adverse events that led to discontinuation of therapy (RR 0.96, 95% CI 0.56 to 1.66; 5530 participants, 13 trials, low quality evidence). We conducted a sensitivity analysis excluding studies at high risk of bias and this did not alter the review findings. Authors' conclusions Fixed-dose combinations and single-drug formulations probably have similar effects for treating people with newly diagnosed pulmonary TB. PLAIN LANGUAGE SUMMARY Fixed-dose combinations for treating pulmonary tuberculosis What are fixed-dose combinations and how might they improve care of people with tuberculosis Tuberculosis (TB) is an important health problem, especially in developing countries. The treatment for pulmonary TB in new patients includes four oral medicines taken for six months, sometimes as fixed-dose combinations (FDCs) that are combined in one tablet, or taken separately as single-drug formulations. The World Health Organization recommends prescribers use fixed-dose combinations to reduce the number of tablets that people take. On the supply side, this might reduce prescribing errors and improve drug supply efficiency; on the patient's side, FDCS simplify treatment and improve adherence. We conducted a review to assess the efficacy, safety, and acceptability of FDCs compared with single-drug formulations for treating people with newly diagnosed pulmonary TB. What the research says We searched for relevant trials up to 20 November 2015, and included 13 randomized controlled trials that enrolled 5824 people. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants. There is probably little or no difference in FDCs compared to single-drug formulations for treatment failure (moderate quality evidence); relapse may be more frequent (low quality evidence); and the number of deaths were similar (moderate quality evidence). There is little or no difference in sputum smear or culture conversion (high quality evidence), and no difference was shown for serious adverse events (moderate quality evidence) or adverse events that led to discontinuation of therapy (low quality evidence). Authors' conclusions We concluded that fixed-dose combinations have similar efficacy to single-drug formulations for treating people with newly diagnosed pulmonary TB. PMID:27186634

Dose estimation and dating of pottery from Turkey

NASA Astrophysics Data System (ADS)

Altay Atlıhan, M.; Şahiner, Eren; Soykal Alanyalı, Feriştah

2012-06-01

The luminescence method is a widely used technique for environmental dosimetry and dating archaeological, geological materials. In this study, equivalent dose (ED) and annual dose rate (AD) of an archaeological sample were measured. The age of the material was calculated by means of equivalent dose divided by the annual dose rate. The archaeological sample was taken from Antalya, Turkey. Samples were prepared by the fine grain technique and equivalent dose was found using multiple-aliquot-additive-dose (MAAD) and single aliquot regeneration (SAR) techniques. Also the short shine normalization-MAAD and long shine normalization-MAAD were applied and the results of the methods were compared with each other. The optimal preheat temperature was found to be 200 °C for 10 min. The annual doses of concentrations of the major radioactive isotopes were determined using a high-purity germanium detector and a low-level alpha counter. The age of the sample was found to be 510±40 years.

Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

PubMed

Chen, Z R; Somogyi, A A; Reynolds, G; Bochner, F

1991-04-01

1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolisers and 8 ml min-1 in the poor metaboliser; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of sublethal fenitrothion ingestion on cholinesterase inhibition, standard metabolism, thermal preference, and prey-capture ability in the Australian central bearded dragon (Pogona vitticeps, Agamidae).

PubMed

Bain, David; Buttemer, William A; Astheimer, Lee; Fildes, Karen; Hooper, Michael J

2004-01-01

The central bearded dragon (Pogona vitticeps) is a medium-sized lizard that is common in semiarid habitats in Australia and that potentially is at risk of fenitrothion exposure from use of the chemical in plague locust control. We examined the effects of single sublethal doses of this organophosphate (OP; low dose = 2.0 mg/kg; high dose = 20 mg/kg; control = vehicle alone) on lizard thermal preference, standard metabolic rate, and prey-capture ability. We also measured activities of plasma total cholinesterase (ChE) and acetylcholinesterase before and at 0, 2, 8, 24, 120, and 504 h after OP dosing. Predose plasma total ChE activity differed significantly between sexes and averaged 0.66 +/- 0.06 and 0.45 +/- 0.06 micromol/min/ml for males and females, respectively. Approximately 75% of total ChE activity was attributable to butyrylcholinesterase. Peak ChE inhibition reached 19% 2 h after OP ingestion in the low-dose group, and 68% 8 h after ingestion in high-dose animals. Neither OP doses significantly affected diurnal body temperature, standard metabolic rate, or feeding rate. Plasma total ChE levels remained substantially depressed up to 21 d after dosing in the high-dose group, making this species a useful long-term biomonitor of OP exposure in its habitat.

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,…

Single administration of intra-articular bupivacaine in arthroscopic knee surgery: a systematic review and meta-analysis.

PubMed

Sun, Qi-Bin; Liu, Shi-Dong; Meng, Qin-Jun; Qu, Hua-Zheng; Zhang, Zheng

2015-02-10

Single administration of intra-articular (IA) bupivacaine for pain relief after arthroscopic knee surgery is effective, but its active duration and dose-response relationship is unclear. We conducted this meta-analysis to summarize all published randomized controlled trials (RCTs), thus providing the most recent information on the safety and efficacy of single-administration IA bupivacaine for pain relief after arthroscopic knee surgery, and to determine whether a dose-response relationship exists. A systematic electronic literature search (through April 2014) was conducted to identify those RCTs that addressed the safety and efficacy of a single administration of IA bupivacaine for pain management after arthroscopic knee surgery. Subgroup analysis was conducted to determine changes in visual analog scale (VAS) scores at seven postoperative time points. Meta-regression and subgroup analyses were carried out to assess the effects of various treatment factors on efficacy and to evaluate the dose-response relationship of bupivacaine. Weighted mean differences or relative risks were calculated and pooled using a random-effects model. Twenty-eight trials involving 1,560 patients who underwent arthroscopic knee surgery met the inclusion criteria. The trials were subject to medium risk of bias. VAS scores at 2, 4, 6, 12, and 24 h postoperatively were significantly lower, the number of patients requiring supplementary analgesia was smaller, and the time to first request for analgesia was longer in the IA bupivacaine group than in the placebo group. The analgesic effect of single-administration IA bupivacaine may be associated with the effect of concomitant administration of epinephrine and concentration of bupivacaine, and no dose-response relationship was identified. No significant difference in side effects was detected between groups. Current evidence shows that the use of single-administration IA bupivacaine is effective for postoperative pain management in patients undergoing arthroscopic knee surgery, with satisfactory short-term safety. Low-dose administration of IA bupivacaine 0.5% combined with epinephrine adjuvant in clinical practice should be performed. Additional high-quality RCTs with longer follow-up periods are required to examine the safety of single-administration IA bupivacaine.

Rad-Hard/HI-REL FPGA

NASA Technical Reports Server (NTRS)

Wang, Jih-Jong; Cronquist, Brian E.; McGowan, John E.; Katz, Richard B.

1997-01-01

The goals for a radiation hardened (RAD-HARD) and high reliability (HI-REL) field programmable gate array (FPGA) are described. The first qualified manufacturer list (QML) radiation hardened RH1280 and RH1020 were developed. The total radiation dose and single event effects observed on the antifuse FPGA RH1280 are reported on. Tradeoffs and the limitations in the single event upset hardening are discussed.

Radiation Tests on 2Gb NAND Flash Memories

NASA Technical Reports Server (NTRS)

Nguyen, Duc N.; Guertin, Steven M.; Patterson, J. D.

2006-01-01

We report on SEE and TID tests of highly scaled Samsung 2Gbits flash memories. Both in-situ and biased interval irradiations were used to characterize the response of the total accumulated dose failures. The radiation-induced failures can be categorized as followings: single event upset (SEU) read errors in biased and unbiased modes, write errors, and single-event-functional-interrupt (SEFI) failures.

The impact of low-Z and high-Z metal implants in IMRT: A Monte Carlo study of dose inaccuracies in commercial dose algorithms

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

Spadea, Maria Francesca, E-mail: mfspadea@unicz.it; Verburg, Joost Mathias; Seco, Joao

2014-01-15

Purpose: The aim of the study was to evaluate the dosimetric impact of low-Z and high-Z metallic implants on IMRT plans. Methods: Computed tomography (CT) scans of three patients were analyzed to study effects due to the presence of Titanium (low-Z), Platinum and Gold (high-Z) inserts. To eliminate artifacts in CT images, a sinogram-based metal artifact reduction algorithm was applied. IMRT dose calculations were performed on both the uncorrected and corrected images using a commercial planning system (convolution/superposition algorithm) and an in-house Monte Carlo platform. Dose differences between uncorrected and corrected datasets were computed and analyzed using gamma index (Pγ{submore » <1}) and setting 2 mm and 2% as distance to agreement and dose difference criteria, respectively. Beam specific depth dose profiles across the metal were also examined. Results: Dose discrepancies between corrected and uncorrected datasets were not significant for low-Z material. High-Z materials caused under-dosage of 20%–25% in the region surrounding the metal and over dosage of 10%–15% downstream of the hardware. Gamma index test yielded Pγ{sub <1}>99% for all low-Z cases; while for high-Z cases it returned 91% < Pγ{sub <1}< 99%. Analysis of the depth dose curve of a single beam for low-Z cases revealed that, although the dose attenuation is altered inside the metal, it does not differ downstream of the insert. However, for high-Z metal implants the dose is increased up to 10%–12% around the insert. In addition, Monte Carlo method was more sensitive to the presence of metal inserts than superposition/convolution algorithm. Conclusions: The reduction in terms of dose of metal artifacts in CT images is relevant for high-Z implants. In this case, dose distribution should be calculated using Monte Carlo algorithms, given their superior accuracy in dose modeling in and around the metal. In addition, the knowledge of the composition of metal inserts improves the accuracy of the Monte Carlo dose calculation significantly.« less

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.

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.

Serum biomarkers for acute hepatotoxicity of Echis pyramidum snake venom in rats.

PubMed

Asmari, Abdulrahman K Al; Khan, Haseeb A; Banah, Faisal A; Buraidi, Ahmed A Al; Manthiri, Rajamohammed A

2015-01-01

Echis pyramidum is a venomous viper responsible for most cases of envenomation in Arabian Peninsula. We determined the acute phase (3-6 h) changes in serum markers of liver function including alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and bilirubin in adult male Sprague Dawley rats injected with Echis pyramidum venom (EPV) in the doses of 0.00 (control), 0.25, 0.50 and 1.00 mg/kg bodyweight. We also analyzed markers of oxidative stress including superoxide dismutase (SOD), catalase (CAT), total thiols (T-SH) and thiobarbituric acids reactive substances (TBARS) in liver. The results showed significant and dose- and time-dependent increases in serum ALT, ALP and GGT activities after a single injection of EPV. Serum bilirubin was significantly increased by medium and high doses of EVP after 3 h post-injection and then decreased at 6 h. The low dose of EPV neither affected the activity of SOD nor altered the levels of liver T-SH and TBARS, however, it significantly decreased the activity of CAT at 6 h post-injection of EPV. The medium dose of EPV significantly reduced liver SOD activity after 6 h whereas the high dose significantly reduced the SOD activity at 3 h and 6 h post-dosing. Both medium and high doses of EPV caused significant as well as dose- and time-dependent reductions in liver CAT activities. The high dose significantly reduced T-SH and increased TBARS in rat liver. Further studies are warranted to test the pharmacological potential of early phase antioxidant therapy for neutralizing the toxic effects of EPV.

Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy

PubMed Central

Ricotti, Valeria; Spinty, Stefan; Roper, Helen; Hughes, Imelda; Tejura, Bina; Robinson, Neil; Layton, Gary; Davies, Kay

2016-01-01

Purpose SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration ClinicalTrials.gov NCT02383511 PMID:27055247

Treatment of Human Scabies with Oral Ivermectin. Eczematous Eruptions as a New Non-Reported Adverse Event.

PubMed

Sanz-Navarro, J; Feal, C; Dauden, E

2017-09-01

Oral ivermectin is an alternative therapy for human scabies infection due to its ease of administration and good safety profile. However, there is no definitive consensus on the optimal dosing regimen. To describe the treatment of human scabies with different dosages of oral ivermectin and the possible adverse events. 23 patients with human scabies were treated with oral ivermectin: 10 patients received a single oral dose of 200μg/kg and 13 a dose of 400μg/kg. A second, or even a third dose, was administered in cases of treatment failure. A complete clinical response was achieved by all of the patients. The first ten patients required at least two (80%) or three (20%) doses of ivermectin for complete resolution of the infection. The remaining cases resolved with a single 400μg/kg oral dose. Within the first 72h after the administration of oral ivermectin, new cutaneous lesions were observed in eleven patients (47.8%). Cutaneous biopsies showed signs of subacute eczema. The eruption was treated with topical corticosteroids and emollient therapy. There was no other new drug administration or a history of irritants. There was no history of atopic diathesis except for one patient. Oral ivermectin is an effective therapy for the treatment of human scabies. A single 400μg/kg oral dose demonstrated high efficacy and good tolerance. However, the appearance of eczematous cutaneous lesions induced by oral ivermectin has not previously been reported in the literature. Dermatologists should be aware of this possible adverse event. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Monomeric DR2/MOG-35-55 recombinant TCR ligand treats relapses of experimental encephalomyelitis in DR2 transgenic mice.

PubMed

Link, Jason M; Rich, Cathleen M; Korat, Maya; Burrows, Gregory G; Offner, Halina; Vandenbark, Arthur A

2007-04-01

Treatment of human autoimmune diseases such as multiple sclerosis (MS) will likely require agents that can prevent or reverse the inflammatory process that results in clinical relapses and disease progression. We evaluated the ability of a newly designed monomeric recombinant TCR ligand (RTL342M) containing HLA-DR2 peptide-binding domains covalently linked to MOG-35-55 peptide to prevent and treat both the initial episode and subsequent relapses of experimental autoimmune encephalomyelitis (EAE) in HLA-DR2 transgenic mice. Single doses of RTL342M given either i.v. or s.c. to HLA-DR2 mice produced a rapid (within 24 h) and dose-dependent reversal of clinical signs of paralytic EAE, and even a single dose < or = 2 microg could produce a significant treatment effect. Multiple daily doses were even more effective than the same total amount of RTL given as a single dose. By establishing the minimal effective dose, we determined that RTLs may be 50 times more potent than molar equivalent doses of myelin peptide alone. RTL342M given prior to induction of EAE prevented disease in most mice, and the remainder could be successfully retreated with RTL. Most important for clinical application, RTL342M was highly effective for treating EAE relapses when given periodically prior to the relapse or even after relapses had occurred. These data demonstrate the rapid and potent clinical effects of RTL342M at disease onset and during relapses in EAE and establish important principles governing the application of this novel approach as a possible therapy for patients with MS.

Response of the RIF-1 tumor in vitro and in C3H/Km mice to x-radiation (cell survival, regrowth delay, and tumor control), chemotherapeutic agents, and activated macrophages

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

Brown, J.M.; Twentyman, P.R.; Zamvil, S.S.

1980-03-01

The radiation response of logarithmic growth phase and fed plateau phase RIF-1 cells in vitro was found to be characterized by D/sub 0/ values of 110 and 133 rads and extrapolation numbs of 36 and 28, respectively. The response of the tumor in vivo to X-irradiation in nonanesthetized mice showed a dependence on the tumor implantation site. In the leg muscle, the response indicated that most cells were at an intermediate level of oxygenation, whereas in the subcutaneous tissue of the flank, the response of the tumor indicated that it had a small fraction of hypoxic cells of maximum radioresistance.more » Misonidazole radiosensitized the leg-implanted tumor as measured both by cell survival and regrowth delay. The tumor was relatively insensitive to a single dose of 1,3-bis(2-chloroethyl)-1-nitrosourea, sensitive to a single dose of cis-platinum, and highly sensitive to a single dose of cyclophosphamide.« less

A randomized, double-blind, placebo-controlled trial of single-dose ciprofloxacin versus erythromycin for the treatment of chancroid in Nairobi, Kenya.

PubMed

Malonza, I M; Tyndall, M W; Ndinya-Achola, J O; Maclean, I; Omar, S; MacDonald, K S; Perriens, J; Orle, K; Plummer, F A; Ronald, A R; Moses, S

1999-12-01

A randomized, double-blind, placebo-controlled clinical trial was conducted in Nairobi, Kenya, to compare single-dose ciprofloxacin with a 7-day course of erythromycin for the treatment of chancroid. In all, 208 men and 37 women presenting with genital ulcers clinically compatible with chancroid were enrolled. Ulcer etiology was determined using culture techniques for chancroid, serology for syphilis, and a multiplex polymerase chain reaction for chancroid, syphilis, and herpes simplex virus (HSV). Ulcer etiology was 31% unmixed chancroid, 23% unmixed syphilis, 16% unmixed HSV, 15% mixed etiology, and 15% unknown. For 111 participants with chancroid, cure rates were 92% with ciprofloxacin and 91% with erythromycin. For all study participants, the treatment failure rate was 15%, mostly related to ulcer etiologies of HSV infection or syphilis, and treatment failure was 3 times more frequent in human immunodeficiency virus-infected subjects than in others, mostly owing to HSV infection. Ciprofloxacin is an effective single-dose treatment for chancroid, but current recommendations for empiric therapy of genital ulcers may result in high treatment failure due to HSV infection.

Peripheral nervous system injury after high-dose single-fraction image-guided stereotactic radiosurgery for spine tumors.

PubMed

Stubblefield, Michael D; Ibanez, Katarzyna; Riedel, Elyn R; Barzilai, Ori; Laufer, Ilya; Lis, Eric; Yamada, Yoshiya; Bilsky, Mark H

2017-03-01

OBJECTIVE The object of this study was to determine the percentage of high-dose (1800-2600 cGy) single-fraction stereotactic radiosurgery (SF-SRS) treatments to the spine that result in peripheral nervous system (PNS) injury. METHODS All patients treated with SF-SRS for primary or metastatic spine tumors between January 2004 and May 2013 and referred to the Rehabilitation Medicine Service for evaluation and treatment of neuromuscular, musculoskeletal, or functional impairments or pain were retrospectively identified. RESULTS Five hundred fifty-seven SF-SRS treatments in 447 patients resulted in 14 PNS injuries in 13 patients. All injures resulted from SF-SRS delivered to the cervical or lumbosacral spine at 2400 cGy. The overall percentage of SF-SRS treatments resulting in PNS injury was 2.5%, increasing to 4.5% when the thoracic spine was excluded from analysis. The median time to symptom onset following SF-SRS was 10 months (range 4-32 months). The plexus (cervical, brachial, and/or lumbosacral) was affected clinically and/or electrophysiologically in 12 (86%) of 14 cases, the nerve root in 2 (14%) of 14, and both in 6 (43%) of 14 cases. All patients experienced pain and most (93%) developed weakness. Peripheral nervous system injuries were CTCAE Grade 1 in 14% of cases, 2 in 64%, and 3 in 21%. No dose relationship between SF-SRS dose and PNS injury was detected. CONCLUSIONS Single-fraction SRS to the spine can result in PNS injury with major implications for function and quality of life.

Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination

PubMed Central

Derbise, Anne; Hanada, Yuri; Khalifé, Manal; Carniel, Elisabeth; Demeure, Christian E.

2015-01-01

Background No efficient vaccine against plague is currently available. We previously showed that a genetically attenuated Yersinia pseudotuberculosis producing the Yersinia pestis F1 antigen was an efficient live oral vaccine against pneumonic plague. This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably. Methodology/Principal Findings The caf operon encoding F1 was inserted into the chromosome of a genetically attenuated Y. pseudotuberculosis, yielding the VTnF1 strain, which stably produced the F1 capsule. Given orally to mice, VTnF1 persisted two weeks in the mouse gut and induced a high humoral response targeting both F1 and other Y. pestis antigens. The strong cellular response elicited was directed mostly against targets other than F1, but also against F1. It involved cells with a Th1—Th17 effector profile, producing IFNγ, IL-17, and IL-10. A single oral dose (108 CFU) of VTnF1 conferred 100% protection against pneumonic plague using a high-dose challenge (3,300 LD50) caused by the fully virulent Y. pestis CO92. Moreover, vaccination protected 100% of mice from bubonic plague caused by a challenge with 100 LD50 Y. pestis and 93% against a high-dose infection (10,000 LD50). Protection involved fast-acting mechanisms controlling Y. pestis spread out of the injection site, and the protection provided was long-lasting, with 93% and 50% of mice surviving bubonic and pneumonic plague respectively, six months after vaccination. Vaccinated mice also survived bubonic and pneumonic plague caused by a high-dose of non-encapsulated (F1-) Y. pestis. Significance VTnF1 is an easy-to-produce, genetically stable plague vaccine candidate, providing a highly efficient and long-lasting protection against both bubonic and pneumonic plague caused by wild type or un-encapsulated (F1-negative) Y. pestis. To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection against the two forms of plague after a single oral administration. PMID:26473734

Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination.

PubMed

Derbise, Anne; Hanada, Yuri; Khalifé, Manal; Carniel, Elisabeth; Demeure, Christian E

2015-01-01

No efficient vaccine against plague is currently available. We previously showed that a genetically attenuated Yersinia pseudotuberculosis producing the Yersinia pestis F1 antigen was an efficient live oral vaccine against pneumonic plague. This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably. The caf operon encoding F1 was inserted into the chromosome of a genetically attenuated Y. pseudotuberculosis, yielding the VTnF1 strain, which stably produced the F1 capsule. Given orally to mice, VTnF1 persisted two weeks in the mouse gut and induced a high humoral response targeting both F1 and other Y. pestis antigens. The strong cellular response elicited was directed mostly against targets other than F1, but also against F1. It involved cells with a Th1-Th17 effector profile, producing IFNγ, IL-17, and IL-10. A single oral dose (108 CFU) of VTnF1 conferred 100% protection against pneumonic plague using a high-dose challenge (3,300 LD50) caused by the fully virulent Y. pestis CO92. Moreover, vaccination protected 100% of mice from bubonic plague caused by a challenge with 100 LD50 Y. pestis and 93% against a high-dose infection (10,000 LD50). Protection involved fast-acting mechanisms controlling Y. pestis spread out of the injection site, and the protection provided was long-lasting, with 93% and 50% of mice surviving bubonic and pneumonic plague respectively, six months after vaccination. Vaccinated mice also survived bubonic and pneumonic plague caused by a high-dose of non-encapsulated (F1-) Y. pestis. VTnF1 is an easy-to-produce, genetically stable plague vaccine candidate, providing a highly efficient and long-lasting protection against both bubonic and pneumonic plague caused by wild type or un-encapsulated (F1-negative) Y. pestis. To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection against the two forms of plague after a single oral administration.

Variable dose rate single-arc IMAT delivered with a constant dose rate and variable angular spacing

NASA Astrophysics Data System (ADS)

Tang, Grace; Earl, Matthew A.; Yu, Cedric X.

2009-11-01

Single-arc intensity-modulated arc therapy (IMAT) has gained worldwide interest in both research and clinical implementation due to its superior plan quality and delivery efficiency. Single-arc IMAT techniques such as the Varian RapidArc™ deliver conformal dose distributions to the target in one single gantry rotation, resulting in a delivery time in the order of 2 min. The segments in these techniques are evenly distributed within an arc and are allowed to have different monitor unit (MU) weightings. Therefore, a variable dose-rate (VDR) is required for delivery. Because the VDR requirement complicates the control hardware and software of the linear accelerators (linacs) and prevents most existing linacs from delivering IMAT, we propose an alternative planning approach for IMAT using constant dose-rate (CDR) delivery with variable angular spacing. We prove the equivalence by converting VDR-optimized RapidArc plans to CDR plans, where the evenly spaced beams in the VDR plan are redistributed to uneven spacing such that the segments with larger MU weighting occupy a greater angular interval. To minimize perturbation in the optimized dose distribution, the angular deviation of the segments was restricted to <=± 5°. This restriction requires the treatment arc to be broken into multiple sectors such that the local MU fluctuation within each sector is reduced, thereby lowering the angular deviation of the segments during redistribution. The converted CDR plans were delivered with a single gantry sweep as in the VDR plans but each sector was delivered with a different value of CDR. For four patient cases, including two head-and-neck, one brain and one prostate, all CDR plans developed with the variable spacing scheme produced similar dose distributions to the original VDR plans. For plans with complex angular MU distributions, the number of sectors increased up to four in the CDR plans in order to maintain the original plan quality. Since each sector was delivered with a different dose rate, extra mode-up time (xMOT) was needed between the transitions of the successive sectors during delivery. On average, the delivery times of the CDR plans were approximately less than 1 min longer than the treatment times of the VDR plans, with an average of about 0.33 min of xMOT per sector transition. The results have shown that VDR may not be necessary for single-arc IMAT. Using variable angular spacing, VDR RapidArc plans can be implemented into the clinics that are not equipped with the new VDR-enabled machines without compromising the plan quality or treatment efficiency. With a prospective optimization approach using variable angular spacing, CDR delivery times can be further minimized while maintaining the high delivery efficiency of single-arc IMAT treatment.

Disposition and metabolism of a novel prostanoid antiglaucoma medication, tafluprost, following ocular administration to rats.

PubMed

Fukano, Y; Kawazu, K

2009-08-01

The disposition and metabolism of tafluprost, an ester prodrug of the 15,15-difluoro-prostaglandin F(2alpha) antiglaucoma agent, have been studied in rats after ocular administration. Radioactivity was absorbed very rapidly into the eye and systemic circulation after a single ocular dose of 0.005% [(3)H]tafluprost ophthalmic solution, with maximum levels in plasma and most eye tissues occurring within 15 min. The absorption ratio of radioactivity was approximately 75%, suggesting the high availability of ocular administration of tafluprost. Approximately 10% of the dose was present in cornea at this time, and radioactivity concentrations in this tissue exceeded those in aqueous humor and iris/ciliary body throughout the 24-h study period. After repeated daily ocular doses, radioactivity levels remained greatest in cornea, followed by iris/ciliary body that replaced aqueous humor as the eye tissue containing the second highest radioactivity concentration. In female rats, radioactivity was excreted equally between urine and feces after a single ocular dose, whereas in male rats more was excreted in feces, reflecting the greater biliary excretion in males rats (50% dose) compared with females rats (33% dose). Tafluprost was extensively metabolized in the rat, such that intact prodrug was not detected in plasma, tissues, or excreta by radio-high-performance liquid chromatography. On the other hand, the active moiety, tafluprost acid, was the only noteworthy radioactive component in cornea, aqueous humor, and iris/ciliary body for at least 8 h after the ocular dose, and it was also a major plasma metabolite in early time points. The gender differences in conjugation reactions resulted in the differences in the excretion.

Single-case experimental design yielded an effect estimate corresponding to a randomized controlled trial.

PubMed

Shadish, William R; Rindskopf, David M; Boyajian, Jonathan G

2016-08-01

We reanalyzed data from a previous randomized crossover design that administered high or low doses of intravenous immunoglobulin (IgG) to 12 patients with hypogammaglobulinaemia over 12 time points, with crossover after time 6. The objective was to see if results corresponded when analyzed as a set of single-case experimental designs vs. as a usual randomized controlled trial (RCT). Two blinded statisticians independently analyzed results. One analyzed the RCT comparing mean outcomes of group A (high dose IgG) to group B (low dose IgG) at the usual trial end point (time 6 in this case). The other analyzed all 12 time points for the group B patients as six single-case experimental designs analyzed together in a Bayesian nonlinear framework. In the randomized trial, group A [M = 794.93; standard deviation (SD) = 90.48] had significantly higher serum IgG levels at time six than group B (M = 283.89; SD = 71.10) (t = 10.88; df = 10; P < 0.001), yielding a mean difference of MD = 511.05 [standard error (SE) = 46.98]. For the single-case experimental designs, the effect from an intrinsically nonlinear regression was also significant and comparable in size with overlapping confidence intervals: MD = 495.00, SE = 54.41, and t = 495.00/54.41 = 9.10. Subsequent exploratory analyses indicated that how trend was modeled made a difference to these conclusions. The results of single-case experimental designs accurately approximated results from an RCT, although more work is needed to understand the conditions under which this holds. Copyright © 2016 Elsevier Inc. All rights reserved.

