Sample records for multiple dose levels
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Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J
2017-09-01
Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met 5 ]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met 5 ]-enkephalin or β-endorphin in normal mice. Thus, [Met 5 ]-enkephalin (i.e. opioid growth factor) may be a reasonable candidate biomarker for multiple sclerosis, and may signal new pathways for treatment of autoimmune disorders. Impact statement This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met 5 ]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG 35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. β-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy.
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Zheng, H X; Huang, Y; Frassetto, L A; Benet, L Z
2009-01-01
The effects of single doses of intravenous (IV) ciprofloxacin and rifampin and of multiple doses of rifampin on glyburide exposure and blood glucose levels were investigated in nine healthy volunteers. A single IV dose of rifampin significantly increased the area under the concentration-time curve (AUC) of glyburide and its metabolite. Blood glucose levels were significantly lower than those observed after dosing with glyburide alone. Multiple doses of rifampin induced an increase in liver enzyme levels, leading to a marked decrease in glyburide exposure and blood glucose levels. When IV rifampin was administered after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect; however, the relative changes in AUC for glyburide and its hydroxyl metabolite were similar to those seen under noninduced conditions. The studies reported here demonstrate how measurements of the levels of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and in characterizing enzymatic vs. transporter mechanisms.
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NASA Astrophysics Data System (ADS)
Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore
2014-02-01
Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.
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Ribeiro, Maria Estela Bellini; Del Roio Liberatore Junior, Raphael; Custodio, Rodrigo; Martinelli Junior, Carlos Eduardo
2016-01-01
To compare multiple doses of insulin and continuous insulin infusion therapy as treatment for type 1 diabetes melito. 40 patients with type 1 diabetes melito (21 female) with ages between 10 and 20 years (mean=14.2) and mean duration of diabetes of 7 years used multiple doses of insulin for at least 6 months and after that, continuous insulin infusion therapy for at least 6 months. Each one of the patients has used multiple doses of insulin and continuous insulin infusion therapy. For analysis of HbA1c, mean glycated hemoglobin levels (mHbA1c) were obtained during each treatment period (multiple doses of insulin and continuous insulin infusion therapy period). Although mHbA1c levels were lower during continuous insulin infusion therapy the difference was not statistically significant. During multiple doses of insulin, 14.2% had mHbA1c values below 7.5% vs. 35.71% while on continuous insulin infusion therapy; demonstrating better glycemic control with the use of continuous insulin infusion therapy. During multiple doses of insulin, 15-40 patients have severe hypoglycemic events versus 5-40 continuous insulin infusion therapy. No episodes of ketoacidosis events were recorded. This is the first study with this design comparing multiple doses of insulin and continuous insulin infusion therapy in Brazil showing no significant difference in HbA1c; hypoglycemic events were less frequent during continuous insulin infusion therapy than during multiple doses of insulin and the percentage of patients who achieved a HbA1c less than 7.5% was greater during continuous insulin infusion therapy than multiple doses of insulin therapy. Copyright © 2015 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.
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Cumulative effective dose associated with radiography and CT of adolescents with spinal injuries.
Lemburg, Stefan P; Peters, Soeren A; Roggenland, Daniela; Nicolas, Volkmar; Heyer, Christoph M
2010-12-01
The purpose of this study was to analyze the quantity and distribution of cumulative effective doses in diagnostic imaging of adolescents with spinal injuries. At a level 1 trauma center from July 2003 through June 2009, imaging procedures during initial evaluation and hospitalization and after discharge of all patients 10-20 years old with spinal fractures were retrospectively analyzed. The cumulative effective doses for all imaging studies were calculated, and the doses to patients with spinal injuries who had multiple traumatic injuries were compared with the doses to patients with spinal injuries but without multiple injuries. The significance level was set at 5%. Imaging studies of 72 patients (32 with multiple injuries; average age, 17.5 years) entailed a median cumulative effective dose of 18.89 mSv. Patients with multiple injuries had a significantly higher total cumulative effective dose (29.70 versus 10.86 mSv, p < 0.001) mainly owing to the significantly higher CT-related cumulative effective dose to multiple injury patients during the initial evaluation (18.39 versus 2.83 mSv, p < 0.001). Overall, CT accounted for 86% of the total cumulative effective dose. Adolescents with spinal injuries receive a cumulative effective dose equal to that of adult trauma patients and nearly three times that of pediatric trauma patients. Areas of focus in lowering cumulative effective dose should be appropriate initial estimation of trauma severity and careful selection of CT scan parameters.