Amorphization resistance of nano-engineered SiC under heavy ion irradiation

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

Imada, Kenta; Ishimaru, Manabu; Xue, Haizhou

Silicon carbide (SiC) with a high-density of planar defects (hereafter, ‘nano-engineered SiC’) and epitaxially-grown single-crystalline 3C-SiC were simultaneously irradiated with Au ions at room temperature, in order to compare their relative resistance to radiation-induced amorphization. Furthermore, it was found that the local threshold dose for amorphization is comparable for both samples under 2 MeV Au ion irradiation; whereas, nano-engineered SiC exhibits slightly greater radiation tolerance than single crystalline SiC under 10 MeV Au irradiation. Under 10 MeV Au ion irradiation, the dose for amorphization increased by about a factor of two in both nano-engineered and single crystal SiC due tomore » the local increase in electronic energy loss that enhanced dynamic recovery.« less

Amorphization resistance of nano-engineered SiC under heavy ion irradiation

DOE PAGES

Imada, Kenta; Ishimaru, Manabu; Xue, Haizhou; ...

2016-06-19

Silicon carbide (SiC) with a high-density of planar defects (hereafter, ‘nano-engineered SiC’) and epitaxially-grown single-crystalline 3C-SiC were simultaneously irradiated with Au ions at room temperature, in order to compare their relative resistance to radiation-induced amorphization. Furthermore, it was found that the local threshold dose for amorphization is comparable for both samples under 2 MeV Au ion irradiation; whereas, nano-engineered SiC exhibits slightly greater radiation tolerance than single crystalline SiC under 10 MeV Au irradiation. Under 10 MeV Au ion irradiation, the dose for amorphization increased by about a factor of two in both nano-engineered and single crystal SiC due tomore » the local increase in electronic energy loss that enhanced dynamic recovery.« less

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.

New apparatus with high radiation energy between 320 to 460 nm: physical description and dermatological applications

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

Mutzhas, M.F.; Holzle, E.; Hofmann, C.

1981-01-01

A new apparatus (UVASUN 5000) is presented with high radiation energy between 320 to 460 nm. The radiator is a specially developed source for high uv-A intensity, housing a quartz bulb with a mixture of argon, mercury and metal-halides. The uv-A energy in the range of 320 to 400 nm is about 84% of the total radiation energy. Effects of very high doses of uv-A on human skin were studied. Following single uv-A applications the minimal tanning dose uv-A (MTD) and the immediate pigment darkening (IPD) dose of uv-A were established. Repeated exposure to this uv-A delivering system yields longmore » lasting dark brown skin pigmentation without any clinical or histological signs of sunburn (uv-B) damage, epidermal hyperplasia or thickening of the stratum corneum. Minimal therapeutic results were seen in the phototherapy of vitiligo and inflammatory acne.« less

Evaluation of Gafchromic EBT-XD film, with comparison to EBT3 film, and application in high dose radiotherapy verification.

PubMed

Palmer, Antony L; Dimitriadis, Alexis; Nisbet, Andrew; Clark, Catharine H

2015-11-21

There is renewed interest in film dosimetry for the verification of dose delivery of complex treatments, particularly small fields, compared to treatment planning system calculations. A new radiochromic film, Gafchromic EBT-XD, is available for high-dose treatment verification and we present the first published evaluation of its use. We evaluate the new film for MV photon dosimetry, including calibration curves, performance with single- and triple-channel dosimetry, and comparison to existing EBT3 film. In the verification of a typical 25 Gy stereotactic radiotherapy (SRS) treatment, compared to TPS planned dose distribution, excellent agreement was seen with EBT-XD using triple-channel dosimetry, in isodose overlay, maximum 1.0 mm difference over 200-2400 cGy, and gamma evaluation, mean passing rate 97% at 3% locally-normalised, 1.5 mm criteria. In comparison to EBT3, EBT-XD gave improved evaluation results for the SRS-plan, had improved calibration curve gradients at high doses, and had reduced lateral scanner effect. The dimensions of the two films are identical. The optical density of EBT-XD is lower than EBT3 for the same dose. The effective atomic number for both may be considered water-equivalent in MV radiotherapy. We have validated the use of EBT-XD for high-dose, small-field radiotherapy, for routine QC and a forthcoming multi-centre SRS dosimetry intercomparison.

Evaluation of Gafchromic EBT-XD film, with comparison to EBT3 film, and application in high dose radiotherapy verification

NASA Astrophysics Data System (ADS)

Palmer, Antony L.; Dimitriadis, Alexis; Nisbet, Andrew; Clark, Catharine H.

2015-11-01

There is renewed interest in film dosimetry for the verification of dose delivery of complex treatments, particularly small fields, compared to treatment planning system calculations. A new radiochromic film, Gafchromic EBT-XD, is available for high-dose treatment verification and we present the first published evaluation of its use. We evaluate the new film for MV photon dosimetry, including calibration curves, performance with single- and triple-channel dosimetry, and comparison to existing EBT3 film. In the verification of a typical 25 Gy stereotactic radiotherapy (SRS) treatment, compared to TPS planned dose distribution, excellent agreement was seen with EBT-XD using triple-channel dosimetry, in isodose overlay, maximum 1.0 mm difference over 200-2400 cGy, and gamma evaluation, mean passing rate 97% at 3% locally-normalised, 1.5 mm criteria. In comparison to EBT3, EBT-XD gave improved evaluation results for the SRS-plan, had improved calibration curve gradients at high doses, and had reduced lateral scanner effect. The dimensions of the two films are identical. The optical density of EBT-XD is lower than EBT3 for the same dose. The effective atomic number for both may be considered water-equivalent in MV radiotherapy. We have validated the use of EBT-XD for high-dose, small-field radiotherapy, for routine QC and a forthcoming multi-centre SRS dosimetry intercomparison.

The effects of recombinant activated factor VII dose on the incidence of thromboembolic events in patients with coagulopathic bleeding.

PubMed

Bucklin, Mason H; Acquisto, Nicole M; Nelson, Catherine

2014-05-01

Previous studies have suggested the used of off-label recombinant factor VII (rFVIIa) increases the risk of thromboembolic events, but the effect of the dose of rFVIIa is not well described in the literature. All adult patients that received off-label rFVIIa from 2005-2012 were included in this single-center, retrospective cohort study. The primary endpoint was the incidence of a thromboembolic event in the low dose (<50 mcg/kg) compared to the high dose (≥50 mcg/kg) cohort. Secondary endpoints compared time to thromboembolic event, incidence of arterial compared to venous events, and mortality. There were 152 patients that received rFVIIa during the study period with 66 in the low dose cohort and 86 in the high dose cohort. Mean total dose of rFVIIa was 30.2 mcg/kg (SD ± 9.5 mcg/kg) in the low dose and 99.8 mcg/kg (SD ± 64.7 mcg/kg) in the high dose cohort (p=0.0001). The overall incidence of thromboembolic events was 12.5%. There were 12 (14%) events in the low dose cohort and seven (10.6%) in the high dose cohort, RR=0.76 (95% CI 0.31-1.82). There were no differences in any of the secondary outcomes. A higher incidence of thromboembolic events in cardiothoracic surgery (20.8%) and penetrating trauma patients (21.4%) was seen compared to the remaining cohort (6.7%). No significant difference in the incidence of thromboembolic events was seen between low dose versus high dose rFVIIa over a seven year period at our institution. However, due to the relatively low overall incidence and a small sample size, type II error may be present. Copyright © 2014 Elsevier Ltd. All rights reserved.

High-Dose Selenium for the Mitigation of Radiation Injury: A Pilot Study in a Rat Model

PubMed Central

Sieber, Fritz; Muir, Sarah A.; Cohen, Eric P.; North, Paula E.; Fish, Brian L.; Irving, Amy A.; Mäder, Marylou; Moulder, John E.

2009-01-01

The purpose of this study was to evaluate in an animal model the safety and efficacy of dietary supplementation with high doses of selenium for the mitigation of the type of radiation injury that might be sustained during a nuclear accident or an act of radiological terrorism. Age-matched male rats were exposed to 10 Gy (single dose) of total-body irradiation (TBI) followed by a syngeneic bone marrow transplant, then randomized to standard drinking water or drinking water supplemented with sodium selenite or seleno-L-methionine. At 21 weeks after TBI, most rats on standard drinking water had severe renal failure with a mean blood urea nitrogen (BUN) level of 124 ± 29 mg/dl (geometric mean ± SE) whereas rats on selenium-supplemented drinking water (100 μg/day) had a mean BUN level of 67 ± 12 mg/dl. The mitigating effect of selenium was confirmed by histopathological analyses. None of the animals on high-dose selenium showed signs of selenium toxicity. Our results suggest that dietary supplementation with high-dose selenium may provide a safe, effective and practical way to mitigate radiation injury to kidneys. PMID:19267564

Safety and Efficacy of a Single Dose of Anti-D (WinRho®) in Severe Thrombocytopenia Secondary to Dengue Virus Infection

PubMed Central

Pannu, Ashok Kumar; Bhalla, Ashish; Singhal, Mayank; Suri, Vikas; Shafiq, Nusrat; Varma, Subhash

2017-01-01

Objective: To evaluate the efficacy of a single intravenous (IV) dose of anti-D in severe thrombocytopenia (<20,000) due to dengue virus (DEV) infection. Materials and Methods: An open label, investigator-initiated, randomized interventional study was conducted that included thirty dengue patients (all positive for IgM enzyme-linked immunosorbent assay) with severe thrombocytopenia (<20,000/mm3). Patients were randomized to receive anti-D (50 μg/kg single IV dose) plus supportive therapy or supportive therapy alone. Results: The rate of rise in platelet count was significantly high in the intervention group at 24, 36, and 48 h. At the end of 48 h, 60% patients in the intervention group achieved a platelet count of ≥50,000/mm3 as compared to 6.7% in the control group (P = 0.0019). The requirement of the platelet concentrate infusion in the control group was significantly higher, i.e. 342 ml (±193) as compared to the intervention group requiring only 187 ml (±79). The intervention group showed a significant improvement in bleeding manifestations in all the patients by 24 h in Grade 2 bleed (P = 0.032) and by 48 h in Grade 1 bleed (P = 0.014). Conclusions: Severe thrombocytopenia (≤20,000/mm3) secondary to DEV infection was rapidly and safely reversed by administration of a single dose of 50 μg/kg (250 IU/kg) anti-D IV. PMID:28250602

Pharmacokinetics of tilmicosin after oral administration in swine.

PubMed

Shen, Jianzhong; Li, Cun; Jiang, Haiyang; Zhang, Suxia; Guo, Ping; Ding, Shuangyang; Li, Xiaowei

2005-06-01

To determine the pharmacokinetics of tilmicosin after oral administration of a single dose of tilmicosin base in swine. 10 healthy swine. Tilmicosin base was administered via stomach tube at a single dose of 20 mg/kg (n = 5) or 40 mg/kg (5). Blood samples were obtained from a jugular vein immediately before and at 10, 20, and 30 minutes and 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours after administration of tilmicosin. Tilmicosin concentrations in serum were quantified by use of a high-performance liquid chromatography procedure with UV light. Data for tilmicosin concentrations versus time were analyzed by use of compartmental and noncompartmental methods. Tilmicosin concentrations in serum decreased in a biexponential manner after oral administration. Mean +/- SD values for absorption half-lives were 1.49 +/- 0.23 hours and 1.64 +/- 0.40 hours, distribution half-lives were 2.96 +/- 0.58 hours and 3.20 +/- 0.76 hours, elimination half-lives were 25.26 +/- 8.25 and 20.69 +/- 5.07 hours, peak concentrations were 1.19 +/- 0.30 microg/mL and 2.03 +/- 0.28 microg/mL, and time to peak concentrations was 3.12 +/- 0.50 hours and 3.48 +/- 0.77 hours after oral administration of tilmicosin base at a single dose of 20 or 40 mg/kg, respectively. In swine, tilmicosin was rapidly absorbed and slowly eliminated after oral administration of a single dose of tilmicosin base powder.

Cumulative doses analysis in young trauma patients: a single-centre experience.

PubMed

Salerno, Sergio; Marrale, Maurizio; Geraci, Claudia; Caruso, Giuseppe; Lo Re, Giuseppe; Lo Casto, Antonio; Midiri, Massimo

2016-02-01

Multidetector computed tomography (MDCT) represents the main source of radiation exposure in trauma patients. The radiation exposure of young patients is a matter of considerable medical concern due to possible long-term effects. Multiple MDCT studies have been observed in the young trauma population with an increase in radiation exposure. We have identified 249 young adult patients (178 men and 71 women; age range 14-40 years) who had received more than one MDCT study between June 2010 and June 2014. According to the International Commission on Radiological Protection publication, we have calculated the cumulative organ dose tissue-weighting factors by using CT-EXPO software(®). We have observed a mean cumulative dose of about 27 mSv (range from 3 to 297 mSv). The distribution analysis is characterised by low effective dose, below 20 mSv, in the majority of the patients. However, in 29 patients, the effective dose was found to be higher than 20 mSv. Dose distribution for the various organs analysed (breasts, ovaries, testicles, heart and eye lenses) shows an intense peak for lower doses, but in some cases high doses were recorded. Even though cumulative doses may have long-term effects, which are still under debate, high doses are observed in this specific group of young patients.

Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor.

PubMed

Herman, Ann E; Chinn, Leslie W; Kotwal, Shweta G; Murray, Elaine R; Zhao, Rui; Florero, Marilyn; Lin, Alyse; Moein, Anita; Wang, Rena; Bremer, Meire; Kokubu, Serika; Serone, Adrian P; Hanze, Eva L; Viberg, Anders; Morimoto, Alyssa M; Winter, Helen R; Katsumoto, Tamiko R

2018-06-01

GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications. © 2018 American Society for Clinical Pharmacology and Therapeutics.

Heuristic knowledge-based planning for single-isocenter stereotactic radiosurgery to multiple brain metastases.

PubMed

Ziemer, Benjamin P; Sanghvi, Parag; Hattangadi-Gluth, Jona; Moore, Kevin L

2017-10-01

Single-isocenter, volumetric-modulated arc therapy (VMAT) stereotactic radiosurgery (SRS) for multiple brain metastases (multimets) can deliver highly conformal dose distributions and reduce overall patient treatment time compared to other techniques. However, treatment planning for multimet cases is highly complex due to variability in numbers and sizes of brain metastases, as well as their relative proximity to organs-at-risk (OARs). The purpose of this study was to automate the VMAT planning of multimet cases through a knowledge-based planning (KBP) approach that adapts single-target SRS dose predictions to multiple target predictions. Using a previously published artificial neural network (ANN) KBP system trained on single-target, linac-based SRS plans, 3D dose distribution predictions for multimet patients were obtained by treating each brain lesion as a solitary target and subsequently combining individual dose predictions into a single distribution. Spatial dose distributions di(r→) for each of the i = 1…N lesions were merged using the combination function d(r→)=∑iNdin(r→)1/n. The optimal value of n was determined by minimizing root-mean squared (RMS) difference between clinical multimet plans and predicted dose per unit length along the line profile joining each lesion in the clinical cohort. The gradient measure GM=[3/4π]1/3V50%1/3-V100%1/3 is the primary quality metric for SRS plan evaluation at our institution and served as the main comparative metric between clinical plans and the KBP results. A total of 41 previously treated multimet plans, with target numbers ranging from N = 2-10, were used to validate the ANN predictions and subsequent KBP auto-planning routine. Fully deliverable KBP plans were developed by converting predicted dose distribution into patient-specific optimization objectives for the clinical treatment planning system (TPS). Plan parity was maintained through identical arc configuration and target normalization. Overall plan quality improvements were quantified by calculating the difference between SRS quality metrics (QMs): ΔQM = QM clinical  - QM KBP . In addition to GM, investigated QMs were: volume of brain receiving ≥ 10 Gy (V 10 Gy ), volume of brain receiving ≥ 5 Gy (ΔV 5 Gy ), heterogeneity index (HI), dose to 0.1 cc of the brainstem (D 0.1 cc ), dose to 1% of the optic chiasm (D 1% ), and interlesion dose (D IL ). In addition to this quantitative analysis, overall plan quality was assessed via blinded plan comparison of the manual and KBP treatment plans by SRS-specializing physicians. A dose combination factor of n = 8 yielded an integrated dose profile RMS difference of 2.9% across the 41-patient cohort. Multimet dose predictions exhibited ΔGM = 0.07 ± 0.10 cm against the clinical sample, implying either further normal tissue sparing was possible or that dose predictions were slightly overestimating achievable dose gradients. The latter is the more likely explanation, as this bias vanished when dose predictions were converted to deliverable KBP plans ΔGM = 0.00 ± 0.08 cm. Remaining QMs were nearly identical or showed modest improvements in the KBP sample. Equivalent QMs included: ΔV 10 Gy  = 0.37 ± 3.78 cc, ΔHI = 0.02 ± 0.08 and ΔD IL  = -2.22 ± 171.4 cGy. The KBP plans showed a greater degree of normal tissue sparing as indicated by brain ΔV 5 Gy  = 4.11± 24.05 cc, brainstem ΔD 0.1 cc  = 42.8 ± 121.4 cGy, and chiasm ΔD 1%  = 50.8 ± 83.0 cGy. In blinded review by SRS-specializing physicians, KBP-generated plans were deemed equivalent or superior in 32/41(78.1%) of the cases. Heuristic KBP-driven automated planning in linac-based, single-isocenter treatments for multiple brain metastases maintained or exceeded overall plan quality. © 2017 American Association of Physicists in Medicine.

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.

A novel adaptive needle insertion sequencing for robotic, single needle MR-guided high-dose-rate prostate brachytherapy

NASA Astrophysics Data System (ADS)

Borot de Battisti, M.; de Senneville, B. Denis; Hautvast, G.; Binnekamp, D.; Lagendijk, J. J. W.; Maenhout, M.; Moerland, M. A.

2017-05-01

MR-guided high-dose-rate (HDR) brachytherapy has gained increasing interest as a treatment for patients with localized prostate cancer because of the superior value of MRI for tumor and surrounding tissues localization. To enable needle insertion into the prostate with the patient in the MR bore, a single needle MR-compatible robotic system involving needle-by-needle dose delivery has been developed at our institution. Throughout the intervention, dose delivery may be impaired by: (1) sub-optimal needle positioning caused by e.g. needle bending, (2) intra-operative internal organ motion such as prostate rotations or swelling, or intra-procedural rectum or bladder filling. This may result in failure to reach clinical constraints. To assess the first aforementioned challenge, a recent study from our research group demonstrated that the deposited dose may be greatly improved by real-time adaptive planning with feedback on the actual needle positioning. However, the needle insertion sequence is left to the doctor and therefore, this may result in sub-optimal dose delivery. In this manuscript, a new method is proposed to determine and update automatically the needle insertion sequence. This strategy is based on the determination of the most sensitive needle track. The sensitivity of a needle track is defined as its impact on the dose distribution in case of sub-optimal positioning. A stochastic criterion is thus presented to determine each needle track sensitivity based on needle insertion simulations. To assess the proposed sequencing strategy, HDR prostate brachytherapy was simulated on 11 patients with varying number of needle insertions. Sub-optimal needle positioning was simulated at each insertion (modeled by typical random angulation errors). In 91% of the scenarios, the dose distribution improved when the needle was inserted into the most compared to the least sensitive needle track. The computation time for sequencing was less than 6 s per needle track. The proposed needle insertion sequencing can therefore assist in delivering an optimal dose in HDR prostate brachytherapy.

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

Room-temperature ferromagnetism observed in C-/N-/O-implanted MgO single crystals

NASA Astrophysics Data System (ADS)

Li, Qiang; Ye, Bonian; Hao, Yingping; Liu, Jiandang; Zhang, Jie; Zhang, Lijuan; Kong, Wei; Weng, Huimin; Ye, Bangjiao

2013-01-01

MgO single crystals were implanted with 70 keV C/N/O ions at room temperature with respective doses of 2 × 1016 and 2 × 1017 ions/cm2. All samples with high-dose implantation showed room temperature hysteresis in magnetization loops. Magnetization and slow positron annihilation measurements confirmed that room temperature ferromagnetism in O-implanted samples was attributed to the presence of Mg vacancies. Furthermore, the introduction of C or N played more effective role in ferromagnetic performance than Mg vacancies. Moreover, the magnetic moment possibly occurred from the localized wave function of unpaired electrons and the exchange interaction formed a long-range magnetic order.

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.

Anti-inflammatory and antiobesity effects of mulberry leaf and fruit extract on high fat diet-induced obesity.

PubMed

Lim, Hyun Hwa; Lee, Sung Ok; Kim, Sun Yeou; Yang, Soo Jin; Lim, Yunsook

2013-10-01

The purpose of this study was to investigate the anti-inflammatory and antiobesity effect of combinational mulberry leaf extract (MLE) and mulberry fruit extract (MFE) in a high-fat (HF) diet-induced obese mice. Mice were fed a control diet or a HF diet for nine weeks. After obesity was induced, the mice were administered with single MLE at low dose (133 mg/kg/day, LMLE) and high dose (333 mg/kg/day, HMLE) or combinational MLE and MFE (MLFE) at low dose (133 mg MLE and 67 mg MFE/kg/day, LMLFE) and high dose (333 mg MLE and 167 mg MFE/kg/day, HMLFE) by stomach gavage for 12 weeks. The mulberry leaf and fruit extract treatment for 12 weeks did not show liver toxicity. The single MLE and combinational MLFE treatments significantly decreased plasma triglyceride, liver lipid peroxidation levels and adipocyte size and improved hepatic steatosis as compared with the HF group. The combinational MLFE treatment significantly decreased body weight gain, fasting plasma glucose and insulin, and homeostasis model assessment of insulin resistance. HMLFE treatment significantly improved glucose control during intraperitoneal glucose tolerance test compared with the HF group. Moreover, HMLFE treatment reduced protein levels of oxidative stress markers (manganese superoxide dismutase) and inflammatory markers (monocyte chemoattractant protein-1, inducible nitric oxide synthase, C-reactive protein, tumour necrosis factor-α and interleukin-1) in liver and adipose tissue. Taken together, combinational MLFE treatment has potential antiobesity and antidiabetic effects through modulation of obesity-induced inflammation and oxidative stress in HF diet-induced obesity.

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.

Looking into future: challenges in radiation protection in medicine.

PubMed

Rehani, M M

2015-07-01

Radiation protection in medicine is becoming more and more important with increasing wider use of X-rays, documentation of effects besides the potential for long-term carcinogenic effects. With computed tomography (CT) likely to become sub-mSv in coming years, positron emission tomography (PET), single photon emission computed tomography (SPECT) and some of the nuclear medical examination will become focus of attraction as high-dose examinations, even though they are less-frequent ones. Clarity will be needed on radiation effects at levels of radiation doses encountered in a couple of CT scans and if effects are really cumulative. There is challenge to develop radiation metrics that can be used as easily as units of temperature and length and avoidance of multiple meaning of a single dose metric. Other challenges include development of biological indicators of radiation dose, transition from dose to a representative phantom to dose to individual patient, system for tracking of radiation exposure history of patient, avoidance of radiation-induced skin injury in patients and radiation cataract in staff, cutting down inappropriate referrals for radiological examinations, confidence building in patient and patient safety in radiotherapy. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B

PubMed Central

Nathwani, A.C.; Reiss, U.M.; Tuddenham, E.G.D.; Rosales, C.; Chowdary, P.; McIntosh, J.; Della Peruta, M.; Lheriteau, E.; Patel, N.; Raj, D.; Riddell, A.; Pie, J.; Rangarajan, S.; Bevan, D.; Recht, M.; Shen, Y.-M.; Halka, K.G.; Basner-Tschakarjan, E.; Mingozzi, F.; High, K.A.; Allay, J.; Kay, M.A.; Ng, C.Y.C.; Zhou, J.; Cancio, M.; Morton, C.L.; Gray, J.T.; Srivastava, D.; Nienhuis, A.W.; Davidoff, A.M.

2014-01-01

BACKGROUND In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose–response relationship, and the level of persistent or late toxicity. METHODS We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.) PMID:25409372

Acute oral dose of sodium nitrite induces redox imbalance, DNA damage, metabolic and histological changes in rat intestine.

PubMed

Ansari, Fariheen Aisha; Ali, Shaikh Nisar; Arif, Hussain; Khan, Aijaz Ahmed; Mahmood, Riaz

2017-01-01

Industrialization and unchecked use of nitrate/nitrite salts for various purposes has increased human exposure to high levels of sodium nitrite (NaNO2) which can act as a pro-oxidant and pro-carcinogen. Oral exposure makes the gastrointestinal tract particularly susceptible to nitrite toxicity. In this work, the effect of administration of a single acute oral dose of NaNO2 on rat intestine was studied. Animals were randomly divided into four groups and given single doses of 20, 40, 60 and 75 mg NaNO2/kg body weight. Untreated animals served as the control group. An NaNO2 dose-dependent decline in the activities of brush border membrane enzymes, increase in lipid peroxidation, protein oxidation, hydrogen peroxide levels and decreased thiol content was observed in all treated groups. The activities of various metabolic and antioxidant defense enzymes were also altered. NaNO2 induced a dose-dependent increase in DNA damage and DNA-protein crosslinking. Histopathological studies showed marked morphological damage in intestinal cells. The intestinal damage might be due to nitrite-induced oxidative stress, direct action of nitrite anion or chemical modification by reaction intermediates.

Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer.

PubMed

Guckenberger, Matthias; Klement, Rainer Johannes; Allgäuer, Michael; Appold, Steffen; Dieckmann, Karin; Ernst, Iris; Ganswindt, Ute; Holy, Richard; Nestle, Ursula; Nevinny-Stickel, Meinhard; Semrau, Sabine; Sterzing, Florian; Wittig, Andrea; Andratschke, Nicolaus; Flentje, Michael

2013-10-01

To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). There was strong evidence for a dose-response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p=0.07, BF=2.1 and p=0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs>20). Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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.

Meal size of high-fat food is reliably greater than high-carbohydrate food across externally-evoked single-meal tests and long-term spontaneous feeding in rat.

PubMed

Synowski, Stephen J; Smart, Andrew B; Warwick, Zoe S

2005-10-01

A series of studies in rat using isoenergetic (kcal/ml) liquid diets differing in fat content has previously found dietary fat to dose-dependently increase daily caloric intake. In single-meal tests in which meal initiation was externally evoked in feeding-associated environments, the behavioral expression of this overeating was found to be larger meal intake. The present studies confirmed the ecological validity of this larger meal size of high-fat diet (HF) relative to high-carbohydrate diet (HC): meal size of HF>HC in home-cage testing (Experiment 1), and during undisturbed, spontaneous feeding in which ingestive behavior was continuously monitored (Experiments 2 and 3). These findings demonstrate that single-meal paradigms yield results consistent with spontaneous feeding of high-fat and high-carbohydrate liquid diets, thus supporting the use of single-meal studies to better understand the physiological bases of elevated caloric intake associated with chronic consumption of a high-fat diet.

Comparison of optimized single and multifield irradiation plans of antiproton, proton and carbon ion beams.

PubMed

Bassler, Niels; Kantemiris, Ioannis; Karaiskos, Pantelis; Engelke, Julia; Holzscheiter, Michael H; Petersen, Jørgen B

2010-04-01

Antiprotons have been suggested as a possibly superior modality for radiotherapy, due to the energy released when antiprotons annihilate, which enhances the Bragg peak and introduces a high-LET component to the dose. However, concerns are expressed about the inferior lateral dose distribution caused by the annihilation products. We use the Monte Carlo code FLUKA to generate depth-dose kernels for protons, antiprotons, and carbon ions. Using these we then build virtual treatment plans optimized according to ICRU recommendations for the different beam modalities, which then are recalculated with FLUKA. Dose-volume histograms generated from these plans can be used to compare the different irradiations. The enhancement in physical and possibly biological dose from annihilating antiprotons can significantly lower the dose in the entrance channel; but only at the expense of a diffuse low dose background from long-range secondary particles. Lateral dose distributions are improved using active beam delivery methods, instead of flat fields. Dose-volume histograms for different treatment scenarios show that antiprotons have the potential to reduce the volume of normal tissue receiving medium to high dose, however, in the low dose region antiprotons are inferior to both protons and carbon ions. This limits the potential usage to situations where dose to normal tissue must be reduced as much as possible. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Vaccination With a Highly Attenuated Recombinant Vesicular Stomatitis Virus Vector Protects Against Challenge With a Lethal Dose of Ebola Virus

PubMed Central

Matassov, Demetrius; Marzi, Andrea; Latham, Terri; Xu, Rong; Ota-Setlik, Ayuko; Feldmann, Friederike; Geisbert, Joan B.; Mire, Chad E.; Hamm, Stefan; Nowak, Becky; Egan, Michael A.; Geisbert, Thomas W.; Eldridge, John H.; Feldmann, Heinz; Clarke, David K.

2015-01-01

Previously, recombinant vesicular stomatitis virus (rVSV) pseudotypes expressing Ebolavirus glycoproteins (GPs) in place of the VSV G protein demonstrated protection of nonhuman primates from lethal homologous Ebolavirus challenge. Those pseudotype vectors contained no additional attenuating mutations in the rVSV genome. Here we describe rVSV vectors containing a full complement of VSV genes and expressing the Ebola virus (EBOV) GP from an additional transcription unit. These rVSV vectors contain the same combination of attenuating mutations used previously in the clinical development pathway of an rVSV/human immunodeficiency virus type 1 vaccine. One of these rVSV vectors (N4CT1-EBOVGP1), which expresses membrane-anchored EBOV GP from the first position in the genome (GP1), elicited a balanced cellular and humoral GP-specific immune response in mice. Guinea pigs immunized with a single dose of this vector were protected from any signs of disease following lethal EBOV challenge, while control animals died in 7–9 days. Subsequently, N4CT1-EBOVGP1 demonstrated complete, single-dose protection of 2 macaques following lethal EBOV challenge. A single sham-vaccinated macaque died from disease due to EBOV infection. These results demonstrate that highly attenuated rVSV vectors expressing EBOV GP may provide safer alternatives to current EBOV vaccines. PMID:26109675

The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel, comparative clinical trial.

PubMed

Yu, Zhaocai; Liu, Wenchao; Wang, Ling; Liang, Houjie; Huang, Ying; Si, Xiaoming; Zhang, Helong; Liu, Duhu; Zhang, Hongmei

2009-01-01

This clinical trial was conducted to evaluate the efficacy and safety of Palonosetron in preventing chemotherapy-induced vomiting (CIV) among the Chinese cancer patients. Two hundred and forty patients were scheduled to be enrolled and randomized to receive a single intravenous dose of palonosetron 0.25 mg, or granisetron 3 mg, 30 min before receiving highly emetogenic chemotherapy. The primary efficacy endpoint was the complete response (CR) rate for acute CIV (during the 0-24-h interval after chemotherapy). Secondary endpoints included the CR rates for delayed CIV (more than 24 h after chemotherapy). Two hundred and eight patients were accrued and received study medication. CR rates for acute CIV were 82.69% for palonosetron and 72.12% for granisetron, which demonstrated that palonosetron was not inferior to granisetron in preventing acute CIV. Comparisons of CR rates for delayed CIV yielded no statistical difference between palonosetron and granisetron groups and did not reveal non-inferiority of palonosetron to granisetron. Adverse events were mostly mild to moderate, with quite low rates among the two groups. A single dose (0.25 mg) of palonosetron is not inferior to a single dose (3 mg) of granisetron in preventing CIV and possesses an acceptable safety profile in the Chinese population.

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

Tissue responses to low protracted doses of high let radiations or photons: Early and late damage relevant to radio-protective countermeasures

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

Ainsworth, E.J.; Afzal, S.M.J.; Crouse, D.A.

1988-01-01

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for ..gamma..-radiation. When total doses of 96 or 247 cGy of neutrons or ..gamma.. rays were givenmore » as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and ..gamma..-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. 63 refs., 6 figs., 7 tabs.« less

Double versus single high-dose melphalan 200 mg/m2 and autologous stem cell transplantation for multiple myeloma: a region-based study in 484 patients from the Nordic area

PubMed Central

Björkstrand, Bo; Klausen, Tobias W.; Remes, Kari; Gruber, Astrid; Knudsen, Lene M.; Bergmann, Olav J.; Lenhoff, Stig; Johnsen, Hans E.

2009-01-01

Autologous stem cell transplantation is still considered the standard of care in young patients with multiple myeloma (MM). This disease is the most common indication for high-dose therapy (HDT) supported by hematopoietic stem cell transplantation and much data support the benefit of this procedure. Results of randomized studies are in favor of tandem autologous transplantation although the effect on overall survival is unclear. Based on sequential registration trials in the Nordic area, we aimed to evaluate the outcome of conventional single or double HDT. During 1994–2000 we registered a total of 484 previously untreated patients under the age of 60 years at diagnosis who on a regional basis initially were treated with single [Trial NMSG #5/94 and #7/98 (N=383)] or double [Trial Huddinge Karolinska Turku Herlev (N=101)] high-dose melphalan (200 mg/m2) therapy supported by autologous stem cell transplantation. A complete or very good partial response was achieved by 40% of patients in the single transplant group and 60% of patients in the double transplant group (p=0.0006). The probability of surviving progression free for five years after the diagnosis was 25% (95% CL 18–32%) in the singletransplant group and 46% (95% CL 33–55%) in the double transplant group (p=0.0014). The estimated overall five-year survival rate was 60% in the single transplant group and 64% in the doubletransplant (p=0.9). In a multivariate analysis of variables, including single versus double transplantation, β2 microglobulin level, age, sex and disease stage, only β2 microglobulin level was predictive for overall survival (p>0.0001) and progression free survival (p=0.001). In accordance with these results, a 1:1 case-control matched comparison between double and single transplantation did not identify significant differences in overall and progression free survival. In this retrospective analysis up front double transplantation with melphalan (200 mg/m2) as compared to single transplantation did not seem to improve the final outcome among patients in the Nordic area. These data are in accordance with recent publications from the Bologna 96 trial indicating that a second transplant should not be recommended up front as standard care.

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.

Seropositivity among Korean Young Adults Approximately 2 Years after a Single-Dose Vaccination against Hepatitis A Virus.

PubMed

Song, Yeong-Jun; Lim, Jiseun; Park, Woong-Sub; Sohn, Haesook; Lee, Moo-Sik; Shin, Dong-Hoon; Kim, Chun-Bae; Kim, Hwasung; Oh, Gyung-Jae; Ki, Moran

2015-01-01

We previously observed 80.7% seropositivity and a significant interaction between gender and hepatitis A virus (HAV) vaccine type (Havrix vs. Epaxal) on the seropositivity approximately 11 months after single-dose HAV vaccinations in Korean young adults. Our objective was to evaluate seropositivity approximately 2 years after a single-dose HAV vaccination and the influence of demographic characteristics on seropositivity, including the interaction between gender and vaccine type. Seronegative medical school students were randomly vaccinated with Havrix or Epaxal. Based on a total serum anti-HAV antibody titer cutoff of 20 IU/mL, 338 participants (76.0%) of the 445 vaccinees were seropositive 20-25 months after a single-dose HAV vaccination. The seropositive rates were similar after vaccination with Havrix (77.0%) and Epaxal (74.9%). Univariate analysis indicated that female (p = 0.052) and less obese (p < 0.001) participants had a higher seropositive rate, whereas other characteristics such as age, alcohol use, smoking history, vaccine type, and follow-up duration were not associated with seropositivity. Multivariate analysis indicated that women (p = 0.026) and participants with moderate alcohol use (p < 0.001) showed significantly higher seropositive rates than men and participants with no or low alcohol use, respectively. The seropositive rates after vaccination with Havrix and Epaxal were 70.9% and 67.5% in men and 87.7% and 91.3% in women, respectively (p for interaction = 0.304). Compared with the seropositive rate approximately 11 months after vaccination, the seropositive rate decreased substantially only in men in the Havrix group (11.0% points), and consequently, the interaction between gender and vaccine type disappeared while seropositivity remained high (87.7% and 91.3% in Havrix and Epaxal groups, respectively) among women approximately 2 years after vaccination. Further studies are needed to assess whether the seropositive rate would be maintained in all groups more than 2 years after a single-dose HAV vaccination.

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

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.

Healthy individuals' immune response to the Bulgarian Crimean-Congo hemorrhagic fever virus vaccine.

PubMed

Mousavi-Jazi, Mehrdad; Karlberg, Helen; Papa, Anna; Christova, Iva; Mirazimi, Ali

2012-09-28

Crimean-Congo hemorrhagic fever virus (CCHFV) poses a great threat to public health due to its high mortality and transmission rate and wide geographical distribution. There is currently no specific antiviral therapy for CCHF. This study provides the first in-depth analysis of the cellular and humoral immune response in healthy individuals following injection of inactivated Bulgarian vaccine, the only CCHFV vaccine available at present. Vaccinated individuals developed robust, anti-CCHFV-specific T-cell activity as measured by IFN-γ ELISpot assay. The frequency of IFN-γ secreting T-cells was 10-fold higher in individuals after vaccination with four doses than after one single dose. High levels of CCHFV antibodies were observed following the first dose, but repeated doses were required to achieve antibodies with neutralizing activity against CCHFV. However, the neutralizing activity in these groups was low. Copyright © 2012 Elsevier Ltd. All rights reserved.

Detecting and locating light atoms from high-resolution STEM images: The quest for a single optimal design.

PubMed

Gonnissen, J; De Backer, A; den Dekker, A J; Sijbers, J; Van Aert, S

2016-11-01

In the present paper, the optimal detector design is investigated for both detecting and locating light atoms from high resolution scanning transmission electron microscopy (HR STEM) images. The principles of detection theory are used to quantify the probability of error for the detection of light atoms from HR STEM images. To determine the optimal experiment design for locating light atoms, use is made of the so-called Cramér-Rao Lower Bound (CRLB). It is investigated if a single optimal design can be found for both the detection and location problem of light atoms. Furthermore, the incoming electron dose is optimised for both research goals and it is shown that picometre range precision is feasible for the estimation of the atom positions when using an appropriate incoming electron dose under the optimal detector settings to detect light atoms. Copyright © 2016 Elsevier B.V. All rights reserved.

Live Attenuated B. pertussis as a Single-Dose Nasal Vaccine against Whooping Cough

PubMed Central

Mielcarek, Nathalie; Debrie, Anne-Sophie; Raze, Dominique; Bertout, Julie; Rouanet, Carine; Younes, Amena Ben; Creusy, Colette; Engle, Jacquelyn; Goldman, William E; Locht, Camille

2006-01-01

Pertussis is still among the principal causes of death worldwide, and its incidence is increasing even in countries with high vaccine coverage. Although all age groups are susceptible, it is most severe in infants too young to be protected by currently available vaccines. To induce strong protective immunity in neonates, we have developed BPZE1, a live attenuated Bordetella pertussis strain to be given as a single-dose nasal vaccine in early life. BPZE1 was developed by the genetic inactivation or removal of three major toxins. In mice, BPZE1 was highly attenuated, yet able to colonize the respiratory tract and to induce strong protective immunity after a single nasal administration. Protection against B. pertussis was comparable to that induced by two injections of acellular vaccine (aPV) in adult mice, but was significantly better than two administrations of aPV in infant mice. Moreover, BPZE1 protected against Bordetella parapertussis infection, whereas aPV did not. BPZE1 is thus an attractive vaccine candidate to protect against whooping cough by nasal, needle-free administration early in life, possibly at birth. PMID:16839199

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

PubMed Central

Fitzgerald, Kevin; White, Suellen; Borodovsky, Anna; Bettencourt, Brian R.; Strahs, Andrew; Clausen, Valerie; Wijngaard, Peter; Horton, Jay D.; Taubel, Jorg; Brooks, Ashley; Fernando, Chamikara; Kauffman, Robert S.; Kallend, David; Vaishnaw, Akshay; Simon, Amy

2018-01-01

BACKGROUND Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol. METHODS In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442.) PMID:27959715

Customizable radiotherapy enhancement (CuRE) for prostate cancer using platinum based nanoparticles

NASA Astrophysics Data System (ADS)

Cifter, Gizem

New approach to prostate cancer (PCa) therapy titled "Customizable Radiotherapy Enhancement (CuRE)" employs cisplatin (C), carboplatin (Ca) and oxaliplatin (O) nanoparticles (CNPs, CaNPs and ONPs) as adjuvants to brachytherapy and external beam radiation therapy (EBRT), with the CNPs/CaNPs/ONPs released in situ from either brachytherapy spacers or fudicials loaded with the nanoparticles. The chemotherapy dose from the nanoparticles released in situ from within the prostate capsule, is enhanced by the physical dose due to photon interactions with the nanoparticles. The physical dose enhancement is due to low energy photons from the brachytherapy and EBRT sources interacting with the high-Z platinum component of the nanoparticles, causing emission of short-range photoelectrons to boost dose to the tumor. By varying the nanoparticle parameters, such as size, initial concentration, functionalization, location of spacer or fiducial, and intra-tumor biodistribution, the dose enhancement can be customized to maximize dose to tumor cells while minimizing toxicity to healthy cells. The hypothesis is that the CuRE approach will be a more efficacious method for concomitant cisplatin/carboplatin/oxaliplatin and radiotherapy treatment of localized prostate cancer due to significant dose boost to the PCa cells with minimal toxicity to healthy tissue. To investigate this hypothesis, microdosimetry calculations employing the energy loss formula of Cole were used to calculate the dose enhancement to the PCa cells from the CNPs/CaNPs/OPNs. The dose enhancement ratio (DEF) representing the ratio of the overall dose in the presence of CNPs/CaNPs/ONPs to the dose without CNPs/CaNPs/ONPs was determined for a range of CNP/CaNP/OPN concentrations up to their FDA approved limits. The dose enhancement to endothelial cells with (EDEF) with single concentration of cisplatin (42.8 mg/g) was found 2.6 with Pd-103. When EBRT source was used with single concentration of cisplatin, with 10cm x 10cm field size, at 10 cm depth with standard setting, EDEF was found 2.4. Dose enhancement to tumor cells (DEF) with single concentration of cisplatin was found 5.9 with I-125 while it was found 3.1 when EBRT source was used. The results predict that major localized dose enhancement to PCa cells can be achieved using targeted CNP/CaNP/OPN.

Potential for focused beam orthovoltage therapy

NASA Astrophysics Data System (ADS)

Mahato, Dip N.; MacDonald, C. A.

2010-08-01

Radiation therapy typically employs high energy photon beams because the low absorption coefficient at these energies minimizes skin dose with a conventional, unfocused beam. At orthovoltage energies less than 150 keV, the maximum dose for a single beam occurs very close to the skin surface. However a well-focused beam of low energy x rays can provide much higher flux at the target depth while sparing dose to the skin. The measured focal spot size for the polycapillary optic was 0.2 mm and was found to remain unchanged through 50 mm of phantom thickness. The calculated depth-dose curve was found to peak several centimeters below the surface with 25-40 keV radiation. Modeling indicates that the tumor dose would remain much higher than the skin dose even after scanning to cover a 1 cm3 tumor.

Intravenous iron isomaltoside 1000 administered by high single-dose infusions or standard medical care for the treatment of fatigue in women after postpartum haemorrhage: study protocol for a randomised controlled trial.

PubMed

Holm, Charlotte; Thomsen, Lars Lykke; Norgaard, Astrid; Langhoff-Roos, Jens

2015-01-14

Postpartum haemorrhage can lead to iron deficiency with and without anaemia, the clinical consequences of which include physical fatigue. Although oral iron is the standard treatment, it is often associated with gastrointestinal side effects and poor compliance. To date, no published randomised controlled studies have compared the clinical efficacy and safety of standard medical care with intravenous administration of iron supplementation after postpartum haemorrhage.The primary objective of this study is to compare the efficacy of an intravenous high single-dose of iron isomaltoside 1000 with standard medical care on physical fatigue in women with postpartum haemorrhage. In a single centre, open-labelled, randomised trial, women with postpartum haemorrhage exceeding 700 mL will be allocated to either a single dose of 1,200 mg of iron isomaltoside 1000 or standard medical care. Healthy parturients with a singleton pregnancy will be included within 48 hours after delivery.Participants will complete structured questionnaires that focus on several dimensions of fatigue and mental health (Multidimensional Fatigue Inventory, Edinburgh Postnatal Depression Scale and the Postpartum Questionnaire), at inclusion and at follow-up visits after three days, one week, three weeks, eight weeks, and 12 weeks postpartum. The primary endpoint is the aggregated change in physical fatigue score within 12 weeks postpartum, as measured by a subscale of the Multidimensional Fatigue Inventory. The primary objective will be considered to have been met if an intravenous high single dose of iron isomaltoside 1000 is shown to be superior to standard medical care in women after postpartum haemorrhage regarding physical fatigue.For claiming superiority, we set the minimal clinically relevant difference between the mean scores at 1.8, and the assumed standard deviation at 4.2. Hence, 87 participants per treatment group are needed in order to demonstrate superiority; to provide an extra margin for missing data and dropouts, 200 women will be included. The study will provide evidence on relevant clinical outcomes beyond biochemical parameters for intravenous iron isomaltoside 1000 compared to standard medical care in women after postpartum haemorrhage. This trial is registered with Clinicaltrials.gov (identifier: NCT01895218) on 26 June 2013.

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.

Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers: a double-blind, randomized, controlled study.

PubMed

Ragavendran, J Vaigunda; Laferrière, André; Bennett, Gary J; Ware, Mark A; Gandhi, Wiebke; Bley, Keith; Schweinhardt, Petra; Coderre, Terence J

2016-10-01

This double-blind randomized controlled study was designed to evaluate the analgesic effects of topical treatments with clonidine (CLON) and pentoxifylline (PTX) tested alone or as low- and high-dose combinations in a human experimental model of pain. Of 69 healthy subjects aged 18 to 60 years, 23 each were randomly allocated to low-dose (0.04% + 2%) and high-dose (0.1% + 5%) CLON + PTX groups. Both of these groups also received their corresponding placebos in one of 2 treatment periods separated by at least 48 hours. Twenty-three additional subjects received either CLON (0.1%) or PTX (5%) as single drug treatments, in each of 2 treatment periods. Assessment of analgesic efficacy was based on allodynic effects of previous intraepidermal capsaicin injection, as well as postcapsaicin tourniquet-induced pain 50 minutes following capsaicin injection. Visual Analogue Scale (VAS) ratings of pain intensity and the area of dynamic mechanical allodynia were the primary outcome measures, whereas area of punctate mechanical allodynia (PMA) served as a secondary outcome measure. Topical treatments with high- or low-dose combinations significantly reduced VAS ratings compared with corresponding placebo treatments throughout the period of postcapsaicin tourniquet-induced pain. Importantly, the high-dose combination produced lower VAS ratings than CLON alone, which were lower than PTX alone. Results also revealed significant inhibition of postcapsaicin dynamic mechanical allodynia and PMA for the high-dose combination compared with placebo, and of PMA for CLON compared with the low-dose combination. Hence, the present data are supportive of further clinical investigation of the high-dose topical combination of CLON + PTX in complex regional pain syndrome and neuropathic pain patients, for which our preclinical data predict efficacy.

Trial Evaluating Ambulatory Therapy of Travelers' Diarrhea (TrEAT TD) Study: A Randomized Controlled Trial Comparing 3 Single-Dose Antibiotic Regimens With Loperamide.

PubMed

Riddle, Mark S; Connor, Patrick; Fraser, Jamie; Porter, Chad K; Swierczewski, Brett; Hutley, Emma J; Danboise, Brook; Simons, Mark P; Hulseberg, Christine; Lalani, Tahaniyat; Gutierrez, Ramiro L; Tribble, David R

2017-11-29

Recommended treatment for travelers' diarrhea includes the combination of an antibiotic, usually a fluoroquinolone or azithromycin, and loperamide for rapid resolution of symptoms. However, adverse events, postdose nausea with high-dose azithromycin, effectiveness of single-dose rifaximin, and emerging resistance to front-line agents are evidence gaps underlying current recommendations. A randomized, double-blind trial was conducted in 4 countries (Afghanistan, Djibouti, Kenya, and Honduras) between September 2012 and July 2015. US and UK service members with acute watery diarrhea were randomized and received single-dose azithromycin (500 mg; 106 persons), levofloxacin (500 mg; 111 persons), or rifaximin (1650 mg; 107 persons), in combination with loperamide (labeled dosing). The efficacy outcomes included clinical cure at 24 hours and time to last unformed stool. Clinical cure at 24 hours occurred in 81.4%, 78.3%, and 74.8% of the levofloxacin, azithromycin, and rifaximin arms, respectively. Compared with levofloxacin, azithromycin was not inferior (P = .01). Noninferiority could not be shown with rifaximin (P = .07). At 48 and 72 hours, efficacy among regimens was equivalent (approximately 91% at 48 and 96% at 72 hours). The median time to last unformed stool did not differ between treatment arms (azithromycin, 3.8 hours; levofloxacin, 6.4 hours; rifaximin, 5.6 hours). Treatment failures were uncommon (3.8%, 4.4%, and 1.9% in azithromycin, levofloxacin, and rifaximin arms, respectively) (P = .55). There were no differences between treatment arms with postdose nausea, vomiting, or other adverse events. Single-dose azithromycin, levofloxacin, and rifaximin with loperamide were comparable for treatment of acute watery diarrhea. NCT01618591. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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.

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.

Pathology, Organ Distribution, and Immune Response after Single and Repeated Intravenous Injection of Rats with Clinical-Grade Parvovirus H1

PubMed Central

Geletneky, Karsten; Leoni, Anne-Laure; Pohlmeyer-Esch, Gabriele; Loebhard, Stephanie; Baetz, Andrea; Leuchs, Barbara; Roscher, Mandy; Hoefer, Constance; Jochims, Karin; Dahm, Michael; Huber, Bernard; Rommelaere, Jean; Krebs, Ottheinz; Hajda, Jacek

2015-01-01

Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated. PMID:25730754

An in-beam PET system for monitoring ion-beam therapy: test on phantoms using clinical 62 MeV protons

NASA Astrophysics Data System (ADS)

Camarlinghi, N.; Sportelli, G.; Battistoni, G.; Belcari, N.; Cecchetti, M.; Cirrone, G. A. P.; Cuttone, G.; Ferretti, S.; Kraan, A.; Retico, A.; Romano, F.; Sala, P.; Straub, K.; Tramontana, A.; Del Guerra, A.; Rosso, V.

2014-04-01

Ion therapy allows the delivery of highly conformal dose taking advantage of the sharp depth-dose distribution at the Bragg-peak. However, patient positioning errors and anatomical uncertainties can cause dose distortions. To exploit the full potential of ion therapy, an accurate monitoring system of the ion range is needed. Among the proposed methods to monitor the ion range, Positron Emission Tomography (PET) has proven to be the most mature technique, allowing to reconstruct the β+ activity generated in the patient by the nuclear interaction of the ions, that can be acquired during or after the treatment. Taking advantages of the spatial correlation between positron emitters created along the ions path and the dose distribution, it is possible to reconstruct the ion range. Due to the high single rates generated during the beam extraction, the acquisition of the β+ activity is typically performed after the irradiation (cyclotron) or in between the synchrotron spills. Indeed the single photon rate can be one or more orders of magnitude higher than normal for cyclotron. Therefore, acquiring the activity during the beam irradiation requires a detector with a very short dead time. In this work, the DoPET detector, capable of sustaining the high event rate generated during the cyclotron irradiation, is presented. The capability of the system to acquire data during and after the irradiation will be demonstrated by showing the reconstructed activity for different PMMA irradiations performed using clinical dose rates and the 62 MeV proton beam at the CATANA-LNS-INFN. The reconstructed activity widths will be compared with the results obtained by simulating the proton beam interaction with the FLUKA Monte Carlo. The presented data are in good agreement with the FLUKA Monte Carlo.

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.

Effect of Low- and High-Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First-in-Class BCL-2 Inhibitor.

PubMed

Salem, Ahmed Hamed; Agarwal, Suresh K; Dunbar, Martin; Nuthalapati, Silpa; Chien, David; Freise, Kevin J; Wong, Shekman L

2016-11-01

Venetoclax is a selective, first-in-class, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: (1) a bioequivalence study to compare the bioavailability of the film-coated tablet with that of an earlier uncoated tablet and (2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open-label, single-dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50 mg under nonfasting conditions, in each of 2 periods; one period used the uncoated tablet, and the other used the film-coated tablet. In the food effect study, 24 subjects received a single dose of venetoclax film-coated 100-mg tablet under fasting conditions, after a low-fat breakfast or after a high-fat breakfast in different periods. The venetoclax film-coated tablet was bioequivalent to the uncoated tablet, which indicates that the film coating does not affect bioavailability. The median T max of venetoclax was delayed by about 2 hours when administered with food. Compared with fasting conditions, C max and AUC increased by approximately 3.4-fold following a low-fat breakfast. High-fat meals increased C max and AUC by approximately 50% relative to low-fat meals. The mean terminal half-life was comparable between the high-fat meal and fasting conditions (19.1 versus 16.1 hours). Based on these results and the venetoclax exposure-response profile, venetoclax should be administered with food and without specific recommendations for fat content to ensure adequate and consistent bioavailability. © 2016, The American College of Clinical Pharmacology.

Childhood mortality after a high dose of vitamin A in a high risk population.

PubMed Central

Daulaire, N. M.; Starbuck, E. S.; Houston, R. M.; Church, M. S.; Stukel, T. A.; Pandey, M. R.

1992-01-01

OBJECTIVES--To determine whether a single high dose of vitamin A given to all children in communities with high mortality and malnutrition could affect mortality and to assess whether periodic community wide supplementation could be readily incorporated into an ongoing primary health programme. DESIGN--Opportunistic controlled trial. SETTING--Jumla district, Nepal. SUBJECTS--All children aged under 5 years; 3786 in eight subdistricts given single dose of vitamin A and 3411 in remaining eight subdistricts given no supplementation. MAIN OUTCOME MEASURES--Mortality and cause of death in the five months after supplementation. RESULTS--Risk of death for children aged 1-59 months in supplemented communities was 26% lower (relative risk 0.74, 95% confidence interval 0.55 to 0.99) than in unsupplemented communities. The reduction in mortality was greatest among children aged 6-11 months: death rate (deaths/1000 child years at risk) was 133.8 in supplemented children and 260.8 in unsupplemented children (relative risk 0.51, 0.30 to 0.89). The death rate from diarrhoea was also reduced (63.5 supplemented v 97.5 unsupplemented; relative risk 0.65, 0.44 to 0.95). The extra cost per death averted was about $11. CONCLUSION--The results support a role for Vitamin A in increasing child survival. The supplementation programme was readily integrated with the ongoing community health programme at little extra cost. PMID:1739794

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

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.