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Welsch, C W; DeHoog, J V; O'Connor, D H
1988-04-15
The effect of caffeine and/or coffee consumption (via the drinking water) during the initiation phase and promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a commercial laboratory animal chow was examined. In the initiation studies, DMBA was administered once at 53-55 days of age; caffeine (100-860 mg/liter of drinking water) and/or coffee (moderate or high dose, sole source of drinking water) treatments were for 32 consecutive days, commencing 29 days prior to DMBA treatment and terminating 3 days after DMBA treatment. In the promotion studies, DMBA was administered once at 54-55 days of age; caffeine and/or coffee treatments were daily from 57-58 days of age to termination of experiments (12-21 weeks after carcinogen treatment). In the initiation studies, either moderate (100-400 mg) or high (860 mg) dose levels of caffeine or moderate to high dose levels of caffeinated coffee significantly (P less than 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat). Consumption of high or moderate dose levels of decaffeinated coffee did not significantly alter mammary carcinoma multiplicity. The addition of caffeine to the moderate dose level of decaffeinated coffee resulted in a significant (P less than 0.05) reduction in mammary carcinoma multiplicity. In the promotion studies, prolonged consumption of moderated dose levels of caffeine or moderate or high dose levels of caffeinated coffee or decaffeinated coffee did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, however, a significant (p less than 0.05) stimulatory effect of caffeine on mammary carcinoma multiplicity was observed; an effect that was temperate and transitory. In both the initiation and promotion studies caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency period of mammary tumor appearance. These results provide evidence that caffeine and/or caffeinated coffee consumption can significantly influence mammary carcinoma multiplicity in female rats treated with DMBA, an effect that is dependent upon the dose level, duration, and time-span of caffeine administration.
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Rao, Shripada C; Srinivasjois, Ravisha; Moon, Kwi
2016-12-06
Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups (typical RR 1.69, 95% CI 0.18 to 16.25; typical RD 0.01, 95% CI -0.04 to 0.05; 5 trials; N = 214). Nephrotoxicity was not noted with either of the treatment regimens. Overall, the quality of evidence was considered to be moderate on GRADE analysis, given the small sample size and unclear/high risk of bias in some of the domains in a few of the included studies. There is insufficient evidence from the currently available RCTs to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggest that pharmacokinetic properties of a 'once a day' gentamicin regimen are superior to a 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There was no change in nephrotoxicity or auditory toxicity. Based on the assessment of pharmacokinetics, a 'once a day regimen' may be superior in treating sepsis in neonates of more than 32 weeks' gestation.
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Hyun, Seung Won; Wong, Weng Kee
2016-01-01
We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs. PMID:26565557
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Hyun, Seung Won; Wong, Weng Kee
2015-11-01
We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs.
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Salicylic acid plasma levels following multiple doses of Norgesic Forte and aspirin.
Harrison, L I; Kehe, C R; Goldlust, M B; Kvam, D C; Bianchine, J R
1983-01-01
Plasma salicyclic acid levels from the recommended multiple dose regimen of Norgesic Forte (orphenadrine citrate, aspirin, and caffeine) were compared to those from an equivalent multiple dose regimen of aspirin alone in 24 volunteers. The drugs were administered double-blind so that side effects could also be compared. No statistically significant differences were found between Norgesic Forte and aspirin in peak or trough levels, time to peak level, area under the curve, or mean steady-state level of salicylic acid. Mean steady-state levels averaged 154 +/- 46 (+/- SD) and 152 +/- 49 micrograms/ml on days 5 and 10 following Norgesic Forte versus 161 +/- 49 and 154 +/- 47 micrograms/ml following aspirin. Thus, the aspirin in Norgesic Forte provides an anti-inflammatory amount of salicylic acid equivalent to that of plain aspirin. There was no evidence that the combination of orphenadrine citrate, caffeine, and aspirin in Norgesic Forte caused increased or unusual side effects compared with aspirin alone.
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A Highly Durable RNAi Therapeutic Inhibitor of PCSK9
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
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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.