Development of TV003/TV005, a single dose, highly immunogenic live attenuated dengue vaccine; what makes this vaccine different from the Sanofi-Pasteur CYD™ vaccine?

PubMed

Whitehead, Stephen S

2016-01-01

Dengue is caused by four serotype-distinct dengue viruses (DENVs), and developing a multivalent vaccine against dengue has not been straightforward since partial immunity to DENV may predispose to more severe disease upon subsequent DENV infection. The vaccine that is furthest along in development is CYD™, a live attenuated tetravalent vaccine (LATV) produced by Sanofi Pasteur. Although the multi-dose vaccine demonstrated protection against severe dengue, its overall efficacy was limited by DENV serotype, serostatus at vaccination, region and age. The National Institute of Allergy and Infectious Diseases has developed the LATV dengue vaccines TV003/TV005. A single dose of either TV003 or TV005 induced seroconversion to four DENV serotypes in 74-92% (TV003) and 90% (TV005) of flavivirus seronegative adults and elicited near-sterilizing immunity to a second dose of vaccine administered 6-12 months later. The important differences in the structure, infectivity and immune responses to TV003/TV005 are compared with CYD™.

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.

Interstitial pneumonitis following bone marrow transplantation after low dose rate total body irradiation.

PubMed

Barrett, A; Depledge, M H; Powles, R L

1983-07-01

Idiopathic and infective interstitial pneumonitis (IPn) is a common complication after bone marrow transplantation (BMT) in many centers and carries a high mortality. We report here a series of 107 patients with acute leukemia grafted at the Royal Marsden Hospital in which only 11 (10.3%) developed IPn and only 5 died (5%). Only one case of idiopathic IPn was seen. Factors which may account for this low incidence are discussed. Sixty of 107 patients were transplanted in first remission of acute myeloid leukemia (AML) and were therefore in good general condition. Lung radiation doses were carefully monitored and doses of 10.5 Gy were not exceeded except in a group of 16 patients in whom a study of escalating doses of TBI (up to 13 Gy) was undertaken. The dose rate used for total body irradiation (TBI) was lower than that used in other centers and as demonstrated elsewhere by ourselves and others, reduction of dose rate to less than 0.05 Gy/min may be expected to lead to substantial reduction in lung damage. Threshold doses of approximately 8 Gy for IPn have been reported, but within the dose range of 8 to 10.5 Gy we suggest that dose rate may significantly affect the incidence. Data so far available suggest a true improvement in therapeutic ratio for low dose rate single fraction TBI compared with high dose rate.

Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity

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

Olson, J.J.; Friedman, R.; Orr, K.

1990-05-01

Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose,more » a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time.« less

SR-TXRF analysis of trace elements in whole blood and heart of rats: effects of irradiation with low and high doses

NASA Astrophysics Data System (ADS)

Mota, C. L.; Pickler, A.; Braz, D.; Barroso, R. C.; Mantuano, A.; Salata, C.; Ferreira-Machado, S. C.; Lau, C. C.; de Almeida, C. E.

2018-04-01

In the last decades, studies showed that the exposure to low doses of ionizing radiation of the body could sense and activate the cell signaling pathways needed to respond to any induced cellular damage. This procedure reduces cell killing compared with a single dose of high radiation dose. Damage to the vasculature can affect the function of most body organs by restricting blood flow and oxygen to tissues; however, the heart and brain are of main concern. The precise relationship between long-term health effects and low-dose exposures remain poorly understood. Biological markers are powerful tools that can be used to determine dose- response relationships and to estimate risk, especially when dealing with, the effects of low dose exposures in humans. These markers should be specific, sensitive, as well as easy and fast to quantify. Various types of biologic specimens are potential candidates for identifying biomarkers but blood has the advantage of being minimally invasive to obtain. In this study, we propose to apply total reflection X-ray fluorescence to quantify possible chemical elemental concentration (sulfer, iron, zinc, potassium and calcium) changes in blood and heart tissues of Wistar rats after total body irradiation with low (0.1 Gy) and high (2.5 Gy) doses. The fluorescence measurements were carried out at the X-ray Fluorescence beamline in the Brazilian Synchrotron Light Laboratory. The results showed that the irradiated animals with low doses have significant alterations in blood and cardiac tissue when compared with animals that received high doses of radiation. Taken together the analysis of all the elements, we can observe that the radiation induced oxidative stress may be the leading cause for alteration of the elemental level in the studied samples.

Using a single tablet daily to treat latent tuberculosis infection in Brazil: bioequivalence of two different isoniazid formulations (300 mg and 100 mg) demonstrated by a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry method in a randomised, crossover study.

PubMed

Daher, André; Pitta, Luciana; Santos, Tereza; Barreira, Draurio; Pinto, Douglas

2015-06-01

The recommended treatment for latent tuberculosis (TB) infection in adults is a daily dose of isoniazid (INH) 300 mg for six months. In Brazil, INH was formulated as 100 mg tablets. The treatment duration and the high pill burden compromised patient adherence to the treatment. The Brazilian National Programme for Tuberculosis requested a new 300 mg INH formulation. The aim of our study was to compare the bioavailability of the new INH 300 mg formulation and three 100 mg tablets of the reference formulation. We conducted a randomised, single dose, open label, two-phase crossover bioequivalence study in 28 healthy human volunteers. The 90% confidence interval for the INH maximum concentration of drug observed in plasma and area under the plasma concentration vs. time curve from time zero to the last measurable concentration "time t" was 89.61-115.92 and 94.82-119.44, respectively. The main limitation of our study was that neither adherence nor the safety profile of multiple doses was evaluated. To determine the level of INH in human plasma, we developed and validated a sensitive, simple and rapid high-performance liquid chromatography-tandem mass spectrometry method. Our results showed that the new formulation was bioequivalent to the 100 mg reference product. This finding supports the use of a single 300 mg tablet daily strategy to treat latent TB. This new formulation may increase patients' adherence to the treatment and quality of life.

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.

Current clinical use of reteplase for thrombolysis. A pharmacokinetic-pharmacodynamic perspective.

PubMed

Martin, U; Kaufmann, B; Neugebauer, G

1999-04-01

Clinical evaluation of a new thrombolytic agent should start with a dose that provides adequate efficacy and has an acceptably low bleeding risk; this results in a narrow therapeutic window at the upper end of the dose-response curve. Angiographic patency of the infarct-related artery is still the clinical surrogate end-point for mortality in phase II dose-ranging studies. There is experimental and clinical evidence that the area under the concentration-time curve (AUC) for plasminogenolytic activity of a thrombolytic agent is positively correlated with patency of the infarct-related artery. Dose-ranging studies of the novel recombinant plasminogen activator reteplase in healthy volunteers enabled computation of a linear regression curve by which a clinical starting dose could be calculated for an adapted target AUC that would be clinically effective. Pharmacokinetic analysis also revealed that the half-life of reteplase is 4 times longer than that of the reference thrombolytic alteplase, thus allowing bolus injection. The suggested single bolus starting dose of 10U was supported by results from studies in a canine model of coronary thrombolysis. The feedback of insufficiently high patency rates compared with the increased efficacy of front-loaded and accelerated alteplase demanded optimisation strategies for reteplase. Animal experiments suggested that a double bolus regimen of reteplase would be preferable to doubling the single bolus dose. Pharmacokinetic modelling suggested a time interval of 30 min between the 2 bolus injections. Selection of the tested double bolus regimens was conservative and empirical. First, the previously tested single bolus of 15U was divided to 10 + 5U; secondly, the second bolus dose was increased to 10U. This strategy proved to be successful. The current dosage recommendation for reteplase is a double bolus intravenous injection of 10 + 10U, each over 2 min, 30 min apart. This produces a reduction in mortality in patients with acute myocardial infarction that is equivalent to that produced by front-loaded and accelerated infusion of alteplase.

Single-dose Intramuscular-injection Toxicology Test of Water-soluble Carthami-flos and Cervi cornu parvum Pharmacopuncture in a Rat Model.

PubMed

Park, Sunju; Sun, Seung-Ho

2015-09-01

The aim of the study is to investigate both the single-dose intramuscular injection toxicity and the approximate lethal dose of water-soluble Carthami-flos and Cervi cornu parvum pharmacopuncture (WCFC) in male and female Sprague-Dawley (SD) rats. The study was conducted at Biotoxtech Co. according to the Good Laboratory Practice (GLP) regulation and the toxicity test guidelines of the Ministry of Food and Drug Safety (MFDS) after approval of the Institutional Animal Care and Use Committee. Dosages for the control, high dose, middle dose and low dose groups were 0.5 mL/animal of saline and 0.5, 0.25 and 0.125 mL/animal of WCFC, respectively. WCFC was injected into the muscle of the left femoral region by using a disposable syringe (1 mL, 26 gauge). The general symptoms and mortality were observed 30 minutes, 1, 2, 4, and 6 hours after the first injection and then daily for 14 days after the injection. The body weights of the SD rats were measured on the day of the injection (before injection) and on the third, seventh, and fourteenth days after the injection. Serum biochemical and hematologic tests, necropsy examinations, and histopathologic examinations at the injection site were performed after the observation period. No deaths, abnormal clinical symptoms, or significant weight changes were observed in either male or female SD rats in the control or the test (0.125, 0.25, and 0.5 mL/animal) groups during the observation period. No significant differences in hematology and serum biochemistry and no macroscopic abnormalities at necropsy were found. No abnormal reactions at injection sites were noted on the topical tolerance tests. The results of this single-dose toxicity study show that WCFC is safe, its lethal doses in male and female SD rats being estimated to be higher than 0.5 mL/animal.

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.

Industrial-scale separation of high-purity single-chirality single-wall carbon nanotubes for biological imaging

PubMed Central

Yomogida, Yohei; Tanaka, Takeshi; Zhang, Minfang; Yudasaka, Masako; Wei, Xiaojun; Kataura, Hiromichi

2016-01-01

Single-chirality, single-wall carbon nanotubes are desired due to their inherent physical properties and performance characteristics. Here, we demonstrate a chromatographic separation method based on a newly discovered chirality-selective affinity between carbon nanotubes and a gel containing a mixture of the surfactants. In this system, two different selectivities are found: chiral-angle selectivity and diameter selectivity. Since the chirality of nanotubes is determined by the chiral angle and diameter, combining these independent selectivities leads to high-resolution single-chirality separation with milligram-scale throughput and high purity. Furthermore, we present efficient vascular imaging of mice using separated single-chirality (9,4) nanotubes. Due to efficient absorption and emission, blood vessels can be recognized even with the use of ∼100-fold lower injected dose than the reported value for pristine nanotubes. Thus, 1 day of separation provides material for up to 15,000 imaging experiments, which is acceptable for industrial use. PMID:27350127

A beam radiation monitor based on CVD diamonds for SuperB

NASA Astrophysics Data System (ADS)

Cardarelli, R.; Di Ciaccio, A.

2013-08-01

Chemical Vapor Deposition (CVD) diamond particle detectors are in use in the CERN experiments at LHC and at particle accelerator laboratories in Europe, USA and Japan mainly as beam monitors. Nowadays it is considered a proven technology with a very fast signal read-out and a very high radiation tolerance suitable for measurements in high radiation environment zones i.e. near the accelerators beam pipes. The specific properties of CVD diamonds make them a prime candidate for measuring single particles as well as high-intensity particle cascades, for timing measurements on the sub-nanosecond scale and for beam protection systems in hostile environments. A single-crystalline CVD (scCVD) diamond sensor, read out with a new generation of fast and high transition frequency SiGe bipolar transistor amplifiers, has been tested for an application as radiation monitor to safeguard the silicon vertex tracker in the SuperB detector from excessive radiation damage, cumulative dose and instantaneous dose rates. Test results with 5.5 MeV alpha particles from a 241Am radioactive source and from electrons from a 90Sr radioactive source are presented in this paper.

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.

Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission.

PubMed

Graves, Patricia M; Choi, Leslie; Gelband, Hellen; Garner, Paul

2018-02-02

The 8-aminoquinoline (8AQ) drugs act on Plasmodium falciparum gametocytes, which transmit malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to malaria treatment schedules in low-transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose-6-phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear. To assess the effects of single dose or short-course PQ (or an alternative 8AQ) alongside treatment for people with P. falciparum malaria. We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using 'malaria*', 'falciparum', 'primaquine', '8-aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017. Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. falciparum malaria. Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non-artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups. We included 24 RCTs and one quasi-RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non-artemisinin treatments (13 arms), and two trials included both artemisinin and non-artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing.No cluster trials evaluating community effects on malaria transmission met the inclusion criteria.With artemisinin treatmentLow dose PQInfectiousness (participants infectious to mosquitoes) was reduced (day 3 or 4: RR 0.12, 95% CI 0.02 to 0.88, 3 trials, 105 participants; day 8: RR 0.34, 95% CI 0.07 to 1.58, 4 trials, 243 participants; low certainty evidence). This translates to a reduction in percentage of people infectious on day 3 or 4 from 14% to 2%, and, for day 8, from 4% to 1%; the waning infectiousness in the control group by day 8 making the absolute effect smaller by day 8. For gametocytes detected by PCR, there was little or no effect of PQ at day 3 or 4 (RR 1.02, 95% CI 0.87 to 1.21; 3 trials, 414 participants; moderate certainty evidence); with reduction at day 8 (RR 0.52, 95% CI 0.41 to 0.65; 4 trials, 532 participants; high certainty evidence). Severe haemolysis was infrequent, with or without PQ, in these groups with few G6PD-deficient individuals (RR 0.98, 95% CI 0.69 to 1.39; 4 trials, 752 participants, moderate certainty evidence).Moderate dose PQInfectiousness was reduced (day 3 or 4: RR 0.13, 95% CI 0.02 to 0.94; 3 trials, 109 participants; day 8 RR 0.33, 95% CI 0.07 to 1.57; 4 trials, 246 participants; low certainty evidence). Illustrative risk estimates for moderate dose were the same as low dose. The pattern and level of certainty of evidence with gametocytes detected by PCR was the same as low dose, and severe haemolysis was infrequent in both groups.High dose PQInfectiousness was reduced (day 4: RR 0.2, 95% CI 0.02 to 1.68, 1 trial, 101 participants; day 8: RR 0.18, 95% CI 0.02 to 1.41, 2 trials, 181 participants, low certainty evidence). The effects on gametocyte prevalence showed a similar pattern to moderate and low dose PQ. Trials did not systematically report evidence of haemolysis.With non-artemisinin treatmentTrials with non-artemisinin treatment have been conducted only for moderate and high dose PQ. With high dose, infectiousness appeared markedly reduced on day 5 (RR 0.09, 95% CI 0.01 to 0.62; 30 participants, very low certainty evidence), with similar reductions at day 8. For both moderate dose (two trials with 221 people) and high dose (two trials with 30 people), reduction in gametocytes (detected by microscopy) showed similar patterns as for artemisinin treatments, with little or no effect at day 4 or 5, and larger effects by day 8. No trials with non-artemisinin partner drugs systematically sought evidence of severe haemolysis.Two trials comparing bulaquine with PQ suggest bulaquine may have larger effects on gametocytes by microscopy on day 8 (RR 0.41, 95% CI 0.26 to 0.66; 2 trials, 112 participants). A single low dose of PQ (0.25 mg/kg) added to artemisinin-based combination therapy for malaria reduces infectiousness of people to mosquitoes at day 3-4 and day 8, and appears as effective as higher doses. The absolute effect is greater at day 3 or 4, and smaller at day 8, in part because of the lower infectiousness in the control group. There was no evidence of increased haemolysis at 0.25 mg/kg, but few G6PD-deficient individuals were included in the trials. The effect on infectiousness precedes the effect of PQ on gametocyte prevalence. We do not know whether single dose PQ could reduce malaria transmission at community level.

Factors associated with higher oxytocin requirements in labor.

PubMed

Frey, Heather A; Tuuli, Methodius G; England, Sarah K; Roehl, Kimberly A; Odibo, Anthony O; Macones, George A; Cahill, Alison G

2015-09-01

To identify clinical characteristics associated with high maximum oxytocin doses in women who achieve complete cervical dilation. A retrospective nested case-control study was performed within a cohort of all term women at a single center between 2004 and 2008 who reached the second stage of labor. Cases were defined as women who had a maximum oxytocin dose during labor >20 mu/min, while women in the control group had a maximum oxytocin dose during labor of ≤20 mu/min. Exclusion criteria included no oxytocin administration during labor, multiple gestations, major fetal anomalies, nonvertex presentation, and prior cesarean delivery. Multiple maternal, fetal, and labor factors were evaluated with univariable analysis and multivariable logistic regression. Maximum oxytocin doses >20 mu/min were administered to 108 women (3.6%), while 2864 women received doses ≤20 mu/min. Factors associated with higher maximum oxytocin dose after adjusting for relevant confounders included maternal diabetes, birthweight >4000 g, intrapartum fever, administration of magnesium, and induction of labor. Few women who achieve complete cervical dilation require high doses of oxytocin. We identified maternal, fetal and labor factors that characterize this group of parturients.

Dosimetric characterization of a synthetic single crystal diamond detector in a clinical 62 MeV ocular therapy proton beam

NASA Astrophysics Data System (ADS)

Marinelli, Marco; Pompili, F.; Prestopino, G.; Verona, C.; Verona-Rinati, G.; Cirrone, G. A. P.; Cuttone, G.; La Rosa, R. M.; Raffaele, L.; Romano, F.; Tuvè, C.

2014-12-01

A synthetic single crystal diamond based Schottky photodiode was tested at INFN-LNS on the proton beam line (62 MeV) dedicated to the radiation treatment of ocular disease. The diamond detector response was studied in terms of pre-irradiation dose, linearity with dose and dose rate, and angular dependence. Depth dose curves were measured for the 62 MeV pristine proton beam and for three unmodulated range-shifted proton beams; furthermore, the spread-out Bragg peak was measured for a modulated therapeutic proton beam. Beam parameters, recommended by the ICRU report 78, were evaluated to analyze depth-dose curves from diamond detector. Measured dose distributions were compared with the corresponding dose distributions acquired with reference plane-parallel ionization chambers. Field size dependence of the output factor (dose per monitor unit) in a therapeutic modulated proton beam was measured with the diamond detector over the range of ocular proton therapy collimator diameters (5-30 mm). Output factors measured with the diamond detector were compared to the ones by a Markus ionization chamber, a Scanditronix Hi-p Si stereotactic diode and a radiochromic EBT2 film. Signal stability within 0.5% was demonstrated for the diamond detector with no need of any pre-irradiation dose. Dose and dose rate dependence of the diamond response was measured: deviations from linearity resulted to be within ±0.5% over the investigated ranges of 0.5-40.0 Gy and 0.3-30.0 Gy/min respectively. Output factors from diamond detector measured with the smallest collimator (5 mm in diameter) showed a maximum deviation of about 3% with respect to the high resolution radiochromic EBT2 film. Depth-dose curves measured by diamond for unmodulated and modulated beams were in good agreement with those from the reference plane-parallel Markus chamber, with relative differences lower than ±1% in peak-to-plateau ratios, well within experimental uncertainties. A 2.5% variation in diamond detector response was observed in angular dependence measurements carried-out by varying the proton beam incidence angle in the polar direction. The dosimetric characterization of the tested synthetic single crystal diamond detector clearly indicates its suitability for relative dosimetry in ocular therapy proton beams, with no need of any correction factors accounting for dose rate and linear energy transfer dependence.

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.

High Dose Cyclophosphamide without Stem Cell Rescue in 207 Patients with Aplastic anemia and other Autoimmune Diseases

PubMed Central

DeZern, Amy E.; Petri, Michelle; Drachman, Daniel B.; Kerr, Doug; Hammond, Edward R.; Kowalski, Jeanne; Tsai, Hua-Ling; Loeb, David M.; Anhalt, Grant; Wigley, Fredrick; Jones, Richard J.; Brodsky, Robert A.

2011-01-01

High-dose cyclophosphamide has long been used an anticancer agent, a conditioning regimen for hematopoietic stem cell transplantation and as potent immunosuppressive agent in autoimmune diseases including aplastic anemia. High-dose cyclophosphamide is highly toxic to lymphocytes but spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase, the major mechanism of cyclophosphamide inactivation. High dose cyclophosphamide therapy induces durable remissions in most patients with acquired aplastic anemia. Moreover, high-dose cyclophosphamide without hematopoietic stem cell rescue has shown activity in a variety of other severe autoimmune diseases. Here we review the history of cyclophosphamide as is applies to aplastic anemia (AA) and other autoimmune diseases. Included here are the historical data from early patients treated for AA as well as an observational retrospective study in a single tertiary care hospital. This latter component was designed to assess the safety and efficacy of high-dose cyclophosphamide therapy without stem cell rescue in patients with refractory autoimmune diseases. We analyzed fully the 140 patients with severe, progressive autoimmune diseases treated. All patients discussed here received cyclophosphamide, 50 mg/kg per day for 4 consecutive days. Response, relapse and overall survival were measured. Response was defined as a decrease in disease activity in conjunction with a decrease or elimination of immune modulating drugs. Relapse was defined as worsening disease activity and/or a requirement of an increase in dose of, or administration of new, immunosuppressive medications. Hematologic recovery occurred in all patients. The overall response rate of the was 95%, and 44% of those patients remain progression-free with a median follow up time of 36 (range 1–120) months for the 140 patients analyzed together. The overall actuarial and event free survival across all diseases at 60 months is 90.7% and 20.6%, respectively. High- dose cyclophosphamide without stem cell rescue is well-tolerated and induces a high rate of remissions in severe autoimmune diseases. PMID:21358440

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.

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.

Randomized trials of high-dose chemotherapy in breast cancer: fraud, the press and the data (or lessons learned in medical policy governing clinical research).

PubMed Central

Antman, Karen

2002-01-01

High dose therapy for breast cancer remains controversial. Of the 15 randomized trials of high dose therapy in breast cancer reported to date, two South African studies have been discredited leaving 13 remaining studies. Mortality was consistently low, in the 0 to 2.5% range, except for the BCNU containing American Intergroup study, which had a 7.4% toxic mortality rate. Seven of the remaining 13 studies randomized fewer than 200 patients. Three of these small studies have significant differences in disease free survival, and a fourth study has a trend in favor of high dose therapy. The other three small studies cannot exclude a survival difference of 20%. Of the 6 remaining moderately large trials of 219 to 885 randomized patients, 5 are adjuvant studies and one included patients with metastatic disease. Of the five adjuvant trials, four have significant differences in relapse rate favoring the high dose arm, and the remaining study has a trend (with a high dose sequential single agent design rather than combination therapy as in the other studies). A planned subset analysis of the first 284 patients in the largest study funded by the Dutch insurance industry showed a significant advantage for high dose therapy. Given the 2-year median time to relapse and an addition 2-year median to death after relapse, the follow up for survival of 3-5 years on these studies is still short. In the only moderately sized metastatic trial from the National Cancer Institute of Canada with a very short median follow-up of 19 months, a significant difference in disease free survival has emerged, with no difference in survival. PMID:12053718

Randomized trials of high-dose chemotherapy in breast cancer: fraud, the press and the data (or lessons learned in medical policy governing clinical research).

PubMed

Antman, Karen

2002-01-01

High dose therapy for breast cancer remains controversial. Of the 15 randomized trials of high dose therapy in breast cancer reported to date, two South African studies have been discredited leaving 13 remaining studies. Mortality was consistently low, in the 0 to 2.5% range, except for the BCNU containing American Intergroup study, which had a 7.4% toxic mortality rate. Seven of the remaining 13 studies randomized fewer than 200 patients. Three of these small studies have significant differences in disease free survival, and a fourth study has a trend in favor of high dose therapy. The other three small studies cannot exclude a survival difference of 20%. Of the 6 remaining moderately large trials of 219 to 885 randomized patients, 5 are adjuvant studies and one included patients with metastatic disease. Of the five adjuvant trials, four have significant differences in relapse rate favoring the high dose arm, and the remaining study has a trend (with a high dose sequential single agent design rather than combination therapy as in the other studies). A planned subset analysis of the first 284 patients in the largest study funded by the Dutch insurance industry showed a significant advantage for high dose therapy. Given the 2-year median time to relapse and an addition 2-year median to death after relapse, the follow up for survival of 3-5 years on these studies is still short. In the only moderately sized metastatic trial from the National Cancer Institute of Canada with a very short median follow-up of 19 months, a significant difference in disease free survival has emerged, with no difference in survival.

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.

Assessment of hepatitis B virus antibody titers in childhood cancer survivors.

PubMed

Fayea, Najwa Yahya; Kandil, Shaimaa Mohamed; Boujettif, Khadijah; Fouda, Ashraf Elsayed

2017-09-01

Pediatric patients suffering from cancer are at risk of hepatitis B virus (HBV) infection and its related complications even though it is considered a vaccine preventable disease. Little is known of the effects of chemotherapy, and even less is known regarding the impact of HBV booster on HBV antibody titers. It is the purpose of this study to investigate and measure the prevalence of the antihepatitis B surface antibodies (HBsAb) in childhood cancer survivors after completion of their chemotherapy treatment and to further evaluate survivors' response to a single booster dose of HBV vaccine. This observational, cross-sectional retrospective study included 43 patients, of which 37 (86%) were found to be seronegative (HBsAb titer <10 mIU/ml). The notable result was that, of the seronegative patients who received a booster dose of HBV vaccine, 90% of the tested cases exhibited a successful raising of HBsAb titers >10 mIU/ml. Childhood cancer survivors have high seronegative rates for HBV and the majority of the patients achieved HBsAb titer > 10mIU/ml with a single booster dose of HBV vaccine, which is worth further investigation and research. This study suggests revaccination against HBV post-chemotherapy treatment, as the recommended advice, especially in countries with a high prevalence of HBV infection. What is Known: • There is a variable prevalence of low HBsAb titers measured after the end of chemotherapy in childhood cancer survivors. • There are no universal guidelines for revaccination of these patients. What is New: • This research identified that 86% of childhood cancer survivors treated with standard chemotherapy were seronegative for HBV infection. • A single booster dose HBV vaccine was successful for the majority of patients (90%) to achieve HBsAb titers >10 mIU/ml.

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

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

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.

Radon Exposure and the Definition of Low Doses-The Problem of Spatial Dose Distribution.

PubMed

Madas, Balázs G

2016-07-01

Investigating the health effects of low doses of ionizing radiation is considered to be one of the most important fields in radiological protection research. Although the definition of low dose given by a dose range seems to be clear, it leaves some open questions. For example, the time frame and the target volume in which absorbed dose is measured have to be defined. While dose rate is considered in the current system of radiological protection, the same cancer risk is associated with all exposures, resulting in a given amount of energy absorbed by a single target cell or distributed among all the target cells of a given organ. However, the biological effects and so the health consequences of these extreme exposure scenarios are unlikely to be the same. Due to the heterogeneous deposition of radon progeny within the lungs, heterogeneous radiation exposure becomes a practical issue in radiological protection. While the macroscopic dose is still within the low dose range, local tissue doses on the order of Grays can be reached in the most exposed parts of the bronchial airways. It can be concluded that progress in low dose research needs not only low dose but also high dose experiments where small parts of a biological sample receive doses on the order of Grays, while the average dose over the whole sample remains low. A narrow interpretation of low dose research might exclude investigations with high relevance to radiological protection. Therefore, studies important to radiological protection should be performed in the frame of low dose research even if the applied doses do not fit in the dose range used for the definition of low doses.

Tissue responses to low protracted doses of high let radiations or photons - Early and late damage relevant to radio-protective countermeasures

NASA Technical Reports Server (NTRS)

Ainsworth, E. J.; Afzal, S. M. J.; Crouse, D. A.; Hanson, W. R.; Fry, R. J. M.

1989-01-01

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Recent studies on protection against early and late effects by aminothiols, prostaglandins, and other compounds are discussed.

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.

Letrozole combined with low dose highly purified HMG for ovulation induction in clomiphene citrate-resistant infertile Chinese women with polycystic ovary syndrome: a prospective study.

PubMed

Zhao, Yue; Ruan, Xiangyan; Mueck, Alfred O

2017-06-01

There are still open questions about ovulation induction in clomiphene citrate-(CC)-resistant infertile women. Especially little is known about efficacy and safety of letrozole (LTZ) combined with low-dose highly purified human menopausal gonadotropin (Hp-HMG) in women with polycystic ovary syndrome (PCOS). Prospective, single-arm single-center trial in 200 infertile PCOS patients refractory for at least three CC-treatment cycles. Women with hyperandrogenism took Diane-35 for at least 3 months. All patients got LTZ on day 3 for 5 d in combination with Hp-HMG, starting with 75 IU from cycle day 7 and maintained for up to 3 d. The maximum dose was 150 IU. Primary end-points were ongoing and clinical pregnancy rate, secondary end-points mono-follicular development, ovulation rate, OHSS, multiple pregnancy and early pregnancy loss. Major safety end-point was the incidence of adverse events. Within 395 cycles the ongoing pregnancy rate was 28.24%, for cycles 35.23%, for patients 68%. The rate of ovulation per cycle was 97.7%, percentage of mono-follicular development 70.9%. No severe OHSS, multiple pregnancy, local or systemic side effects were seen. LTZ combined with low-dose Hp-HMG is an effective and safe choice for reducing hyperstimulation and increasing pregnancy rate in CC-resistant women with PCOS.

Mucuna pruriens in Parkinson disease

PubMed Central

Laguna, Janeth; Cassani, Erica; Cereda, Emanuele; Pozzi, Nicolò G.; Isaias, Ioannis U.; Contin, Manuela; Barichella, Michela; Pezzoli, Gianni

2017-01-01

Objective: To investigate whether Mucuna pruriens (MP), a levodopa-containing leguminous plant growing in all tropical areas worldwide, may be used as alternative source of levodopa for indigent individuals with Parkinson disease (PD) who cannot afford long-term therapy with marketed levodopa preparations. Methods: We investigated efficacy and safety of single-dose intake of MP powder from roasted seeds obtained without any pharmacologic processing. Eighteen patients with advanced PD received the following treatments, whose sequence was randomized: (1) dispersible levodopa at 3.5 mg/kg combined with the dopa-decarboxylase inhibitor benserazide (LD+DDCI; the reference treatment); (2) high-dose MP (MP-Hd; 17.5 mg/kg); (3) low-dose MP (MP-Ld; 12.5 mg/kg); (4) pharmaceutical preparation of LD without DDCI (LD−DDCI; 17.5 mg/kg); (5) MP plus benserazide (MP+DDCI; 3.5 mg/kg); (6) placebo. Efficacy outcomes were the change in motor response at 90 and 180 minutes and the duration of on state. Safety measures included any adverse event (AE), changes in blood pressure and heart rate, and the severity of dyskinesias. Results: When compared to LD+DDCI, MP-Ld showed similar motor response with fewer dyskinesias and AEs, while MP-Hd induced greater motor improvement at 90 and 180 minutes, longer ON duration, and fewer dyskinesias. MP-Hd induced less AEs than LD+DDCI and LD−DDCI. No differences in cardiovascular response were recorded. Conclusion: Single-dose MP intake met all noninferiority efficacy and safety outcome measures in comparison to dispersible levodopa/benserazide. Clinical effects of high-dose MP were similar to levodopa alone at the same dose, with a more favorable tolerability profile. ClinicalTrials.gov identifier: NCT02680977. PMID:28679598

Mucuna pruriens in Parkinson disease: A double-blind, randomized, controlled, crossover study.

PubMed

Cilia, Roberto; Laguna, Janeth; Cassani, Erica; Cereda, Emanuele; Pozzi, Nicolò G; Isaias, Ioannis U; Contin, Manuela; Barichella, Michela; Pezzoli, Gianni

2017-08-01

To investigate whether Mucuna pruriens (MP), a levodopa-containing leguminous plant growing in all tropical areas worldwide, may be used as alternative source of levodopa for indigent individuals with Parkinson disease (PD) who cannot afford long-term therapy with marketed levodopa preparations. We investigated efficacy and safety of single-dose intake of MP powder from roasted seeds obtained without any pharmacologic processing. Eighteen patients with advanced PD received the following treatments, whose sequence was randomized: (1) dispersible levodopa at 3.5 mg/kg combined with the dopa-decarboxylase inhibitor benserazide (LD+DDCI; the reference treatment); (2) high-dose MP (MP-Hd; 17.5 mg/kg); (3) low-dose MP (MP-Ld; 12.5 mg/kg); (4) pharmaceutical preparation of LD without DDCI (LD-DDCI; 17.5 mg/kg); (5) MP plus benserazide (MP+DDCI; 3.5 mg/kg); (6) placebo. Efficacy outcomes were the change in motor response at 90 and 180 minutes and the duration of on state. Safety measures included any adverse event (AE), changes in blood pressure and heart rate, and the severity of dyskinesias. When compared to LD+DDCI, MP-Ld showed similar motor response with fewer dyskinesias and AEs, while MP-Hd induced greater motor improvement at 90 and 180 minutes, longer ON duration, and fewer dyskinesias. MP-Hd induced less AEs than LD+DDCI and LD-DDCI. No differences in cardiovascular response were recorded. Single-dose MP intake met all noninferiority efficacy and safety outcome measures in comparison to dispersible levodopa/benserazide. Clinical effects of high-dose MP were similar to levodopa alone at the same dose, with a more favorable tolerability profile. NCT02680977. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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.

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

[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.

Dosage effects of histamine-2 receptor antagonist on the primary prophylaxis of non-steroidal anti-inflammatory drug (NSAID)-associated peptic ulcers: a retrospective cohort study.

PubMed

He, Ying; Chan, Esther W; Man, Kenneth K C; Lau, Wallis C Y; Leung, Wai K; Ho, Lai M; Wong, Ian C K

2014-09-01

A histamine-2 receptor antagonist (H2RA) is one of the common gastroprotective co-therapies used with non-steroidal anti-inflammatory drugs (NSAIDs) for the prevention or treatment of peptic ulcers (PUs). To date, no study has directly compared the prophylactic effectiveness between high-dose and low-dose H2RA. Our objective was to compare the effectiveness of high-dose versus low-dose H2RAs in the primary prophylaxis of PUs among short-term NSAID users. A retrospective cohort study was conducted using the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong. Patients aged 18 years or above who received a single prescription of oral NSAID with oral H2RA were identified within the study period (1 January 2009-31 December 2012). Patients with a history of or risk factors for PU in the corresponding 2 years prior to the index date (of the first NSAID prescription) were excluded. Log binomial regression analysis was used to calculate the relative risk of PU among NSAID users with high-dose H2RA versus low-dose H2RA exposure. Among the NSAID cohort (n = 102,042), 77,509 (76 %) were on low-dose H2RA and 24,533 (24 %) were on high-dose H2RA. Of the total 69 PU cases identified during the drug exposure period, 64 (0.08 %) received low-dose-H2RA and five (0.02 %) received high-dose H2RA. The overall absolute risk of PUs for NSAID users whilst on H2RA was approximately 1 per 1,479 patients. The adjusted relative risk for NSAID users receiving high-dose H2RA versus low-dose H2RA was 0.32 (95 % confidence interval [CI] 0.13-0.79). Patients aged ≥65 years, receiving a longer duration of treatment, or with concomitant use of antiplatelet agents were found to be at higher risk of PU. High-dose H2RA showed greater effectiveness than low-dose H2RA in the primary prophylaxis of NSAID-associated PUs in short-term new users.

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

High dynamic range CMOS-based mammography detector for FFDM and DBT

NASA Astrophysics Data System (ADS)

Peters, Inge M.; Smit, Chiel; Miller, James J.; Lomako, Andrey

2016-03-01

Digital Breast Tomosynthesis (DBT) requires excellent image quality in a dynamic mode at very low dose levels while Full Field Digital Mammography (FFDM) is a static imaging modality that requires high saturation dose levels. These opposing requirements can only be met by a dynamic detector with a high dynamic range. This paper will discuss a wafer-scale CMOS-based mammography detector with 49.5 μm pixels and a CsI scintillator. Excellent image quality is obtained for FFDM as well as DBT applications, comparing favorably with a-Se detectors that dominate the X-ray mammography market today. The typical dynamic range of a mammography detector is not high enough to accommodate both the low noise and the high saturation dose requirements for DBT and FFDM applications, respectively. An approach based on gain switching does not provide the signal-to-noise benefits in the low-dose DBT conditions. The solution to this is to add frame summing functionality to the detector. In one X-ray pulse several image frames will be acquired and summed. The requirements to implement this into a detector are low noise levels, high frame rates and low lag performance, all of which are unique characteristics of CMOS detectors. Results are presented to prove that excellent image quality is achieved, using a single detector for both DBT as well as FFDM dose conditions. This method of frame summing gave the opportunity to optimize the detector noise and saturation level for DBT applications, to achieve high DQE level at low dose, without compromising the FFDM performance.

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).

The effect of single dose versus two doses of praziquantel on Schistosoma haematobium infection and pathology among school-aged children in Mali.

PubMed

Sacko, M; Magnussen, P; Traoré, M; Landouré, A; Doucouré, A; Reimert, C M; Vennervald, B J

2009-11-01

The aim of this study was to assess the effect of two doses of 40 mg/kg praziquantel with 2 weeks interval versus a standard single dose of 40 mg/kg on cure rates, egg reduction, intensity of infection, and micro-haematuria in Schistosoma haematobium infections. A randomised controlled intervention study was carried out among school-aged children in two different endemic settings with follow-up at 3, 6 and 18 months following drug administration. Differences in cure rates between the two treatment regimens were not significant. However, in high transmission areas, the double treatment regimen was more effective in egg reduction than single treatment regimen and the difference in egg reduction between the two treatments was significant at 3 months (P<0.005), 6 months (P<0.0001) and 18 months (P<0.003) after treatment. There was a significant difference in the effect of the two treatments on prevalence of micro-haematuria at 18-month follow-up in both Koulikoro (P<0.001) and Selingue (P<0.003). The study shows that although no significant difference could be observed in the overall cure-rates between the two treatment regimens, the effect of double treatment was a significant reduction in infection intensity as well as micro-haematuria which may have a great impact in reducing subtle morbidity.

Irradiation influence on the detection of genetic-modified soybeans

NASA Astrophysics Data System (ADS)

Villavicencio, A. L. C. H.; Araújo, M. M.; Baldasso, J. G.; Aquino, S.; Konietzny, U.; Greiner, R.

2004-09-01

Three soybean varieties were analyzed to evaluate the irradiation influence on the detection of genetic modification. Samples were treated in a 60Co facility at dose levels of 0, 500, 800, and 1000Gy. The seeds were at first analyzed by Comet Assay as a rapid screening irradiation detection method. Secondly, germination test was performed to detect the viability of irradiated soybeans. Finally, because of its high sensitivity, its specificity and rapidity the polimerase chain reaction was the method applied for genetic modified organism detection. The analysis of DNA by the single technique of microgel electrophoresis of single cells (DNA Comet Assay) showed that DNA damage increased with increasing radiation doses. No negative influence of irradiation on the genetic modification detection was found.

A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova(®) compared to Lovaza(®) in a pharmacokinetic single-dose evaluation) study.

PubMed

Davidson, Michael H; Johnson, Judith; Rooney, Michael W; Kyle, Michael L; Kling, Douglas F

2012-01-01

Omega-3 (OM-3) fatty acid products are indicated for the treatment of severe hypertriglyceridemia; however, the omega-3-acid ethyl ester (OM-3 EE) formulations require significant pancreatic lipase stimulation with high-fat meals for adequate intestinal absorption of the metabolites eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A novel omega-3 free fatty acid (OM-3 FFA) formulation (Epanova(®), Omthera Pharmaceuticals Inc., Princeton, NJ) was developed to maximize EPA and DHA bioavailability during a low-fat diet. To compare the relative bioavailability of EPA and DHA from single 4-gram doses of OM-3 FFA and a prescription OM-3 EE (Lovaza(®), GlaxoSmithKline, Research Triangle Park, NC). This was a randomized, open-label, single dose, 4-way crossover, bioavailability study of OM-3 FFA and OM-3 EE administered during periods of low-fat and high-fat consumption to 54 overweight adults. Bioavailability was determined by the ln-transformed area under the plasma concentration versus time curve (AUC(0-t)) during a 24-hour interval for EPA and DHA (baseline-adjusted). The baseline-adjusted AUC(0-t) for total EPA + DHA during the low-fat period was 4.0-fold greater with OM-3 FFA compared with OM-3 EE (2650.2 vs 662.0 nmol·h/mL, respectively; P < .0001). During the high-fat period, AUC(0-t) for OM-3 FFA was approximately 1.3-fold greater than OM-3 EE (P < .0001). During the low-fat period, 30 of 51 (58.8%) subjects dosed with OM-3 FFA maintained an AUC(0-t) that was ≥50% of the respective high-fat AUC(0-t) in contrast to only 3 of 50 (6.0%) subjects dosed with OM-3 EE. During a low-fat consumption period, the OM-3 FFA formulation provided dramatically improved bioavailability over the OM-3 EE formulation in overweight subjects. These findings offer a potential therapeutic advantage of the OM-3 FFA formulation for the treatment of severe hypertriglyceridemia as these patients are expected to adhere to a low-fat diet. Copyright © 2012 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Safety aspects of incobotulinumtoxinA high-dose therapy.

PubMed

Dressler, Dirk; Saberi, Fereshte Adib; Kollewe, Katja; Schrader, Christoph

2015-02-01

Botulinum toxin (BT) used for dystonia and spasticity is dosed according to the number of target muscles and the severity of their muscle hyperactivities. With this no other drug is used in a broader dose range than BT. The upper end of this range, however, still needs to be explored. We wanted to do this by a prospective non-interventional study comparing a randomly selected group of dystonia and spasticity patients receiving incobotulinumtoxinA (Xeomin(®)) high-dose therapy (HD group, n = 100, single dose ≥400 MU) to a control group receiving incobotulinumtoxinA regular-dose therapy (RD group, n = 30, single dose ≤200 MU). At the measurement point all patients were evaluated for systemic BT toxicity, i.e. systemic motor impairment or systemic autonomic dysfunction. HD group patients (56.1 ± 13.8 years, 46 dystonia, 54 spasticity) were treated with Xeomin(®) 570.1 ± 158.9 (min 400, max 1,200) MU during 10.2 ± 7.0 (min 4, max 37) injection series. In dystonia patients the number of target muscles was 46 and the dose per target muscle 56.4 ± 19.1 MU, in spasticity patients 35 and 114.9 ± 67.1 MU. HD and RD group patients reported 58 occurrences of items on the systemic toxicity questionnaire. Generalised weakness, being bedridden, feeling of residual urine and constipation were caused by the underlying tetra- or paraparesis, blurred vision by presbyopia. Dysphagia and dryness of eye were local BT adverse effects. Neurologic examination, serum chemistry and full blood count did not indicate any systemic adverse effects. Elevated serum levels for creatine kinase/MB, creatine kinase and lactate dehydrogenase were most likely iatrogenic artefacts. None of the patients developed antibody-induced therapy failure. Xeomin(®) can be used safely in doses ≥400 MU and up to 1,200 MU without detectable systemic toxicity. This allows expanding the use of BT therapy to patients with more widespread and more severe muscle hyperactivity conditions. Further studies-carefully designed and rigorously monitored-are necessary to explore the threshold dose for clinically detectable systemic toxicity.

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.

Protection against bubonic and pneumonic plague with a single dose microencapsulated sub-unit vaccine.

PubMed

Elvin, Stephen J; Eyles, James E; Howard, Kenneth A; Ravichandran, Easwaran; Somavarappu, Satyanarayan; Alpar, H Oya; Williamson, E Diane

2006-05-15

Protection against virulent plague challenge by the parenteral and aerosol routes was afforded by a single administration of microencapsulated Caf1 and LcrV antigens from Yersinia pestis in BALB/c mice. Recombinant Caf1 and LcrV were individually encapsulated in polymeric microspheres, to the surface of which additional antigen was adsorbed. The microspheres containing either Caf1 or LcrV were blended and used to immunise mice on a single occasion, by either the intra-nasal or intra-muscular route. Both routes of immunisation induced systemic and local immune responses, with high levels of serum IgG being developed in response to both vaccine antigens. In Elispot assays, secretion of cytokines by spleen and draining lymph node cells was demonstrated, revealing activation of both Th1 and Th2 associated cytokines; and spleen cells from animals immunised by either route were found to proliferate in vitro in response to both vaccine antigens. Virulent challenge experiments demonstrated that non-invasive immunisation by intra-nasal instillation can provide strong systemic and local immune responses and protect against high level challenge. Microencapsulation of these vaccine antigens has the added advantage that controlled release of the antigens occurs in vivo, so that protective immunity can be induced after only a single immunising dose.

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.

Efficacy and safety of a single 2 mg dose or 4 mg double dose of alteplase for 50 occluded chest ports using a unique instillation technique

PubMed Central

Sharma, Rajinder P; Ree, Chung Ja; Ree, Alexander

2008-01-01

PURPOSE: To evaluate the effectiveness and safety of a single 2 mg dose or a 4 mg double dose of alteplase for restoring function in occluded chest ports. METHODS: A prospective, open-label, nonblinded study was performed on 40 enrolled patients with a total of 50 chest ports at the Henry Ford Hospital Interventional Radiology Department (Detroid, Michigan, USA). Alteplase (Cathflo Activase; Genentech, USA), a recombinant tissue plasminogen activator produced by recombinant DNA technology, was used to restore the function of 50 occluded chest ports. Occlusion was defined as the inability to withdraw blood freely from the port, or the inability to flush the port easily. A 2 mg (2 mL) dose of alteplase was injected into the port through a Huber needle, using a gentle push and pull technique, and was left to dwell for 30 min. If the port remained occluded after the initial 2 mg alteplase treatment, an additional 2 mg alteplase treatment was administered with the same dwell time of 30 min. If a port had remained occluded despite the above regimen, this outcome would have been considered a failure and the chest port would have required surgical intervention. However, all ports were successfully treated, and no surgical intervention was required. The safety end points included minor or major hemorrhages, such as intracranial hemorrhages, or sepsis. Safety end points were determined by a 24 h follow-up telephone call. RESULTS: Of the 50 chest ports (30 single ports and 10 double ports) treated with alteplase, 36 required 2 mg (72%) and 14 required 4 mg (28%). The efficacy end point was 100% for all chest ports treated, without any adverse events. CONCLUSION: High efficacy and safety rates of restoring function in occluded chest ports were obtained with 2 mg or 4 mg doses of alteplase. Part of this high efficacy rate may be due to the gentle push and pull technique used in the present study. PMID:22477414

Surface dose measurement for helical tomotherapy.

PubMed

Snir, Jonatan A; Mosalaei, Homeira; Jordan, Kevin; Yartsev, Slav

2011-06-01

To compare the surface dose measurements made by different dosimeters for the helical tomotherapy (HT) plan in the case of the target close to the surface. Surface dose measurements in different points for the HT plan to deliver 2 Gy to the planning target volume (PTV) at 5 mm below the surface of the cylindrical phantom were performed by radiochromic films, single use metal oxide semiconductor field-effect transistor (MOSFET) dosimeters, silicon IVD QED diode, and optically stimulated luminescence (OSL) dosimeters. The measured doses by all dosimeters were within 12 +/- 8% difference of each other. Radiochromic films, EBT, and EBT2, provide high spatial resolution, although it is difficult to get accurate measurements of dose. Both the OSL and QED measured similar dose to that of the MOSFET detectors. The QED dosimeter is promising as a reusable on-line wireless dosimeter, while the OSL dosimeters are easier to use, require minimum setup time and are very precise.

Safety and long-term humoral immune response in adults after vaccination with an H1N1 2009 pandemic influenza vaccine with or without AS03 adjuvant.

PubMed

Ferguson, Murdo; Risi, George; Davis, Matthew; Sheldon, Eric; Baron, Mira; Li, Ping; Madariaga, Miguel; Fries, Louis; Godeaux, Olivier; Vaughn, David

2012-03-01

In this study (NCT00985088) we evaluated different formulations of an H1N1 2009 pandemic influenza vaccine that deliver various viral hemagglutinin (HA) doses with or without AS03 (a tocopherol-based oil-in-water adjuvant system). A total of 1340 healthy subjects aged ≥18 years were randomized to receive 1 or 2 doses of an adjuvanted (3.75-μg HA/AS03(A) or 1.9-μg HA/AS03(B)) or nonadjuvanted vaccine formulation. Safety and immunogenicity (by hemagglutination-inhibition [HI] assay) after each dose and 6 months after dose 1 are reported here. A single dose of AS03(A)-adjuvanted 3.75-μg HA H1N1 2009 induced the strongest immune responses in subjects aged 18-64 years (seroprotection rate [SPR], 97.2%; seroconversion rate [SCR], 90.1%) as well as in subjects aged >64 years (SPR, 91.1%; SCR, 78.2%) 21 days after vaccination. Six months after dose 1, subjects who received 2 doses of either the adjuvanted formulation or 1 dose of the adjuvanted 3.75-μg HA formulation continued to meet all Center for Biologics Evaluation and Research and Committee for Medicinal Products for Human Use criteria. All formulations had clinically acceptable safety profiles. A single dose of the 3.75-μg HA AS03(A)-adjuvanted H1N1 2009 influenza vaccine was highly immunogenic in both age strata (18-64 and >64 years), inducing long-term persistence of the immune response until at least 6 months after dose 1.

Quantification of damage due to low-dose radiation exposure in mice: construction and application of a biodosimetric model using mRNA indicators in circulating white blood cells

PubMed Central

Ishihara, Hiroshi; Tanaka, Izumi; Yakumaru, Haruko; Tanaka, Mika; Yokochi, Kazuko; Fukutsu, Kumiko; Tajima, Katsushi; Nishimura, Mayumi; Shimada, Yoshiya; Akashi, Makoto

2016-01-01

Biodosimetry, the measurement of radiation damage in a biologic sample, is a reliable tool for increasing the accuracy of dose estimation. Although established chromosome analyses are suitable for estimating the absorbed dose after high-dose irradiation, biodosimetric methodology to measure damage following low-dose exposure is underdeveloped. RNA analysis of circulating blood containing radiation-sensitive cells is a candidate biodosimetry method. Here we quantified RNA from a small amount of blood isolated from mice following low-dose body irradiation (<0.5 Gy) aimed at developing biodosimetric tools for situations that are difficult to study in humans. By focusing on radiation-sensitive undifferentiated cells in the blood based on Myc RNA expression, we quantified the relative levels of RNA for DNA damage-induced (DDI) genes, such as Bax, Bbc3 and Cdkn1a. The RNA ratios of DDI genes/Myc in the blood increased in a dose-dependent manner 4 h after whole-body irradiation at doses ranging from 0.1 to 0.5 Gy (air-kerma) of X-rays, regardless of whether the mice were in an active or resting state. The RNA ratios were significantly increased after 0.014 Gy (air-kerma) of single X-ray irradiation. The RNA ratios were directly proportional to the absorbed doses in water ranging from 0.1 to 0.5 Gy, based on gamma-irradiation from 137Cs. Four hours after continuous irradiation with gamma-rays or by internal contamination with a beta-emitter, the increased RNA ratios resembled those following single irradiation. These findings indicate that the RNA status can be utilized as a biodosimetric tool to estimate low-dose radiation when focusing on undifferentiated cells in blood. PMID:26589759

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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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.

High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience.

PubMed

Filipczak-Bryniarska, Iwona; Krzyzewski, Roger M; Kucharz, Jakub; Michalowska-Kaczmarczyk, Anna; Kleja, Justyna; Woron, Jarosław; Strzepek, Katarzyna; Kazior, Lucyna; Wordliczek, Jerzy; Grodzicki, Tomasz; Krzemieniecki, Krzysztof

2017-08-17

High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV-associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 ± 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m 2 . Mean pain level after 12 weeks of treatment was 0.20 ± 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment (69.55 ± 12.09 vs. 49.40 ± 20.34%; p = 0.02) and after 12 weeks (96.96 ± 5.56 vs. 83.93 ± 18.59%; p = 0.04). High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction.

High-dose levofloxacin in community-acquired pneumonia: a randomized, open-label study.

PubMed

Lee, Jin Hwa; Kim, Seo Woo; Kim, Ji Hye; Ryu, Yon Ju; Chang, Jung Hyun

2012-09-01

The conventional treatment for community-acquired pneumonia (CAP) involves combination therapy consisting of a β-lactam penicillin or a cephalosporin with a macrolide. Alternatively, high-dose levofloxacin treatment has been used as single-agent therapy for treating CAP, covering atypical pathogens. This study compared the clinical efficacy and safety of high-dose levofloxacin with combined ceftriaxone and azithromycin for the treatment of CAP. This phase IV, prospective, randomized, open-label trial enrolled patients admitted to a tertiary referral hospital for CAP treatment from 2010 to 2011. Hospital admission was decided based on clinical judgement and the pneumonia severity index. Forty subjects were enrolled and assigned to two treatment arms using a random numbers table. The 20 subjects in the experimental group were given levofloxacin 750 mg intravenously once daily, followed by the same dose of oral levofloxacin at discharge when clinically improved and the 20 subjects in the control group were given ceftriaxone 2.0 g intravenously once daily plus oral azithromycin 500 mg for 3 consecutive days, followed by oral cefpodoxime 200 mg per day at discharge after clinical improvement. The primary outcome was the clinical success rate. Secondary outcomes were the microbiological success rate and adverse events during the study. Of the 40 subjects enrolled, 36 completed the study: 17 in the experimental group and 19 in the control group. The groups did not differ in terms of demographic factors or clinical findings at baseline. The clinical success rate (cured + improved) was 94% in the experimental (levofloxacin) group and 84% in the control group (p > 0.05). The microbiological success rate and overall adverse events were also similar in both groups. Single-agent, high-dose levofloxacin treatment exhibited excellent clinical and microbiological efficacy with a safety profile comparable to that of ceftriaxone plus azithromycin therapy. Large-scale clinical trials are required to verify these results. WHO International Clinical Trials Registry: KCT0000374; Daiichi-Sankyo Korea study code: T11-13-V1.