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Zheng, HX; Huang, Y; Frassetto, LA; Benet, LZ
2013-01-01
The effects of single doses of intravenous ciprofloxacin and rifampin, multiple doses of rifampin, on glyburide exposure and effect on blood glucose levels in 9 healthy volunteers were investigated. The single intravenous dose of rifampin significantly increased the AUCs of glyburide and metabolite. Blood glucose levels dropped significantly in comparison to when glyburide was dosed alone. Multiple doses of rifampin induced liver enzymes leading to a marked decrease in glyburide exposure and in blood glucose measurements. When intravenous rifampin was given after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect, however, relative changes in AUC for glyburide and its hydroxyl metabolite were the same as that seen under non-induced conditions. The studies reported here demonstrate how measurements of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and characterizing enzymatic versus transporter mechanisms. PMID:18843263
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Thygesen, Peter; Andersen, Henrik Sune; Behrens, Carsten; Fels, Johannes Josef; Nørskov-Lauritsen, Leif; Rischel, Christian; Johansen, Nils Langeland
2017-08-01
Somapacitan is an albumin-binding growth hormone derivative intended for once weekly administration, currently in clinical development for treatment of adult as well as juvenile GH deficiency. Nonclinical in vivo pharmacological characterisation of somapacitan was performed to support the clinical trials. Here we present the pharmacokinetic and pharmacodynamic effects of somapacitan in rats, minipigs, and cynomolgus monkeys. Pharmacokinetic studies investigating exposure, absorption, clearance, and bioavailability after single intravenous (i.v.) and subcutaneous (s.c.) administration were performed in all species. A dose-response study with five dose levels and a multiple dose pharmacodynamic study with four once weekly doses was performed in hypophysectomised rats to evaluate the effect of somapacitan on growth and IGF-I production. Pharmacokinetic profiles indicated first order absorption from the subcutaneous tissue after s.c. injections for somapacitan in all three species. Apparent terminal half-lives were 5-6h in rats, 10-12h in minipigs, and 17-20h in monkeys. Somapacitan induced a dose-dependent growth in hypophysectomised rats (p<0.001) and an increase in plasma IGF-I levels in rats (p<0.01), minipigs (p<0.01), and cynomolgus monkeys (p<0.05) after single dose administration. Multiple once weekly dosing of somapacitan in hypophysectomised rats induced a step-wise increase in body weight with an initial linear phase the first 3-4days in each dosing interval (p<0.001). The nonclinical pharmacokinetic and pharmacodynamic studies of somapacitan showed similar pharmacokinetic properties, with no absorption-limited elimination, increased clearance and increased and sustained levels of IGF-I in plasma for up to 10days after a single dose administration in all three species. Somapacitan induced a dose-dependent increase in body weight and IGF-I levels in hypophysectomised rats. Multiple dosing of somapacitan in hypophysectomised rats suggested a linear growth for the first 3-4days in each weekly dosing interval, whereas daily hGH dosing showed linear growth for approximately two weeks before reaching a plateau level. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Cicek, M N; Kahyaoglu, I; Kahyaoglu, S
2015-02-01
Elevated progesterone levels surpassing exact treshold values impede endometrial receptivity and decrease clinical pregnancy rates in different responder patients during assisted reproductive techniques. A progesterone (P): estradiol (E2) ratio of > 1 on the day of hCG administration has also been suggested to be a manifestation of low ovarian reserve. The clinical significance of P/E2 ratio on the day of hCG administration was investigated among poor responder patients. Based on the ESHRE Bologna consensus criteria related to poor ovarian response diagnosis, 48 poor responder patients were treated with the microdose flare-up regimen and 34 patients were treated with the multiple-dose GnRH antagonist protocol. All patients were destined to perform a ICSI-ET procedure at the end of the stimulation protocols. Progesterone levels and P/E2 ratios have been detected during controlled ovarian hyperstimulation. In the microdose flare-up group; the duration of stimulation, total gonadotropin dose used and hCG day E2 levels were significantly higher than the multiple dose antagonist group. However, the mean hCG day P/E2 rate in the microdose flare-up group was less than that in the multiple-dose antagonist group. The clinical pregnancy rates were non significantly higher in the multiple dose antagonist protocol group than in microdose flare-up group. Impaired endometrial receptivity caused by elevated P levels results with lower pregnancy rates. Regardless of the selected stimulation protocol, poor responder patients are not prone to exhibit high P and E2 secretion. Increased P/E2 ratio of > 1 on hCG day has limited value to predict cycle outcomes in poor responder patients because of ovarian follicle depletion.