Perioperative Interstitial High-Dose-Rate Brachytherapy for the Treatment of Recurrent Keloids: Feasibility and Early Results

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

Jiang, Ping, E-mail: ping.jiang@uksh.de; Baumann, René; Dunst, Juergen

Purpose: To prospectively evaluate high-dose-rate brachytherapy in the treatment of therapy-resistant keloids and report first results, with emphasis on feasibility and early treatment outcome. Methods and Materials: From 2009 to 2014, 24 patients with 32 recurrent keloids were treated with immediate perioperative high-dose-rate brachytherapy; 3 patients had been previously treated with adjuvant external beam radiation therapy and presented with recurrences in the pretreated areas. Two or more different treatment modalities had been tried in all patients and had failed to achieve remission. After (re-)excision of the keloids, a single brachytherapy tube was placed subcutaneously before closing the wound. The target volumemore » covered the scar in total length. Brachytherapy was given in 3 fractions with a single dose of 6 Gy in 5 mm tissue depth. The first fraction was given within 6 hours after surgery, the other 2 fractions on the first postoperative day. Thus, a total dose of 18 Gy in 3 fractions was administered within 36 hours after the resection. Results: The treatment was feasible in all patients. No procedure-related complications (eg, secondary infections) occurred. Nineteen patients had keloid-related symptoms before treatment like pain and pruritus; disappearance of symptoms was noticed in all patients after treatment. After a median follow-up of 29.4 months (range, 7.9-72.4 months), 2 keloid recurrences and 2 mildly hypertrophied scars were observed. The local control rate was 94%. Pigmentary abnormalities were detected in 3 patients, and an additional 6 patients had a mild delay in the wound-healing process. Conclusions: The early results of this study prove the feasibility and the efficacy of brachytherapy for the prevention of keloids. The results also suggest that brachytherapy may be advantageous in the management of high-risk keloids or as salvage treatment for failure after external beam therapy.« less

Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery

PubMed Central

Hill, Kevin D.; Tunks, Robert D.; Barker, Piers C. A.; Benjamin, Daniel K.; Cohen-Wolkowiez, Michael; Fleming, Gregory A.; Laughon, Matthew; Li, Jennifer S.

2013-01-01

Objective To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery. Design Prospective, dose escalation trial. Setting Single-center, pediatric catheterization laboratory. Patients 12 children post stage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range: 0.8, 4.0), weight 11 kg (8, 13), 9 females, and 10 with a single right ventricle. Interventions Catheterization and echocardiography performed before and immediately after single-dose intravenous sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 minutes). Measurements Peak sildenafil and des-methyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance. Main Results Maximum sildenafil concentrations ranged from 92–775 ng/ml and were above the in vitro threshold needed for 77% phosphodiesterase type-5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index (PVRI) in all 12 subjects (median PVRI 2.2 [range: 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU x m2; p<0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p=0.04) and saturations (+2% [0, 16], p=0.04) in those with baseline PVRI ≥2 WU x m2 (n=7). Change in saturations correlated inversely with change in PVRI (r2 = 0.74 p<0.01). Sildenafil also lowered mean blood pressure (−12% [−20, +10]; p=0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events. Conclusions Sildenafil demonstrated non-linear exposure with high inter-individual variability but was well tolerated and effectively lowered PVRI in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index. PMID:23823195

Significant increase in salivary substance p level after a single oral dose of cevimeline in humans.

PubMed

Suzuki, Yosuke; Itoh, Hiroki; Amada, Kohei; Yamamura, Ryota; Sato, Yuhki; Takeyama, Masaharu

2013-01-01

Cevimeline is a novel muscarinic acetylcholine receptor agonist currently being developed as a therapeutic agent for xerostomia. We examined the effects of cevimeline on salivary and plasma levels of substance-P- (SP-), calcitonin-gene-related-peptide- (CGRP-), and vasoactive-intestinal-polypeptide- (VIP-) like immunoreactive substances (ISs) in humans. An open-labeled crossover study was conducted on seven healthy volunteers. Saliva volume was measured, and saliva and venous blood samples were collected before and 30-240 min after a single oral dose of cevimeline or placebo. Salivary and plasma levels of SP-, CGRP-, and VIP-IS were measured using a highly sensitive enzyme immunoassay. A single oral dose of cevimeline resulted in significant increases in salivary but not plasma SP-IS level compared to placebo. Cevimeline administration did not alter the salivary or plasma levels of CGRP-IS or VIP-IS compared to placebo. Significant increases in salivary volume were observed after cevimeline administration compared to placebo. A significant correlation was observed between the total release of SP-IS and that of salivary volume. These findings suggest an association of SP with the enhancement of salivary secretion by cevimeline.

Significant Increase in Salivary Substance P Level after a Single Oral Dose of Cevimeline in Humans

PubMed Central

Suzuki, Yosuke; Itoh, Hiroki; Amada, Kohei; Yamamura, Ryota; Sato, Yuhki; Takeyama, Masaharu

2013-01-01

Cevimeline is a novel muscarinic acetylcholine receptor agonist currently being developed as a therapeutic agent for xerostomia. We examined the effects of cevimeline on salivary and plasma levels of substance-P- (SP-), calcitonin-gene-related-peptide- (CGRP-), and vasoactive-intestinal-polypeptide- (VIP-) like immunoreactive substances (ISs) in humans. An open-labeled crossover study was conducted on seven healthy volunteers. Saliva volume was measured, and saliva and venous blood samples were collected before and 30–240 min after a single oral dose of cevimeline or placebo. Salivary and plasma levels of SP-, CGRP-, and VIP-IS were measured using a highly sensitive enzyme immunoassay. A single oral dose of cevimeline resulted in significant increases in salivary but not plasma SP-IS level compared to placebo. Cevimeline administration did not alter the salivary or plasma levels of CGRP-IS or VIP-IS compared to placebo. Significant increases in salivary volume were observed after cevimeline administration compared to placebo. A significant correlation was observed between the total release of SP-IS and that of salivary volume. These findings suggest an association of SP with the enhancement of salivary secretion by cevimeline. PMID:23589717

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

Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission

PubMed Central

Graves, Patricia M; Choi, Leslie; Gelband, Hellen; Garner, Paul

2018-01-01

Background The 8-aminoquinoline (8AQ) drugs act on Plasmodium falciparum gametocytes, which transmit malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to malaria treatment schedules in low-transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose-6-phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear. Objectives To assess the effects of single dose or short-course PQ (or an alternative 8AQ) alongside treatment for people with P. falciparum malaria. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using ‘malaria*', ‘falciparum', ‘primaquine', ‘8-aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017. Selection criteria Randomized controlled trials (RCTs) or quasi-RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. falciparum malaria. Data collection and analysis Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non-artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups. Main results We included 24 RCTs and one quasi-RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non-artemisinin treatments (13 arms), and two trials included both artemisinin and non-artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing. No cluster trials evaluating community effects on malaria transmission met the inclusion criteria. With artemisinin treatment Low dose PQ Infectiousness (participants infectious to mosquitoes) was reduced (day 3 or 4: RR 0.12, 95% CI 0.02 to 0.88, 3 trials, 105 participants; day 8: RR 0.34, 95% CI 0.07 to 1.58, 4 trials, 243 participants; low certainty evidence). This translates to a reduction in percentage of people infectious on day 3 or 4 from 14% to 2%, and, for day 8, from 4% to 1%; the waning infectiousness in the control group by day 8 making the absolute effect smaller by day 8. For gametocytes detected by PCR, there was little or no effect of PQ at day 3 or 4 (RR 1.02, 95% CI 0.87 to 1.21; 3 trials, 414 participants; moderate certainty evidence); with reduction at day 8 (RR 0.52, 95% CI 0.41 to 0.65; 4 trials, 532 participants; high certainty evidence). Severe haemolysis was infrequent, with or without PQ, in these groups with few G6PD-deficient individuals (RR 0.98, 95% CI 0.69 to 1.39; 4 trials, 752 participants, moderate certainty evidence). Moderate dose PQ Infectiousness was reduced (day 3 or 4: RR 0.13, 95% CI 0.02 to 0.94; 3 trials, 109 participants; day 8 RR 0.33, 95% CI 0.07 to 1.57; 4 trials, 246 participants; low certainty evidence). Illustrative risk estimates for moderate dose were the same as low dose. The pattern and level of certainty of evidence with gametocytes detected by PCR was the same as low dose, and severe haemolysis was infrequent in both groups. High dose PQ Infectiousness was reduced (day 4: RR 0.2, 95% CI 0.02 to 1.68, 1 trial, 101 participants; day 8: RR 0.18, 95% CI 0.02 to 1.41, 2 trials, 181 participants, low certainty evidence). The effects on gametocyte prevalence showed a similar pattern to moderate and low dose PQ. Trials did not systematically report evidence of haemolysis. With non-artemisinin treatment Trials with non-artemisinin treatment have been conducted only for moderate and high dose PQ. With high dose, infectiousness appeared markedly reduced on day 5 (RR 0.09, 95% CI 0.01 to 0.62; 30 participants, very low certainty evidence), with similar reductions at day 8. For both moderate dose (two trials with 221 people) and high dose (two trials with 30 people), reduction in gametocytes (detected by microscopy) showed similar patterns as for artemisinin treatments, with little or no effect at day 4 or 5, and larger effects by day 8. No trials with non-artemisinin partner drugs systematically sought evidence of severe haemolysis. Two trials comparing bulaquine with PQ suggest bulaquine may have larger effects on gametocytes by microscopy on day 8 (RR 0.41, 95% CI 0.26 to 0.66; 2 trials, 112 participants). Authors' conclusions A single low dose of PQ (0.25 mg/kg) added to artemisinin-based combination therapy for malaria reduces infectiousness of people to mosquitoes at day 3-4 and day 8, and appears as effective as higher doses. The absolute effect is greater at day 3 or 4, and smaller at day 8, in part because of the lower infectiousness in the control group. There was no evidence of increased haemolysis at 0.25 mg/kg, but few G6PD-deficient individuals were included in the trials. The effect on infectiousness precedes the effect of PQ on gametocyte prevalence. We do not know whether single dose PQ could reduce malaria transmission at community level. What is the aim of this review? To assess the effects of adding a single dose of primaquine (PQ) to treatment for falciparum malaria to reduce disease transmission. This Cochrane Review update includes 25 controlled trials. The date of latest search was 21 July 2017. Key messages A single low dose of PQ, at 0.25 mg/kg, which the World Health Organization (WHO) recommends adding to artemisinin-based combination therapy for malaria, reduces infectiousness (transmission from people to mosquitoes). In the trials, the percentage of people who infected mosquitoes three to four days after treatment was reduced from 14% to 2%, with a smaller effect at day 8, from 4% to 1%, with no evidence of harm. What was studied in the review PQ kills gametocytes (malaria transmission stages) of the falciparum malaria parasite. Gametocytes infect mosquitoes during a bite, thus perpetuating transmission. There is concern that PQ may cause red blood cells to burst (haemolysis) in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a genetically-determined condition common in many malaria-endemic settings, which can lead to anaemia. Recognizing concerns about the risk of haemolysis, the WHO reduced the recommended PQ dose from 0.75 mg/kg to 0.25 mg/kg in 2012. Ideally, this approach would be tested by randomly assigning villages to standard malaria treatment, or standard treatment plus a low dose of PQ, then measuring the effect on malaria over time but this would be difficult and expensive. So, indirect indicators are used to shed light on effectiveness, including feeding studies, in which mosquitoes are allowed to feed on people (or their blood), comparing those who were assigned PQ with those who were not. Alternatively, researchers may simply monitor the presence (prevalence), number (density), and duration (time of persistence) of gametocytes in the blood of people after different treatments, assuming that gametocytes are viable irrespective of exposure to PQ. What the research says The 25 included trials span several decades and include a variety of treatments and PQ doses. Related to safety assessment, some trials tested participants for G6PD activity. Other trials reported results based on their G6PD status, others did not test (or did not say whether they did), and others tested and excluded people with G6PD deficiency. There were no ideal community-level studies that would answer the question directly. Five feeding trials with multiple arms included three low-dose, three medium-dose, and two high-dose comparisons, showing a markedly reduced proportion of people infectious who received PQ in trials with any events. Two trials using older malaria treatments and high dose PQ had similar results. The other trials focused on indirect measures of potential infectiousness of humans to mosquitoes. In these trials, PQ shortened the period of potential infectiousness, with a lower prevalence and density of gametocytes up to day 8 after treatment. The effect was similar at all PQ dose levels. Few serious haemolytic events occurred in these trials, but PQ did affect non-serious haemoglobin measures, even at low doses. What are the main results of the review? A single low dose of PQ added to an artemisinin regimen for malaria reduces infectiousness to mosquitoes and is relatively safe for most people. PQ at WHO-recommended dose reduces infectiousness to mosquitoes on day 3-4 and day 8 with no evidence of harm. It is unclear whether this reduction would materially reduce malaria transmission in communities. PMID:29393511

Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial.

PubMed

Zhu, Feng-Cai; Wurie, Alie H; Hou, Li-Hua; Liang, Qi; Li, Yu-Hua; Russell, James B W; Wu, Shi-Po; Li, Jing-Xin; Hu, Yue-Mei; Guo, Qiang; Xu, Wen-Bo; Wurie, Abdul R; Wang, Wen-Juan; Zhang, Zhe; Yin, Wen-Jiao; Ghazzawi, Manal; Zhang, Xu; Duan, Lei; Wang, Jun-Zhi; Chen, Wei

2017-02-11

A recombinant adenovirus type-5 vector-based vaccine expressing the glycoprotein of Ebola Zaire Makona variant showed good safety and immunogenicity in a phase 1 trial of healthy Chinese adults. We aimed to assess the safety and immunogenicity of this vaccine in healthy adults in Sierra Leone and to determine the optimal dose. We did a single-centre, randomised, double-blind, placebo-controlled, phase 2 clinical trial at Sierra Leone-China Friendship Hospital, Freetown, Sierra Leone. We recruited healthy adults aged 18-50 years who were HIV negative, had no history of Ebola virus infection, and had no previous immunisation with other Ebola vaccine candidates. Participants were sequentially enrolled and randomly assigned (2:1:1), by computer-generated block randomisation (block size of eight), to receive the high-dose vaccine (1·6 × 10 11 viral particles), low-dose vaccine (8·0 × 10 10 viral particles), or placebo (containing only vaccine excipients, with no viral particles). Participants, investigators, and study staff (except two study pharmacists) were masked from treatment allocation. The primary safety outcome was occurrence of solicited adverse reactions within 7 days of vaccination, analysed by intention to treat. The primary immunogenicity outcome was glycoprotein-specific antibody responses at days 14, 28, and 168 after vaccination, analysed in all vaccinated participants who had blood samples drawn for antibody tests. The trial is registered with the Pan African Clinical Trials Registry, number PACTR201509001259869, and is completed. During Oct 10-28, 2015, 500 participants were enrolled and randomly assigned to receive the high-dose vaccine (n=250), low-dose vaccine (n=125), or placebo (n=125). 132 (53%) participants in the high-dose group, 60 (48%) in the low-dose group, and 54 (43%) in the placebo group reported at least one solicited adverse reaction within 7 days of vaccination. Most adverse reactions were mild and self-limiting. Solicited injection-site adverse reactions were significantly more frequent in vaccine recipients (65 [26%] in high-dose group and 31 [25%] in low-dose group) than in those receiving placebo (17 [14%]; p=0·0169). Glycoprotein-specific antibody responses were detected from day 14 onwards (geometric mean titre 1251·0 [95% CI 976·6-1602·5] in low-dose group and 1728·4 [1459·4-2047·0] in high-dose group) and peaked at day 28 (1471·8 [1151·0-1881·8] and 2043·1 [1762·4-2368·4]), but declined quickly in the following months (223·3 [148·2-336·4] and 254·2 [185·0-349·5] at day 168). Geometric mean titres in the placebo group remained around 6·0-6·8 throughout the study period. Three serious adverse events (malaria, gastroenteritis, and one fatal asthma episode) were reported in the high-dose vaccine group, but none was deemed related to the vaccine. The recombinant adenovirus type-5 vector-based Ebola vaccine was safe and highly immunogenic in healthy Sierra Leonean adults, and 8·0 × 10 10 viral particles was the optimal dose. Chinese Ministry of Science and Technology and the National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

Use of the UKHCDO Database for a postmarketing surveillance study of different doses of recombinant factor VIIa in haemophilia.

PubMed

Hay, C R M; Sharpe, T; Dolan, G

2017-05-01

Recombinant factor VIIa (rFVIIa) is recommended in Europe at standard (3 × 90 μg kg -1 ) or high (1 × 270 μg kg -1 ) doses. When granting the license for the high dose, the European Medicines Agency (EMA) requested postmarketing surveillance for thrombosis. This was conducted by the United Kingdom National Haemophilia Database (NHD) on behalf of Novo Nordisk and the EMA. To assess the use and safety of rFVIIa utilizing prospective data collected by the NHD (1 January 2008 to 30 June 2011). Data were obtained from 67 haemophilia A/B patients with inhibitors treated for 1057 bleeds and 31 acquired haemophilia patients treated for 70 bleeds. Initial rFVIIa dose was categorized post hoc as low (<90 μg kg -1 ), intermediate (≥90-<180 μg kg -1 ) or high (≥180-<270 or ≥270 μg kg -1 ). For haemophilia A/B, high and lower initial rFVIIa dose was used for 38.4% and 51.4% of episodes, respectively, while for acquired haemophilia, the values were 11.4% and 77.1% respectively. Median initial doses were higher for haemophilia A/B (146.3 μg kg -1 ) than acquired haemophilia (90.5 μg kg -1 ). A single administration of rFVIIa was the most frequently used regimen for haemophilia A/B, in contrast with standard recommendations and previous reports. For acquired haemophilia, most episodes were treated with multiple doses. No adverse drug reactions or thromboembolic events were reported for any rFVIIa dose. The novel use of a national database for postmarketing surveillance has demonstrated acceptable safety for all recommended doses of rFVIIa. © 2016 John Wiley & Sons Ltd.

Efficacy of a high potency O1 Manisa monovalent vaccine against heterologous challenge with foot-and-mouth disease virus of O/SEA/Mya-98 lineage in sheep.

PubMed

Singanallur, N B; Pacheco, J M; Arzt, J; Stenfeldt, C; Fosgate, G T; Rodriguez, L; Vosloo, W

2017-09-01

Potency tests for commercial oil-adjuvanted foot-and-mouth disease (FMD) vaccines are usually carried out in cattle, using a full dose (2 ml) of vaccine and homologous virus challenge. However, in sheep the recommended vaccine dose is half of the cattle dose (1 ml) and most vaccines have not been potency tested for this species, especially with heterologous viruses. To determine the efficacy of a high potency (>6PD 50 ) FMD virus (FMDV) O1Manisa vaccine in sheep, we carried out a study using a heterologous FMDV (FMDV O/SKR/2010 - Mya-98 strain) challenge. Groups of seven animals each were vaccinated with 2×, 1×, 1/2× or 1/4× dose (2 ml, 1 ml, 0.5 ml or 0.25 ml respectively) and challenged at 7 days post vaccination (dpv). Only 3 of the 7 sheep in the group vaccinated with 2 ml were protected. With 2 additional groups, receiving double or single doses and challenged at 14 dpv, 4 of 7 sheep were protected in each group. None of the sheep had measurable neutralising antibodies against the vaccine or challenge virus at 7 dpv. However, all vaccinated animals challenged at 14 dpv had a homologous neutralising response against FMDV O1 Manisa on the day of challenge and all but one animal also had a heterologous response to FMDV O/SKR/2010. Infectious FMDV and viral RNA could be found in nasal swabs between 1 and 6 days post challenge (dpc) in most vaccinated sheep, but those vaccinated with higher doses or challenged at 14 dpv showed significant decreases in the level of FMDV detection. Intermittent virus shedding was noticed between 1 and 35 dpc in all vaccinated groups, but persistent infection could be demonstrated only in 4 sheep (20%). This study showed that at the recommended dose, a high potency (>6 PD 50 ) FMDV O1Manisa vaccine does not protect sheep against a heterologous challenge at 7 dpv. However, partial protection was observed when a double dose was used at 7 dpv or when double or single dose vaccinated sheep were challenged at 14 dpv. Copyright © 2017 Elsevier B.V. All rights reserved.

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...

Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies.

PubMed

Linssen, A M W; Sambeth, A; Vuurman, E F P M; Riedel, W J

2014-06-01

Methylphenidate (MPH), a stimulant drug with dopamine and noradrenaline reuptake inhibition properties, is mainly prescribed in attention deficit hyperactivity disorder, is increasingly used by the general population, intending to enhance their cognitive function. In this literature review, we aim to answer whether this is effective. We present a novel way to determine the extent to which MPH enhances cognitive performance in a certain domain. Namely, we quantify this by a percentage that reflects the number of studies showing performance enhancing effects of MPH. To evaluate whether the dose-response relationship follows an inverted-U-shaped curve, MPH effects on cognition are also quantified for low, medium and high doses, respectively. The studies reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the dose-response relationship differs between cognitive domains. MPH use is associated with side effects and other adverse consequences, such as potential abuse. Future studies should focus on MPH specifically to adequately asses its benefits in relation to the risks specific to this drug.

Pharmacodynamics and pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients.

PubMed

Chang, W H; Lin, S K; Jann, M W; Lam, Y W; Chen, T Y; Chen, C T; Hu, W H; Yeh, E K

1989-07-01

Twelve male chronic schizophrenic inpatients, neuroleptic-free for at least 4 weeks, were given an oral test dose of 10 mg haloperidol (HAL) and reduced HAL (RHAL) in a random order, with a 2-week interval. Two weeks after the last test dose, the patients were given HAL, 5 mg orally twice daily for 7 days. Blood samples were drawn at baseline and between 0.5 and 24 hr after the test doses, and during HAL treatment as well. Plasma drug concentrations and homovanillic acid (HVA) levels were measured with high-performance liquid chromatography using electrochemical detection. HAL, but not RHAL, produced increments in plasma HVA (pHVA) levels at 24 hr after a test dose. pHVA levels remained higher than baseline during HAL treatment. Detectable interconversion between HAL and RHAL was observed in eight patients. The capacity of the reductive drug-metabolizing enzyme system, however, was greater than that of the oxidative processes. The plasma RHAL:HAL ratios on days 6 and 7 were higher than and positively correlated with those at Tmax after a single dose of HAL and were negatively correlated with the HAL:RHAL ratios at Tmax after a single dose of RHAL. Thus, both reductive and oxidative drug-metabolizing systems probably contribute to individual differences in plasma RHAL:HAL ratios in HAL-treated schizophrenic patients.

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

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

Massimino, Maura; Gandola, Lorenza; Spreafico, Filippo

Purpose: Myeloablative regimens were frequently used for medulloblastoma relapsing after craniospinal irradiation (CSI): in 1997-2002, we used repeated surgery, standard-dose and myeloablative chemotherapy, and reirradiation. Methods and Materials: In 10 patients, reinduction included sequential high-dose etoposide, high-dose cyclophosphamide/vincristine, and high-dose carboplatin/vincristine, then two myeloablative courses with high-dose thiotepa ({+-} carboplatin); 6 other patients received two of four courses of cisplatin/etoposide. Hematopoietic precursor mobilization followed high-dose etoposide or high-dose cyclophosphamide or cisplatin/etoposide therapy. After the overall chemotherapy program, reirradiation was prescribed when possible. Results: Seventeen patients were treated: previous treatment included CSI of 19.5-36 Gy with posterior fossa/tumor boost and chemotherapymore » in 16 patients. Fifteen patients were in their first and 2 in their second and third relapses, respectively. First progression-free survival had lasted a median of 26 months. Relapse sites included leptomeninges in 9 patients, spine in 4 patients, posterior fossa in 3 patients, and brain in 1 patient. Three patients underwent complete resection of recurrence, and 10 underwent reirradiation. Twelve of 14 patients with assessable tumor had an objective response after reinduction; 2 experienced progression and were not given the myeloablative courses. Remission lasted a median of 16 months. Additional relapses appeared in 13 patients continuing the treatment. Fifteen patients died of progression and 1 died of pneumonia 13 months after relapse. The only survivor at 93 months had a single spinal metastasis that was excised and irradiated. Survival for the series as a whole was 11-93 months, with a median of 41 months. Conclusions: Despite responses being obtained and ample use of surgery and reirradiation, second-line therapy with myeloablative schedules was not curative, barring a few exceptions. A salvage therapy for medulloblastoma after CSI still needs to be sought.« less

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.

Advantages of Repeated Low Dose against Single High Dose of Kainate in C57BL/6J Mouse Model of Status Epilepticus: Behavioral and Electroencephalographic Studies

PubMed Central

Beamer, Edward; Sills, Graeme J.; Thippeswamy, Thimmasettappa

2014-01-01

A refined kainate (KA) C57BL/6J mouse model of status epilepticus (SE) using a repeated low dose (RLD) of KA (5 mg/kg, intraperitoneal; at 30 min intervals) was compared with the established single high dose (SHD) of KA (20 mg/kg, intraperitoneal) model. In the RLD group, increased duration of convulsive motor seizures (CMS, Racine scale stage ≥3) with a significant reduction in mortality from 21% to 6% and decreased variability in seizure severity between animals/batches were observed when compared to the SHD group. There was a significant increase in the percentage of animals that reached stage-5 seizures (65% versus 96%) in the RLD group. Integrated real-time video-EEG analysis of both groups, using NeuroScore software, revealed stage-specific spikes and power spectral density characteristics. When the seizures progressed from non-convulsive seizures (NCS, stage 1–2) to CMS (stage 3–5), the delta power decreased which was followed by an increase in gamma and beta power. A transient increase in alpha and sigma power marked the transition from NCS to CMS with characteristic ‘high frequency trigger’ spikes on the EEG, which had no behavioral expression. During SE the spike rate was higher in the RLD group than in the SHD group. Overall these results confirm that RLD of KA is a more robust and consistent mouse model of SE than the SHD of KA mouse model. PMID:24802808

PHARMACOKINETICS OF SINGLE-DOSE ORALLY ADMINISTERED CIPROFLOXACIN IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

PubMed

Barbosa, Lorraine; Johnson, Shawn P; Papich, Mark G; Gulland, Frances

2015-06-01

Ciprofloxacin is commonly selected for clinical use due to its broad-spectrum efficacy and is a frequently administered antibiotic at The Marine Mammal Center, a marine mammal rehabilitation facility. Ciprofloxacin is used for treatment of California sea lions ( Zalophus californianus ) suffering from a variety of bacterial infections at doses extrapolated from other mammalian species. However, as oral absorption is variable both within and across species, a more accurate determination of appropriate dosage is needed to ensure effective treatment and avoid emergence of drug-resistant bacterial strains. A pharmacokinetic study was performed to assess plasma concentrations of ciprofloxacin in California sea lions after a single oral dose. Twenty healthy California sea lions received a single 10-mg/kg oral dose of ciprofloxacin administered in a herring fish. Blood was then collected at two of the following times from each individual: 0.5, 0.75, 1, 2, 4, 8, 10, 12, 18, and 24 hr postingestion. Plasma ciprofloxacin concentration was assessed via high-performance liquid chromatography. A population pharmacokinetics model demonstrated that an oral ciprofloxacin dose of 10 mg/kg achieved an area under the concentration vs. time curve of 6.01 μg hr/ml. Absorption was rapid, with ciprofloxacin detectable in plasma 0.54 hr after drug administration; absorption half-life was 0.09 hr. A maximum plasma concentration of 1.21 μg/ml was observed at 1.01 hr, with an elimination half-life of 3.09 hr. Ciprofloxacin administered orally at 10 mg/kg produced therapeutic antibacterial exposure for only some of the most susceptible bacterial organisms commonly isolated from California sea lions.

Impact of organic polyelectrolytes on coagulation of source-separated black water.

PubMed

Kozminykh, Pavlo; Heistad, Arve; Ratnaweera, Harsha C; Todt, Daniel

2016-01-01

Household wastewater is originated from common people's activities and has a potential harmful impact on the environment if discharged directly without proper treatment. Toilet wastewater or black water (BW) contains urine, faeces, toilet paper and flushing water and it contains the majority of pollutants obtained from a single household. In this study, the focus was on BW treatment using chemical methods. The main goal of current research was to define the possibility and applicability of conventional coagulants and flocculants in direct chemical treatment of vacuum-collected BW to remove particles, organic matter and phosphorous. After the definition of dosing ranges, based on the equivalent doses in conventional municipal and industrial wastewater treatment data, aluminium and iron coagulants, organic polyelectrolytes (polymers with anionic, neutral and cationic charge with different molecular weights) and their various combinations were tested using the well-known jar-test laboratory method to study aggregation and solid-liquid separation processes in raw BW. The most important process parameter during the coagulation was pH level, dependent on the type and doses of metal salts. Some side processes were found to occur while using iron-based coagulants. Dosing of either single coagulants or single polymers did not give satisfactory results, while a combination of aluminium salts and cationic polymers showed high removal rates in total suspended solids, total chemical oxygen demand and ortho-phosphates, reaching 97.8%, 92% and 98.6%, respectively, with the optimal doses of chemicals. Cationic polymers with the lowest molecular weight and highest charge density were the most efficient in combination with aluminium coagulants.

Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects.

PubMed

Morcos, Peter N; Yu, Li; Bogman, Katrijn; Sato, Mika; Katsuki, Hisakazu; Kawashima, Kosuke; Moore, David J; Whayman, Matt; Nieforth, Keith; Heinig, Katja; Guerini, Elena; Muri, Dieter; Martin-Facklam, Meret; Phipps, Alex

2017-03-01

1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor. 2. The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50 μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600 mg oral dose of alectinib in the first period, and a single 600 mg/67 μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects. 3. The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5 L/h, volume of distribution was 475 L and the hepatic extraction ratio was low (0.14). 4. Near-complete recovery of administered radioactivity was achieved within 168 h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively. 5. This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans.

A low dose of subperiosteal anaesthesia injection versus a high dose of infiltration anaesthesia to minimise the risk of nerve damage at implant placement: A randomised controlled trial.

PubMed

Sánchez-Siles, Mariano; Camacho-Alonso, Fabio; Salazar-Sánchez, Noemi; Aguinaga-Ontoso, Enrique; Muñoz, Javier Guardia; Calvo-Guirado, Jose Luis

2016-01-01

To evaluate whether a low-dose subperiosteal anaesthesia is effective in minimising risks of inferior alveolar nerve damage at implant placement when compared to high-dose infiltration anaesthesia. One hundred and twenty patients requiring the placement of a single implant in order to replace a missing first mandibular were randomly allocated to two groups: group A (awake hemilip) subperiosteal crestal injection equal to 0.9 ml of articaine with 0.5% epinephrine and group B (numb hemilip) infiltration equal to 7.2 ml of articaine with 0.5% epinephrine in the vestibular fundus. Intraoperative sensory control using sensory tests was carried out in all patients. Outcome measures were neurological complications, intraoperative and postoperative visual analogue scale (VAS) scores for pain and swelling, and a questionnaire evaluating patient satisfaction. Patients were followed for 1 week postoperatively. There were no cases of nerve injury. Seven days after surgery the postoperative VAS score for pain and swelling was lower in group A in a statistically significant manner (difference = -3.41%; 95% CI: -5.57, -1.26; P = 0.002 and difference = -3.33%; 95% CI: -5.41, -1.25; P = 0.002, respectively). No nerve damage occurred using either anaesthesia types, therefore the choice of type of anaesthesia is a subjective clinical decision, however it may be preferable to use a low dose (0.9 ml) of subperiosteal anaesthesia, since it is unnecessary to deliver 7.2 ml of articaine to anaesthetise a single mandibular molar implant site.

An open-label, single-dose, phase 1 study of the absorption, metabolism and excretion of quizartinib, a highly selective and potent FLT3 tyrosine kinase inhibitor, in healthy male subjects, for the treatment of acute myeloid leukemia.

PubMed

Sanga, Madhu; James, Joyce; Marini, Joseph; Gammon, Guy; Hale, Christine; Li, Jianke

2017-10-01

1. Quizartinib absorption, metabolism and excretion were characterized in six healthy men receiving a single oral dose of 60 mg (≈100 μCi) of [ 14 C]-quizartinib. Blood, plasma, urine and faeces were collected ≤336 h postdose. 2. Four hours postdose, maximum mean ± SD blood radioactivity concentrations were 296 ± 67.4 ng equivalents/g. A mean ± SD of 1.64 ± 0.482% and 76.3 ± 6.23% of the dose was recovered in urine and faeces, respectively, within 336 h postdose. 3. Radio-detector high-performance liquid chromatography (radio-HPLC) and liquid chromatography-mass spectrometry (LC-MS) showed two main radioactive peaks in plasma, unchanged quizartinib and mono-oxidative metabolite, AC886. Five additional metabolites in plasma were identified by LC-MS, but low levels prevented radio-HPLC detection. Although unchanged quizartinib was the main radioactive component in faeces (mean, 4.0% of administered dose), 15 metabolites representing a mean of 1.0-3.5% of administered dose were found. Quizartinib was predominantly metabolized by phase I biotransformations (oxidation, reduction, dealkylation, deamination, hydrolysis and combinations thereof). 4. This study indicated that quizartinib was rapidly and orally bioavailable, extensively metabolized, with AC886 as the major circulating metabolite, and predominantly eliminated in faeces. Quizartinib was well tolerated in the subjects.

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.

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.

The attenuated NYCBH vaccinia virus deleted for the immune evasion gene, E3L, completely protects mice against heterologous challenge with ectromelia virus.

PubMed

Denzler, Karen L; Schriewer, Jill; Parker, Scott; Werner, Chas; Hartzler, Hollyce; Hembrador, Ed; Huynh, Trung; Holechek, Susan; Buller, R M; Jacobs, Bertram L

2011-12-06

The New York City Board of Health (NYCBH) vaccinia virus (VACV) vaccine strain was deleted for the immune evasion gene, E3L, and tested for its pathogenicity and ability to protect mice from heterologous challenge with ectromelia virus (ECTV). NYCBHΔE3L was found to be highly attenuated for pathogenicity in a newborn mouse model and showed a similar attenuated phenotype as the NYVAC strain of vaccinia virus. Scarification with one or two doses of the attenuated NYCBHΔE3L was able to protect mice equally as well as NYCBH from death, weight loss, and viral spread to visceral organs. A single dose of NYCBHΔE3L resulted in low poxvirus-specific antibodies, and a second dose increased levels of poxvirus-specific antibodies to a level similar to that seen in animals vaccinated with a single dose of NYCBH. However, similar neutralizing antibody titers were observed following one or two doses of NYCBHΔE3L or NYCBH. Thus, NYCBHΔE3L shows potential as a candidate for a safer human smallpox vaccine since it protects mice from challenge with a heterologous poxvirus. Copyright © 2011 Elsevier Ltd. All rights reserved.

Pre-exercise β-hydroxy-β-methylbutyrate free-acid supplementation improves work capacity recovery: a randomized, double-blinded, placebo-controlled study.

PubMed

Correia, Ana Luiza Matias; de Lima, Filipe Dinato; Bottaro, Martim; Vieira, Amilton; da Fonseca, Andrew Correa; Lima, Ricardo M

2018-02-08

The purpose of this study was to investigate the effects of a single-dose of β-hydroxy-β-methylbutyrate free acid (HMB-FA) supplementation on muscle recovery after a high-intensity exercise bout. Twenty-three trained young males were randomly assigned to receive either a single-dose supplementation of 3g of HMB-FA (n = 12; age 22.8 ± 3.0 years) or placebo (PLA; n = 11; age 22.9 ± 3.1 years). A muscle damage protocol was applied 60 minutes after supplementation, and consisted of seven sets of 20 drop jumps from a 60-cm box with 2-min rest intervals between sets. Muscle swelling, countermovement jump (CMJ), maximal voluntary isometric torque (MVIT) and work capacity (WC) were measured before, immediately after, 24, 48 and 72 hours after the exercise protocol. Muscle swelling, CMJ and MVIT changed similarly in both groups after the exercise protocol (p < 0.001), but returned to pre-exercise levels after 24 hours in both groups. WC decreased similarly in both groups after the exercise protocol (p < 0.01). For HMB-FA, WC returned to pre-exercise level 24 hours after exercise protocol. However, on PLA, WC did not return to pre-exercise level even 72 hours after the exercise protocol. In summary, a single-dose of HMB-FA supplementation improved WC recovery after a high-intensity exercise bout. However, HMB-FA did not affect the time-course of muscle swelling, MVIT and CMJ recovery.

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.

SU-F-T-424: Mitigation of Increased Surface Dose When Treating Through A Carbon Fiber Couch Top

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

Johnson, E; Misgina, F

Purpose: To study the effect of the Varian carbon fiber couch top on surface dose for patients being treated using single PA beams in the supine position and to identify simple methods for surface dose reduction. Methods: Measurements of surface dose were obtained in Solid Water phantoms using both a parallel plate ionization chamber (PTW Advanced Markus) and EBT2 Radiochromic films for both 6 and 10MV photons. All measurements were referenced to a depth considered a typical for PA Spine fields. Techniques used to reduce the surface dose included introducing an air standoff using Styrofoam sheets to suspend the phantommore » surface above the couch top and by adding a thin high Z scattering foil on the table surface. Surface doses were evaluated for typical field sizes, standoff heights, and various scattering materials. Comparisons were made to the surface dose obtainable when treating through a Varian Mylar covered tennis racket style couch top. Results: Dependence on typical spine field sizes was relatively minor. Dependence on air gap was much more significant. Surface doses decreased exponentially with increases in air standoff distance. Surface doses were reduced by approximately 50% for an air gap of 10cm and 40% for a 15cm air gap. Surface doses were reduced by an additional 15% by the addition of a 1mm Tin scattering foil. Conclusion: Using simple techniques, it is possible to reduce the surface dose when treating single PA fields through the Varian carbon fiber couch top. Surface doses can be reduced to levels observed when treating though transparent Mylar tops by adding about 15 cm of air gap. Further reductions are possible by adding thin scattering foils, such as Tin or Lead, on the couch surface. This is a low cost approach to reduce surface dose when using the Varian carbon fiber couch top.« less

Acute high dose of chlorpyrifos alters performance of rats in the elevated plus-maze and the elevated T-maze.

PubMed

López-Crespo, G A; Flores, P; Sánchez-Santed, F; Sánchez-Amate, M C

2009-11-01

Chlorpyrifos (CPF) is a broad spectrum organophosphate (OP) pesticide widely used in agriculture, industry and household. Several animal studies indicate emotional disturbances after CPF exposure, although the results are sometimes puzzling. Thus, both anxiolytic and anxiogenic effects of CPF have been reported in different animal models of anxiety [Sánchez-Amate MC, Flores P, Sánchez-Santed F. Effects of chlorpyrifos in the plus-maze model of anxiety. Behav Pharmacol 2001;12:285-92; Sánchez-Amate MC, Dávila E, Cañadas F, Flores P, Sánchez-Santed F. Chlorpyrifos shares stimulus properties with pentilenetetrazol as evaluated by and operant drug discrimination task. Neurotoxicology 2002;23:795-803; López-Crespo G, Carvajal F, Flores P, Sánchez-Santed F, Sánchez-Amate MC. Time-course of biochemical and behavioural effects of a single high dose of chlorpyrifos. Neurotoxicology 2007;28:541-7]. On the other hand, other behavioural effects of CPF are time-dependent [López-Crespo G, Carvajal F, Flores P, Sánchez-Santed F, Sánchez-Amate MC. Time-course of biochemical and behavioural effects of a single high dose of chlorpyrifos. Neurotoxicology 2007;28:541-7], raising the question that the effects of CPF could be task and post-administration time dependent. To test this hypothesis, three groups of rats were treated with a single high dose of CPF (250 mg/kg); one of the groups was tested on day 5 on the elevated plus-maze, to complete our previous study on day 2 [Sánchez-Amate MC, Flores P, Sánchez-Santed F. Effects of chlorpyrifos in the plus-maze model of anxiety. Behav Pharmacol 2001;12:285-92]. The remaining groups were tested on the elevated T-maze on days 2 and 5. CPF produced an increased open arm activity on the elevated plus-maze on day 5, an increased escape latency on the elevated T-maze on day 2 and an impaired inhibitory avoidance on day 5. Data are discussed taking together all studies carried out in our laboratory, confirming that CPF effects on emotional behaviour are dependent on both task contingencies and post-administration time.

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

SU-G-BRB-06: Commissioning and Evaluation of EPID-Based in Vivo Dosimetry Software Using a Tissue-Maximum Ratio Approach

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

Held, M; Cheung, J; Morin, O

Purpose: To commission and evaluate an in vivo EPID-based transit dosimetry software (EPIgray, DOSIsoft, Cachan, France) using simple fields and TG119-based IMRT treatment plans. Methods: EPIgray was commissioned on a Truebeam based on finite tissue-maximum ratio (fTMR) measurements with solid water blocks of thicknesses between 0 and 37 cm. Field sizes varied from 2×2 to 20×20 cm{sup 2}. Subsequently, treatment plans of single and opposed beams with field sizes between 4×4 and 15×15 cm{sup 2} as well as IMRT plans were measured to evaluate the dose reconstruction accuracy. Single field dose predictions were made for anterior-posterior and lateral beams. IMRTmore » plans were created based on TG119 recommendations. The reconstructed dose was compared to the planned dose for selected points at isocenter and away from isocenter. Results: For single square fields, the dose in EPIgray was reconstructed within 3% accuracy at isocenter relative to the planned dose. Similarly, the relative deviation of the total dose was accurately reconstructed within 3% for all IMRT plans with points placed inside a high dose region near the isocenter. Predictions became less accurate than 5% when the evaluation point was outside the majority of IMRT beam segments. Additionally, points 5 cm or more away from the isocenter or within an avoidance structure were predicted less reliably. Conclusion: EPIgray formalism accuracy is adequate for an efficient error detection system. It provides immediate intra-fractional feedback on the delivery of treatment plans without affecting the treatment beam. Besides the EPID, no additional hardware is required, which makes it accessible to all clinics. The software evaluates point dose measurements to verify treatment plan delivery and patient positioning within 5% accuracy, depending on the placement of evaluation points. EPIgray is not intended to replace patient-specific quality assurance but should be utilized as an additional layer of safety for continuous patient treatment verification. This research is supported by DOSIsoft.« less

Efficacy of Praziquantel against Schistosoma mekongi and Opisthorchis viverrini: A Randomized, Single-Blinded Dose-Comparison Trial

PubMed Central

Phongluxa, Khampheng; Ayé Soukhathammavong, Phonepasong; Vonghachack, Youthanavanh; Keiser, Jennifer; Vounatsou, Penelope; Tanner, Marcel; Hatz, Christoph; Utzinger, Jürg; Odermatt, Peter; Akkhavong, Kongsap

2012-01-01

Background Schistosomiasis and opisthorchiasis are of public health importance in Southeast Asia. Praziquantel (PZQ) is the drug of choice for morbidity control but few dose comparisons have been made. Methodology Ninety-three schoolchildren were enrolled in an area of Lao PDR where Schistosoma mekongi and Opisthorchis viverrini coexist for a PZQ dose-comparison trial. Prevalence and intensity of infections were determined by a rigorous diagnostic effort (3 stool specimens, each examined with triplicate Kato-Katz) before and 28–30 days after treatment. Ninety children with full baseline data were randomized to receive PZQ: the 40 mg/kg standard single dose (n = 45) or a 75 mg/kg total dose (50 mg/kg+25 mg/kg, 4 hours apart; n = 45). Adverse events were assessed at 3 and 24 hours posttreatment. Principal Findings Baseline infection prevalence of S. mekongi and O. viverrini were 87.8% and 98.9%, respectively. S. mekongi cure rates were 75.0% (95% confidence interval (CI): 56.6–88.5%) and 80.8% (95% CI: 60.6–93.4%) for 40 mg/kg and 75 mg/kg PZQ, respectively (P = 0.60). O. viverrini cure rates were significantly different at 71.4% (95% CI: 53.4–84.4%) and 96.6% (95% CI: not defined), respectively (P = 0.009). Egg reduction rates (ERRs) against O. viverrini were very high for both doses (>99%), but slightly lower for S. mekongi at 40 mg/kg (96.4% vs. 98.1%) and not influenced by increasing diagnostic effort. O. viverrini cure rates would have been overestimated and no statistical difference between doses found if efficacy was based on a minimum sampling effort (single Kato-Katz before and after treatment). Adverse events were common (96%), mainly mild with no significant differences between the two treatment groups. Conclusions/Significance Cure rate from the 75 mg/kg PZQ dose was more efficacious than 40 mg/kg against O. viverrini but not against S. mekongi infections, while ERRs were similar for both doses. Trial Registration Controlled-Trials.com ISRCTN57714676 PMID:22848766

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.

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

Stabilization of Tetanus Toxoid Encapsulated in PLGA Microspheres

PubMed Central

Jiang, Wenlei; Schwendeman, Steven P.

2014-01-01

Delivery of vaccine antigens from controlled-release poly(lactic/glycolic acid) (PLGA) microspheres is a novel approach to reduce the number of antigen doses required for protection against infection. A major impediment to developing single-shot vaccines is encapsulated antigen instability during months of exposure to physiological conditions. For example, efforts to control neonatal tetanus in developing countries with a single-dose TT vaccine have been plagued by poor stability of the 150 kDa formaldehyde-detoxified protein antigen, tetanus toxoid (TT) in PLGA microspheres. We examined the denatured states of PLGA-encapsulated TT, revealing two primary TT instability mechanisms: 1) protein aggregation mediated by formaldehyde and 2) acid-induced protein unfolding and epitope damage. Further, we systemically identified excipients which can efficiently inhibit TT aggregation and retain TT antigenicity under simulated deleterious conditions, i.e., elevated temperature and humidity. By employing these novel additives in the PLGA system, we report the slow and continuous release of high doses of TT for one month with retained antigen stability during bioerosion of PLGA. PMID:18710256

Metabolism, distribution and elimination of lisdexamfetamine dimesylate: open-label, single-centre, phase I study in healthy adult volunteers.

PubMed

Krishnan, Suma M; Pennick, Michael; Stark, Jeffrey G

2008-01-01

Attention-deficit/hyperactivity disorder (ADHD) in children often persists into adulthood and is potentially associated with significant social and occupational impairments. It is important to understand the effects of pharmacological treatments of ADHD in adults. This study aimed to assess the absorption, metabolism and elimination of lisdexamfetamine dimesylate in normal, healthy adult subjects following a single oral dose. A secondary objective was to assess the safety and tolerability of treatment. In an open-label, single-centre study, six healthy adult volunteers aged 22-52 years received a single oral 70 mg dose of (14)C-radiolabelled lisdexamfetamine dimesylate in solution following a 10-hour fast. Blood samples drawn pre-dose and at time points up to 120 hours post-dose were used for plasma pharmacokinetic analysis of the active d-amphetamine and the intact parent compound lisdexamfetamine dimesylate. Recovery of radioactivity was determined by liquid scintillation counting of blood samples (whole blood and plasma), urine samples and faecal samples collected pre-dose and at designated time points up to 120 hours post-dose. Urine samples were also analysed for the presence of amphetamine-derived metabolites. Safety was assessed by adverse event reporting, changes in physical findings, vital sign measurements, ECG measurements, and clinical laboratory test results. For intact lisdexamfetamine dimesylate, the median time to reach maximum plasma drug concentration (t(max)) was 1.00 hour, and the mean maximum plasma drug concentration (C(max)) was 58.2 +/- 28.1 ng/mL. Intact lisdexamfetamine dimesylate exhibited modest systemic exposure (area under the drug concentration-time curve from time 0 to infinity [AUC(infinity)] 67.04 +/- 18.94 ng . h/mL), and rapid elimination (mean apparent terminal elimination half-life [t((1/2)beta)] 0.47 hours). For d-amphetamine, the median t(max) was 3.00 hours, and the mean C(max) was 80.3 +/- 11.8 ng/mL. The AUC(infinity) of d-amphetamine was 1342 +/- 216.9 ng . h/mL, and elimination occurred as a first-order process. The t((1/2)beta) of d-amphetamine was 10.39 hours. Peaks consistent with amphetamine and hippuric acid were identified in urine samples by high-performance liquid chromatography radioactive profiling. Relative to dose administered, 41.5% was recovered in urine as d-amphetamine, 24.8% as hippuric acid and 2.2% as intact lisdexamfetamine dimesylate. Less than 0.3% of the administered dose was recovered in the faeces. During the 0- to 48-hour urine samples, no unexpected adverse events or clinically significant laboratory, ECG or physical examination findings related to the study medication were observed. Following a single 70 mg oral dose, lisdexamfetamine dimesylate was quickly absorbed, extensively metabolized to d-amphetamine and its derivatives, and rapidly eliminated. Systemic exposure to d-amphetamine was approximately 20-fold higher than systemic exposure to intact lisdexamfetamine dimesylate in healthy adults. Lisdexamfetamine dimesylate, administered as a single 70 mg dose, was generally well tolerated in this study.

Serotonin and cholecystokinin synergistically stimulate rat vagal primary afferent neurones

PubMed Central

Li, Y; Wu, X Y; Owyang, C

2004-01-01

Recent studies indicate that cholecystokinin (CCK) and serotonin (5-hydroxytryptamine, 5-HT) act via vagal afferent fibres to mediate gastrointestinal functions. In the present study, we characterized the interaction between CCK and 5-HT in the vagal primary afferent neurones. Single neuronal discharges of vagal primary afferent neurones innervating the duodenum were recorded from rat nodose ganglia. Two groups of nodose ganglia neurones were identified: group A neurones responded to intra-arterial injection of low doses of cholecystokinin octapeptide (CCK-8; 10–60 pmol); group B neurones responded only to high doses of CCK-8 (120–240 pmol), and were also activated by duodenal distention. CCK-JMV-180, which acts as an agonist in high-affinity states and as an antagonist in low-affinity states, dose dependently stimulated group A neurones, but inhibited the effect of the high doses of CCK-8 on group B neurones. Duodenal perfusion of 5-HT evoked dose-dependent increases in nodose neuronal discharges. Some neurones that responded to 5-HT showed no response to either high or low doses of CCK-8. A separate group of nodose neurones that possessed high-affinity CCK type A (CCK-A) receptors also responded to luminal infusion of 5-HT. Further, a subthreshold dose of CCK-8 (i.e. 5 pmol) produced no measurable electrophysiological effects but it augmented the neuronal responses to 5-HT. This potentiation effect of CCK-8 was eliminated by CR 1409. From these results we concluded that the vagal nodose ganglion contains neurones that may possess only high- or low-affinity CCK-A receptors or 5-HT3 receptors. Some neurones that express high-affinity CCK-A receptors also express 5-HT3 receptors. Pre-exposure to luminal 5-HT may augment the subsequent response to a subthreshold dose of CCK. PMID:15235095

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.

A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 in Pediatric Patients Undergoing HSCT

ClinicalTrials.gov

2017-06-01

Vitamin D Deficiency; Stem Cell Transplant Complications; Pediatric Cancer; Blood Disorder; Pediatric Acute Myeloid Leukemia; Pediatric Acute Lymphoid Leukemia; Myelodysplastic Syndromes; Sickle Cell Anemia in Children; Aplastic Anemia; Thalassemia in Children

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

Eley, J; Mehta, M; Molitoris, J

Purpose: The purpose of this study was to propose a method to implement arc therapy that is compatible with existing particle therapy systems having gantries and pencil-beam scanning capacities. Furthermore, we sought to demonstrate expected benefits of this method for selected clival chordoma patients. Methods: We propose that a desired particle arc treatment plan can be discretized into a finite number of fixed beams and that only one (or a subset) of these beams be delivered in any single treatment fraction; the target should receive uniform dose during each fraction. For 3 clival-chordoma patients, robust-optimized, scanned proton beams were simulatedmore » to deliver 78 Gy (RBE) to clinical target volumes (CTVs), using either a single-field plan with a posterior-anterior (PA) beam or a discrete-arc plan with 16 beams that were equally spaced throughout a 360-degree axial arc. Dose-volume metrics were compared with emphasis on the brainstem, since risk of radiation necrosis there can often restrict application of tumoricidal doses for chordomas. Results: The mean volume of brainstem receiving a dose of 60 Gy (RBE) or higher (V60Gy) was 10.3±0.9 cm{sup 3} for the single-field plan and 4.7±1.8 cm{sup 3} for the discrete-arc plan, a reduction of 55% in favor of arcs. The mean dose to the brainstem was also reduced using arcs, by 18%, while the maximum dose was nearly identical for both methods. For the whole brain, V60Gy was reduced by 23%, in favor of arcs. Mean dose to the CTVs were nearly identical for both strategies, within 0.3%. Conclusion: Discrete arc treatments can be implemented using existing scanned particle-beam facilities. Aside from the physical advantages, the biological uncertainties of particle therapy, particularly high in the distal edge, can be reduced by arc therapy via rotational smearing, which may be of benefit for tumors near the brainstem.« less

Cataractogenesis from high-LET radiation and the Casarett model

NASA Astrophysics Data System (ADS)

Cox, A. B.; Lee, A. C.; Lett, J. T.; Ainsworth, E. J.; Jose, J. G.

Space radiations, especially heavy ions, constitute significant hazards to astronauts. These hazards will increase as space missions lengthen. Moreover, the dangers to astronauts will be enhanced by the persistence, or even the progression, of biological damage throughout their subsequent life spans. To assist in the assessment of risks to astronauts, we are investigating the long-term effects of heavy ions on specific animal tissues. In one study, the eyes of rabbits of various ages were exposed to a single dose of Bragg plateau 20Ne ions (LET∞ ≅ 30 keV/μm). The development of cataracts has shown a pronounced age-related response during the first year after irradiation, and will be followed for two more years. In other studies, mice were exposed to single or fractionated doses of 12C ions (4-cm spread-out Bragg peak; dose-averaged LET∞ = 70-80 keV/μm) or 60Co γ-photons (LET∞ = 0.3 keV/μm). Measurements of the frequency of posterior lens opacification have shown that the tissue sparing observed with dose fractionation of γ-photons was absent when 12C-ion doses were fractionated. Development of posterior lens cataracts was also followed for long periods (up to 21 months) in mice exposed to single doses of Bragg plateau HZE particles (40Ar, 20Ne and 12C ions: LET∞ ≅ 100, 30 and 10 keV/μm, respectively) or 225 kVp X-rays. Based on average cataract levels at the different observation times, the RBE's (RBE = relative biological effectiveness) for the ions were circa 5, 3 and 1-2, respectively, over the range of doses used (0.05-0.9 Gy). Investigations of cataractogenesis are useful for exploring the model of radiation damage proposed by Casarett [1] and by Rubin and Casarett [2] with a tissue not connected directly to the vasculature.

Randomised field trial to evaluate serological response after foot-and-mouth disease vaccination in Turkey.

PubMed

Knight-Jones, T J D; Bulut, A N; Gubbins, S; Stärk, K D C; Pfeiffer, D U; Sumption, K J; Paton, D J

2015-02-04

Despite years of biannual mass vaccination of cattle, foot-and-mouth disease (FMD) remains uncontrolled in Anatolian Turkey. To evaluate protection after mass vaccination we measured post-vaccination antibodies in a cohort of cattle (serotypes O, A and Asia-1). To obtain results reflecting typical field protection, participants were randomly sampled from across Central and Western Turkey after routine vaccination. Giving two-doses one month apart is recommended when cattle are first vaccinated against FMD. However, due to cost and logistics, this is not routinely performed in Turkey, and elsewhere. Nested within the cohort, we conducted a randomised trial comparing post-vaccination antibodies after a single-dose versus a two-dose primary vaccination course. Four to five months after vaccination, only a third of single-vaccinated cattle had antibody levels above a threshold associated with protection. A third never reached this threshold, even at peak response one month after vaccination. It was not until animals had received three vaccine doses in their lifetime, vaccinating every six months, that most (64% to 86% depending on serotype) maintained antibody levels above this threshold. By this time cattle would be >20 months old with almost half the population below this age. Consequently, many vaccinated animals will be unprotected for much of the year. Compared to a single-dose, a primary vaccination course of two-doses greatly improved the level and duration of immunity. We concluded that the FMD vaccination programme in Anatolian Turkey did not produce the high levels of immunity required. Higher potency vaccines are now used throughout Turkey, with a two-dose primary course in certain areas. Monitoring post-vaccination serology is an important component of evaluation for FMD vaccination programmes. However, consideration must be given to which antigens are present in the test, the vaccine and the field virus. Differences between these antigens affect the relationship between antibody titre and protection. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Impact of Low and High Doses of Marbofloxacin on the Selection of Resistant Enterobacteriaceae in the Commensal Gut Flora of Young Cattle: Discussion of Data from 2 Study Populations.

PubMed

Lhermie, Guillaume; Dupouy, Véronique; El Garch, Farid; Ravinet, Nadine; Toutain, Pierre-Louis; Bousquet-Mélou, Alain; Seegers, Henri; Assié, Sébastien

2017-03-01

In the context of requested decrease of antimicrobial use in veterinary medicine, our objective was to assess the impact of two doses of marbofloxacin administered on young bulls (YBs) and veal calves (VCs) treated for bovine respiratory disease, on the total population of Enterobacteriaceae in gut flora and on the emergence of resistant Enterobacteriaceae. In two independent experiments, 48 YBs from 6 commercial farms and 33 VCs previously colostrum deprived and exposed to cefquinome were randomly assigned to one of the three groups LOW, HIGH, and Control. In LOW and HIGH groups, animals received a single injection of, respectively, 2 and 10 mg/kg marbofloxacin. Feces were sampled before treatment, and at several times after treatment. Total and resistant Enterobacteriaceae enumerating were performed by plating dilutions of fecal samples on MacConkey agar plates that were supplemented or not with quinolone. In YBs, marbofloxacin treatment was associated with a transient decrease in total Enterobacteriaceae count between day (D)1 and D3 after treatment. Total Enterobacteriaceae count returned to baseline between D5 and D7 in all groups. None of the 48 YBs harbored marbofloxacin-resistant Enterobacteriaceae before treatment. After treatment, 1 out of 20 YBs from the Control group and 1 out of 14 YBs from the HIGH group exhibited marbofloxacin-resistant Enterobacteriaceae. In VCs, the rate of fluoroquinolone-resistant Enterobacteriaceae significantly increased after low and high doses of marbofloxacin treatment. However, the effect was similar for the two doses, which was probably related to the high level of resistant Enterobacteriaceae exhibited before treatment. Our results suggest that a single treatment with 2 or 10 mg/kg marbofloxacin exerts a moderate selective pressure on commensal Enterobacteriaceae in YBs and in VCs. A fivefold decrease of marbofloxacin regimen did not affect the selection of resistances among commensal bacteria.

Is it necessary to plan with safety margins for actively scanned proton therapy?

NASA Astrophysics Data System (ADS)

Albertini, F.; Hug, E. B.; Lomax, A. J.

2011-07-01

In radiation therapy, a plan is robust if the calculated and the delivered dose are in agreement, even in the case of different uncertainties. The current practice is to use safety margins, expanding the clinical target volume sufficiently enough to account for treatment uncertainties. This, however, might not be ideal for proton therapy and in particular when using intensity modulated proton therapy (IMPT) plans as degradation in the dose conformity could also be found in the middle of the target resulting from misalignments of highly in-field dose gradients. Single field uniform dose (SFUD) and IMPT plans have been calculated for different anatomical sites and the need for margins has been assessed by analyzing plan robustness to set-up and range uncertainties. We found that the use of safety margins is a good way to improve plan robustness for SFUD and IMPT plans with low in-field dose gradients but not necessarily for highly modulated IMPT plans for which only a marginal improvement in plan robustness could be detected through the definition of a planning target volume.

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.

Compartmental Pharmacokinetics of the Antifungal Echinocandin Caspofungin (MK-0991) in Rabbits

PubMed Central

Groll, Andreas H.; Gullick, Bryan M.; Petraitiene, Ruta; Petraitis, Vidmantas; Candelario, Myrna; Piscitelli, Stephen C.; Walsh, Thomas J.

2001-01-01

The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (Cmax) ± standard error of the mean increased from 16.01 ± 0.61 μg/ml at the 1-mg/kg dose to 105.52 ± 8.92 μg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 ± 2.37 to 158.43 ± 15.58 μg · h/ml, respectively. The mean apparent volume of distribution at steady state (Vdss) was 0.299 ± 0.011 liter/kg at the 1-mg/kg dose and 0.351 ± 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 ± 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 ± 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increased Vdss, there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi. PMID:11158761

Clinical and Immune Responses to Inactivated Influenza A(H1N1)pdm09 Vaccine in Children

PubMed Central

Kotloff, Karen L.; Halasa, Natasha B.; Harrison, Christopher J.; Englund, Janet A.; Walter, Emmanuel B.; King, James C.; Creech, C. Buddy; Healy, Sara A.; Dolor, Rowena J.; Stephens, Ina; Edwards, Kathryn M.; Noah, Diana L.; Hill, Heather; Wolff, Mark

2014-01-01

Background As the influenza AH1N1 pandemic emerged in 2009, children were found to experience high morbidity and mortality and were prioritized for vaccination. This multicenter, randomized, double-blind, age-stratified trial assessed the safety and immunogenicity of inactivated influenza A(H1N1)pdm09 vaccine in healthy children aged 6 months to 17 years. Methods Children received two doses of approximately 15 μg or 30 μg hemagglutin antigen 21 days apart. Reactogenicity was assessed for 8 days after each dose, adverse events through day 42, and serious adverse events or new-onset chronic illnesses through day 201. Serum hemagglutination inhibition (HAI) titers were measured on days 0 (pre-vaccination), 8, 21, 29, and 42. Results A total of 583 children received the first dose and 571 received the second dose of vaccine. Vaccinations were generally well-tolerated and no related serious adverse events were observed. The 15 μg dosage elicited a seroprotective HAI (≥1:40) in 20%, 47%, and 93% of children in the 6-35 month, 3-9 year, and 10-17 year age strata 21 days after dose 1 and in 78%, 82%, and 98% of children 21 days after dose 2, respectively. The 30 μg vaccine dosage induced similar responses. Conclusions The inactivated influenza A(H1N1)pdm09 vaccine exhibited a favorable safety profile at both dosage levels. While a single 15 or 30 μg dose induced seroprotective antibody responses in most 10-17 year olds, younger children required 2 doses, even when receiving dosages 4-6 fold higher than recommended. Well-tolerated vaccines are needed that induce immunity after a single dose for use in young children during influenza pandemics. PMID:25222307

Combining Varenicline (Chantix) with Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in a Rodent Model of Alcoholism.

PubMed

Froehlich, Janice C; Fischer, Stephen M; Dilley, Julian E; Nicholson, Emily R; Smith, Teal N; Filosa, Nick J; Rademacher, Logan C

2016-09-01

This study examined whether varenicline (VAR), or naltrexone (NTX), alone or in combination, reduces alcohol drinking in alcohol-preferring (P) rats with a genetic predisposition toward high voluntary alcohol intake. Alcohol-experienced P rats that had been drinking alcohol (15% v/v) for 2 h/d for 4 weeks were fed either vehicle (VEH), VAR alone (0.5, 1.0, or 2.0 mg/kg body weight [BW]), NTX alone (10.0, 15.0, or 20.0 mg/kg BW), or VAR + NTX in 1 of 4 dose combinations (0.5 VAR + 10.0 NTX, 0.5 VAR + 15.0 NTX, 1.0 VAR + 10.0 NTX, or 1.0 VAR + 15.0 NTX) at 1 hour prior to alcohol access for 10 consecutive days, and the effects on alcohol intake were assessed. When administered alone, VAR in doses of 0.5 or 1.0 mg/kg BW did not alter alcohol intake but a dose of 2.0 mg/kg BW decreased alcohol intake. This effect disappeared when drug treatment was terminated. NTX in doses of 10.0 and 15.0 mg/kg BW did not alter alcohol intake but a dose of 20.0 mg/kg BW decreased alcohol intake. Combining low doses of VAR and NTX into a single medication reduced alcohol intake as well as did high doses of each drug alone. Reduced alcohol intake occurred immediately after onset of treatment with the combined medication and continued throughout prolonged treatment. Low doses of VAR and NTX, when combined in a single medication, reduce alcohol intake in a rodent model of alcoholism. This approach has the advantage of reducing potential side effects associated with each drug. Lowering the dose of NTX and VAR in a combined treatment approach that maintains efficacy while reducing the incidence of negative side effects may increase patient compliance and improve clinical outcomes for alcoholics and heavy drinkers who want to reduce their alcohol intake. Copyright © 2016 by the Research Society on Alcoholism.

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.

Structural and optical effects induced by gamma irradiation on NdPO{sub 4}: X-ray diffraction, spectroscopic and luminescence study

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

Sadhasivam, S.; Rajesh, N.P., E-mail: rajeshnp@hotmail.com

2016-02-15

Highlights: • Inorganic NdPO{sub 4} crystal was grown first time using potassium polyphosphate (K{sub 6}P{sub 4}O{sub 13}) flux. • NdPO{sub 4} crystal is insoluble in water, non-hygroscopic and high radiation resistance favoring for actinides host. • Actinide immobilization can be made at 1273 K. • High yield of 1061 nm photon emission. - Abstract: Rare earth orthophosphate (NdPO{sub 4}) monazite single crystals were grown using high temperature flux growth method employing K{sub 6}P{sub 4}O{sub 13} (K{sub 6}) as molten solvent. Their structural parameters were studied using single crystal X-ray diffraction (XRD) method. The grown crystals were examined by SEM andmore » EDX techniques for their homogeniousity and inclusion in the crystals. The influence of gamma irradiation in structural and optical absorption properties were studied by the powder XRD, FTIR and reflectance spectroscopy. The effect of gamma irradiation on luminescence properties was recorded. No significant structural change is observed up to 150 kGy gamma dose. The gamma ray induced charge trap in the crystal was saturated to 40 kGy dose. The luminescence intensity decreases with an increase in the irradiation. The emission of luminescence intensity stabilizes above 40 kGy gamma dose.« less

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.

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.

Effects of immediate-release niacin and dietary fatty acids on acute insulin and lipid status in individuals with metabolic syndrome.

PubMed

Montserrat-de la Paz, Sergio; Lopez, Sergio; Bermudez, Beatriz; Guerrero, Juan M; Abia, Rocio; Muriana, Francisco Jg

2018-04-01

The nature of dietary fats profoundly affects postprandial hypertriglyceridemia and glucose homeostasis. Niacin is a potent lipid-lowering agent. However, limited data exist on postprandial triglycerides and glycemic control following co-administration of high-fat meals with a single dose of niacin in subjects with metabolic syndrome (MetS). The aim of the study was to explore whether a fat challenge containing predominantly saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) or MUFAs plus omega-3 long-chain polyunsaturated (LCPUFAs) fatty acids together with a single dose of immediate-release niacin have a relevant role in postprandial insulin and lipid status in subjects with MetS. In a randomized crossover within-subject design, 16 men with MetS were given a single dose of immediate-release niacin (2 g) and ∼15 cal kg -1 body weight meals containing either SFAs, MUFAs, MUFAs plus omega-3 LCPUFAs or no fat. At baseline and hourly over 6 h, plasma glucose, insulin, C-peptide, triglycerides, free fatty acids (FFAs), total cholesterol, and both high- and low-density lipoprotein cholesterol were assessed. Co-administered with niacin, high-fat meals significantly increased the postprandial concentrations of glucose, insulin, C-peptide, triglycerides, FFAs and postprandial indices of β-cell function. However, postprandial indices of insulin sensitivity were significantly decreased. These effects were significantly attenuated with MUFAs or MUFAs plus omega-3 LCPUFAs when compared with SFAs. In the setting of niacin co-administration and compared to dietary SFAs, MUFAs limit the postprandial insulin, triglyceride and FFA excursions, and improve postprandial glucose homeostasis in MetS. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Safety and immunogenicity of a single dose 23-valent pneumococcal polysaccharide vaccine in Russian subjects.

PubMed

Ciprero, Karen; Zykov, Kirill A; Briko, Nikolay I; Shekar, Tulin; Sterling, Tina M; Bitieva, Elizaveta; Stek, Jon E; Musey, Luwy

2016-08-02

Pneumococcal infection is a major cause of pneumonia, bacteremia, and meningitis. Incidence of pneumococcal disease (PD) varies worldwide. The 23-valent pneumococcal polysaccharide vaccine (PPV23) displays an acceptable safety profile and has been demonstrated cost-effective in reducing burden of PD. Approximately 100 subjects from the Russian Federation who were either 2 to 49 y of age with increased risk for PD or ≥50 years of age were enrolled into the study (NCT01734239) to receive a single dose of PPV23 administered intramuscularly. Each subject was followed for local and systemic adverse events (AEs) for 5 and 14 days, respectively. Serious AEs were collected for 28 d postvaccination. Blood samples were collected immediately prior to vaccination and 28 d postvaccination for the measurement of IgG to serotypes 1, 6B, 14, 19F, and 23F. High proportion of subjects had ≥2 -fold increase in IgG following receipt of PPV23. Rates were 92.0%, 83.0%, 89.0%, 81%, 84% for serotypes 1, 6B, 14, 19F, and 23F, respectively. Similar rates of responders and increases in the magnitude of immune responses were observed in both age groups (2-49, ≥50 ). PPV23 was generally safe and well tolerated. Injection site and systemic AEs were reported by 14.7% and 18.6% of study subjects, respectively. PPV23 is generally safe, well tolerated, and highly immunogenic when given as a single dose to Russian individuals 50 y of age and older, as well as Russian individuals 2 to 49 y of age who are at high risk for PD.

Using a single tablet daily to treat latent tuberculosis infection in Brazil: bioequivalence of two different isoniazid formulations (300 mg and 100 mg) demonstrated by a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry method in a randomised, crossover study

PubMed Central

Daher, André; Pitta, Luciana; Santos, Tereza; Barreira, Draurio; Pinto, Douglas

2015-01-01

The recommended treatment for latent tuberculosis (TB) infection in adults is a daily dose of isoniazid (INH) 300 mg for six months. In Brazil, INH was formulated as 100 mg tablets. The treatment duration and the high pill burden compromised patient adherence to the treatment. The Brazilian National Programme for Tuberculosis requested a new 300 mg INH formulation. The aim of our study was to compare the bioavailability of the new INH 300 mg formulation and three 100 mg tablets of the reference formulation. We conducted a randomised, single dose, open label, two-phase crossover bioequivalence study in 28 healthy human volunteers. The 90% confidence interval for the INH maximum concentration of drug observed in plasma and area under the plasma concentration vs. time curve from time zero to the last measurable concentration “time t” was 89.61-115.92 and 94.82-119.44, respectively. The main limitation of our study was that neither adherence nor the safety profile of multiple doses was evaluated. To determine the level of INH in human plasma, we developed and validated a sensitive, simple and rapid high-performance liquid chromatography-tandem mass spectrometry method. Our results showed that the new formulation was bioequivalent to the 100 mg reference product. This finding supports the use of a single 300 mg tablet daily strategy to treat latent TB. This new formulation may increase patients’ adherence to the treatment and quality of life. PMID:26038960

Dose reduction in whole-body computed tomography of multiple injuries (DoReMI): protocol for a prospective cohort study

PubMed Central

2014-01-01

Background Single-pass, contrast-enhanced whole body multidetector computed tomography (MDCT) emerged as the diagnostic standard for evaluating patients with major trauma. Modern iterative image algorithms showed high image quality at a much lower radiation dose in the non-trauma setting. This study aims at investigating whether the radiation dose can safely be reduced in trauma patients without compromising the diagnostic accuracy and image quality. Methods/Design Prospective observational study with two consecutive cohorts of patients. Setting: A high-volume, academic, supra-regional trauma centre in Germany. Study population: Consecutive male and female patients who 1. had been exposed to a high-velocity trauma mechanism, 2. present with clinical evidence or high suspicion of multiple trauma (predicted Injury Severity Score [ISS] ≥16) and 3. are scheduled for primary MDCT based on the decision of the trauma leader on call. Imaging protocols: In a before/after design, a consecutive series of 500 patients will undergo single-pass, whole-body 128-row multi-detector computed tomography (MDCT) with a standard, as low as possible radiation dose. This will be followed by a consecutive series of 500 patients undergoing an approved ultra-low dose MDCT protocol using an image processing algorithm. Data: Routine administrative data and electronic patient records, as well as digital images stored in a picture archiving and communications system will serve as the primary data source. The protocol was approved by the institutional review board. Main outcomes: (1) incidence of delayed diagnoses, (2) diagnostic accuracy, as correlated to the reference standard of a synopsis of all subsequent clinical, imaging, surgical and autopsy findings, (3) patients’ safety, (4) radiation exposure (e.g. effective dose), (5) subjective image quality (assessed independently radiologists and trauma surgeons on a 100-mm visual analogue scale), (6) objective image quality (e.g., contrast-to-noise ratio). Analysis: Multivariate regression will be employed to adjust and correct the findings for time and cohort effects. An exploratory interim analysis halfway after introduction of low-dose MDCT will be conducted to assess whether this protocol is clearly inferior or superior to the current standard. Discussion Although non-experimental, this study will generate first large-scale data on the utility of imaging-enhancing algorithms in whole-body MDCT for major blunt trauma. Trial registration Current Controlled Trials ISRCTN74557102. PMID:24589310

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.

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.

Favorable Preliminary Outcomes for Men With Low- and Intermediate-risk Prostate Cancer Treated With 19-Gy Single-fraction High-dose-rate Brachytherapy

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

Krauss, Daniel J., E-mail: dkrauss@beaumont.edu; Ye, Hong; Martinez, Alvaro A.

Purpose: To report the toxicity and preliminary clinical outcomes of a prospective trial evaluating 19-Gy, single-fraction high-dose-rate (HDR) brachytherapy for men with low- and intermediate-risk prostate cancer. Methods and Materials: A total of 63 patients were treated according to an institutional review board-approved prospective study of single-fraction HDR brachytherapy. Eligible patients had tumor stage ≤T2a, prostate-specific antigen level ≤15 ng/mL, and Gleason score ≤7. Patients with a prostate gland volume >50 cm{sup 3} and baseline American Urologic Association symptom score >12 were ineligible. Patients underwent transrectal ultrasound-guided transperineal implantation of the prostate, followed by single-fraction HDR brachytherapy. Treatment was delivered using {sup 192}Irmore » to a dose of 19 Gy prescribed to the prostate, with no additional margin applied. Results: Of the 63 patients, 58 had data available for analysis. Five patients had withdrawn consent during the follow-up period. The median follow-up period was 2.9 years (range 0.3-5.2). The median age was 61.4 years. The median gland volume at treatment was 34.8 cm{sup 3}. Of the 58 patients, 91% had T1 disease, 71% had Gleason score ≤6 (29% with Gleason score 7), and the median pretreatment prostate-specific antigen level was 5.1 ng/mL. The acute and chronic grade 2 genitourinary toxicity incidence was 12.1% and 10.3%, respectively. No grade 3 urinary toxicity occurred. No patients experienced acute rectal toxicity grade ≥2, and 2 experienced grade ≥2 chronic gastrointestinal toxicity. Three patients experienced biochemical failure, yielding a 3-year cumulative incidence estimate of 6.8%. Conclusions: Single-fraction HDR brachytherapy is well-tolerated, with favorable preliminary biochemical and clinical disease control rates.« 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

Long-term survival in primary CNS lymphoma treated by high-dose methotrexate monochemotherapy: role of STAT6 activation as prognostic determinant.

PubMed

Yang, Seung-Ho; Lee, Kun Soo; Kim, Il Sup; Hong, Jae Taek; Sung, Jae Hoon; Son, Byung Chul; Lee, Sang Won; Hong, Yong-Kil

2009-03-01

We report a single-center experience of 16 immunocompetent patients diagnosed with primary central nervous system lymphoma and treated with monochemotherapy with high-dose methotrexate (MTX) and deferred radiotherapy. MTX was given at a dose of 8.0 g/m2 for induction and at a dose of 3.5-8.0 g/m2 for maintenance. There were eight complete responses (CR), one partial response, one stable disease, and six patients whose tumors progressed in spite of the chemotherapy. At final follow-up, five of five CRs were alive and well without radiotherapy, with median follow-up of 26 months. Overall survival in eight non-CRs treated with the subsequent radiotherapy was 36 months. In the immunohistochemical study, STAT6 was positively expressed in 8 out of 13 cases. They included all non-CRs and two CRs. This observation suggests that STAT6 expression can be used as a prognostic determinant for MTX chemotherapy.

Gabapentin pharmacotherapy for antipsychotic-induced akathisia: single-patient experiment and case report.

PubMed

Sullivan, Maria A; Wilbur, Robert

2014-04-01

This clinical study reports upon the efficacy of gabapentin (Neurontin) for treating severe akathisia (3 on the Barnes Akathisia Rating Scale) in two patients receiving quetiapine (Seroquel), one of whom also received olanzapine (Zyprexa) for a short period. The first patient participated in an open-label experiment in which the bedtime dose of gabapentin was discontinued three times at intervals 1 week apart, resulting in severe akathisia which was quickly terminated by taking his usual 1200 mg gabapentin dose. This patient was also taking high doses of two benzodiazepines and a beta blocker, without therapeutic effect upon his akathisia; only gabapentin was efficacious. The second case is a report of a woman taking a high dose of quetiapine for anxiety who experienced severe akathisia which was relieved by taking 1200 mg of gabapentin. Possible mechanisms of action of gabapentin are discussed. Particular attention is drawn to the difference between neuroleptic-induced akathisia and the neurological condition of restless legs syndrome.

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.

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.

Effective protection of monkeys against death from street virus by post-exposure administration of tissue-culture rabies vaccine

PubMed Central

Sikes, R. K.; Cleary, W. F.; Koprowski, H.; Wiktor, T. J.; Kaplan, M. M.

1971-01-01

Three series of experiments on rabies vaccines were carried out on rhesus monkeys using suckling-mouse-brain vaccine, rabbit-brain vaccine, duck-embryo vaccine, and purified, concentrated tissue-culture vaccine. The latter was prepared in a human diploid cell strain and inactivated with β-propiolactone, and consisted of tissue-culture fluid concentrated 200-fold with a final infectivity titre of 109.8 plaque-forming units per ml before inactivation. In the first two series of experiments, several vaccines were tested for relative immunogenicity on a pre-exposure basis. In the third series, a successful model was developed in which a single inoculation of the tissue-culture vaccine administered after exposure to rabies virus, with or without accompanying standard doses of antirabies serum, was evaluated as a method of prevention. A single dose of the tissue-culture vaccine protected 7 out of 8 monkeys from death by street virus. Homologous or heterologous antirabies serum alone gave poor results. The results indicate great promise for prophylaxis in man with one dose, or perhaps a few doses, of highly concentrated, purified tissue-culture vaccine. PMID:5004004

It's All Relative: A Validation of Radiation Quality Comparison Metrics

NASA Technical Reports Server (NTRS)

Chappell, Lori J.; Milder, Caitlin M.; Elgart, S. Robin; Semones, Edward J.

2017-01-01

The difference between high-LET and low-LET radiation is quantified by a measure called relative biological effectiveness (RBE). RBE is defined as the ratio of the dose of a reference radiation to that of a test radiation to achieve the same effect level, and thus, is described either as an iso-effector dose-to-dose ratio. A single dose point is not sufficient to calculate an RBE value; therefore, studies with only one dose point usually calculate an effect-to-effect ratio. While not formally used in radiation protection, these iso-dose values may still be informative. Shuryak, et al 2017 investigated the use of an iso-dose metric termed "radiation effects ratio" (RER) and used both RBE and RER to estimate high-LET risks. To apply RBE or RER to risk prediction, the selected metric must be uniquely defined. That is, the calculated value must be consistent within a model given a constant set of constraints and assumptions, regardless of how effects are defined using statistical transformations from raw endpoint data. We first test the RBE and the RER to determine whether they are uniquely defined using transformations applied to raw data. Then, we test whether both metrics can predict heavy ion response data after simulated effect size scaling between human populations or when converting animal to human endpoints.

Single hair analysis of small molecules using MALDI-triple quadrupole MS imaging and LC-MS/MS: investigations on opportunities and pitfalls.

PubMed

Poetzsch, Michael; Steuer, Andrea E; Roemmelt, Andreas T; Baumgartner, Markus R; Kraemer, Thomas

2014-12-02

Single hair analysis normally requires extensive sample preparation microscale protocols including time-consuming steps like segmentation and extraction. Matrix assisted laser desorption and ionization mass spectrometric imaging (MALDI-MSI) was shown to be an alternative tool in single hair analysis, but still, questions remain. Therefore, an investigation of MALDI-MSI in single hair analysis concerning the extraction process, usage of internal standard (IS), and influences on the ionization processes were systematically investigated to enable the reliable application to hair analysis. Furthermore, single dose detection, quantitative correlation to a single hair, and hair strand LC-MS/MS results were performed, and the performance was compared to LC-MS/MS single hair monitoring. The MALDI process was shown to be independent from natural hair color and not influenced by the presence of melanin. Ionization was shown to be reproducible along and in between different hair samples. MALDI image intensities in single hair and hair snippets showed good semiquantitative correlation to zolpidem hair concentrations obtained from validated routine LC-MS/MS methods. MALDI-MSI is superior to LC-MS/MS analysis when a fast, easy, and cheap sample preparation is necessary, whereas LC-MS/MS showed higher sensitivity with the ability of single dose detection for zolpidem. MALDI-MSI and LC-MS/MS segmental single hair analysis showed good correlation, and both are suitable for consumption monitoring of drugs of abuse with a high time resolution.

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.;

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

Half doses of PEG-ES and senna vs. high-dose senna for bowel cleansing before colonoscopy: a randomized, investigator-blinded trial.

PubMed

Amato, Arnaldo; Radaelli, Franco; Paggi, Silvia; Terruzzi, Vittorio

2010-03-01

Patients' compliance with and tolerance of large-volume polyethylene glycol electrolyte solution (PEG-ES) have prompted continuous investigation with alternative forms of cleansing. High-dose senna is superior to PEG-ES for the quality of bowel cleansing, patient compliance, and tolerance, but its acceptance may be influenced by the incidence of abdominal pain. We hypothesized that a combination of half doses of PEG-ES and senna could minimize the incidence of abdominal pain without affecting the quality of bowel preparation. This randomized, investigator-blinded trial has been conducted on consecutive outpatients scheduled for elective colonoscopy at a single community-based hospital. Patients were randomly assigned to receive either 12 tablets of 12 mg senna and 2 l of PEG-ES (half-dose group, HDG) or 24 tablets of senna divided in two doses (senna group, SG) the day before colonoscopy. The main outcome measures were the quality of colon cleansing (Aronchick scoring scale) and the incidence of preparation-related abdominal pain. Secondary outcome measures were patients' compliance with the cleansing regimen, overall tolerability, prevalence of predefined side effects, and quality of right colon cleansing. A total of 296 patients were enrolled (HDG=151 and SG=145). Overall cleansing was excellent to good in 90.1 and 88.3% patients in HDG and SG, respectively (P=0.62). Preparation-related moderate-to-severe abdominal pain was reported by 6% patients in HDG and 15.2% in SG (P=0.009). No significant differences were observed for secondary outcomes. The regimen combining half doses of PEG-ES and senna provides high-quality bowel preparation and acceptable patient tolerance, with less abdominal pain compared with high-dose senna.