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Abd-Elaziz, Khalid; Duijkers, Ingrid; Stöckl, Lars; Dietrich, Bruno; Klipping, Christine; Eckert, Kelvin; Goletz, Steffen
2017-08-01
What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters. Recombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule. Both studies were randomized, placebo- and comparator-controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing. In the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or 150 IU once daily [QD], or 150 IU every other day [QAD], 10 subjects each) and 27 subjects received 150 IU Gonal-f, 150 IU Bravelle, or placebo for 7 days (11/10/6 subjects). Blood samples for measuring PK as well as PD parameters were collected systematically before, during and after dosing. Adverse events (AEs) and other relevant safety parameters were recorded. Data were summarized using descriptive statistics. The single- and multiple-dose PK parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) increased in a linear fashion with increasing dose levels of follitropin epsilon. Follitropin epsilon showed PK characteristics comparable to the comparators indicating that well established treatment schemes could be applied. There was a dose-response effect of single and multiple doses of follitropin epsilon on follicular growth, which was shown for the biomarker inhibin B as well as for the mean number and size of follicles. Multiple doses of 75 IU follitropin epsilon given daily, as well as 150 IU follitropin epsilon every second day, showed a follicle growth comparable with 150 IU Gonal-f given daily, while in case of daily administration of 150 IU Bravelle only weak follicle stimulation was observed. Multiple doses of 150 IU follitropin epsilon induced a much higher follicle growth compared to the same dose of Gonal-f. All single and multiple follitropin epsilon doses tested were safe and well tolerated, and overall there were no relevant differences between follitropin epsilon and the comparators in terms of safety. The average number of AEs increased with increasing dose levels. No clinically relevant abnormalities were reported for any of the other safety parameters assessed. No follitropin epsilon anti-drug antibodies were observed. The studies were conducted as a single-blind design. Hormone levels or other parameters assessed in serum are generally not considered as being subject to bias. Other assessments directly performed by the investigators, such as transvaginal ultrasound assessments, may have been subject to personal bias. No prospective calculations of statistical power had been made, as is common practice for first in human and early phase I studies in healthy volunteers. These early development studies showed that follitropin epsilon exhibits comparable PK characteristics, as well as inducing stronger PD effects in terms of follicle growth and serum inhibin B, than the comparators. Follitropin epsilon induced a dose-dependent increase in follicular growth. The results warrant further studies with this new fully human recombinant FSH. The studies were sponsored by GLYCOTOPE GmbH, Berlin, Germany. K.A-E. is an employee of QPS-Netherlands, B.V., which received funding for the studies from Glycotope GmbH; I.D. and C.K. are employees of Dinox B.V., which received funding for the studies from Glycotope GmbH; L.S. and S.G. are employees and shareholders of Glycotope GmbH; B.D. and K.E. are employees of Glycotope GmbH. www.clinicaltrials.gov: NCT01354886 (single-dose); NCT01477073 (multiple-dose). The single-dose trial was registered on 11 May 2011 while the multiple-dose trial was registered on 09 November 2011. First subject was enroled in the single-dose trial in 27 April 2011 and in the multiple-dose trial in 02 October 2011. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
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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.
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Lee, Min Sun; Kim, Joong Hyun; Paeng, Jin Chul; Kang, Keon Wook; Jeong, Jae Min; Lee, Dong Soo; Lee, Jae Sung
2017-12-14
Personalized dosimetry with high accuracy is becoming more important because of the growing interests in personalized medicine and targeted radionuclide therapy. Voxel-based dosimetry using dose point kernel or voxel S-value (VSV) convolution is available. However, these approaches do not consider medium heterogeneity. Here, we propose a new method for whole-body voxel-based personalized dosimetry for heterogeneous media with non-uniform activity distributions, which is referred to as the multiple VSV approach. Methods: The multiple numbers (N) of VSVs for media with different densities covering the whole-body density ranges were used instead of using only a single VSV for water. The VSVs were pre-calculated using GATE Monte Carlo simulation; those were convoluted with the time-integrated activity to generate density-specific dose maps. Computed tomography-based segmentation was conducted to generate binary maps for each density region. The final dose map was acquired by the summation of N segmented density-specific dose maps. We tested several sets of VSVs with different densities: N = 1 (single water VSV), 4, 6, 8, 10, and 20. To validate the proposed method, phantom and patient studies were conducted and compared with direct Monte Carlo, which was considered the ground truth. Finally, patient dosimetry (10 subjects) was conducted using the multiple VSV approach and compared with the single VSV and organ-based dosimetry approaches. Errors at the voxel- and organ-levels were reported for eight organs. Results: In the phantom and patient studies, the multiple VSV approach showed significant improvements regarding voxel-level errors, especially for the lung and bone regions. As N increased, voxel-level errors decreased, although some overestimations were observed at lung boundaries. In the case of multiple VSVs ( N = 8), we achieved voxel-level errors of 2.06%. In the dosimetry study, our proposed method showed much improved results compared to the single VSV and organ-based dosimetry. Errors at the organ-level were -6.71%, 2.17%, and 227.46% for the single VSV, multiple VSV, and organ-based dosimetry, respectively. Conclusion: The multiple VSV approach for heterogeneous media with non-uniform activity distributions offers fast personalized dosimetry at whole-body level, yielding results comparable to those of the direct Monte Carlo approach. Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
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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.
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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
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Developmental toxicity of orally administered sildenafil citrate (Viagra) in SWR/J mice
Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy; Al-Meteri, Mokhlid Hamed
2010-01-01
Normal adult inbred SWR/J mice were used to investigate the teratogenic and other possible toxic effects of various dose levels of sildenafil citrate (Viagra) on fetuses. Multiple dose levels of 6.5, 13.0, 19.5, 26.0, 32.5 or 40.0 mg of sildenafil citrate/kg body weight (which correspond to the multiples of 1, 2, 3, 4, 5 or 6 of human 50 mg Viagra, respectively) were orally administered into pregnant mice on days 7–9, 10–12 or 13–15 of gestation. On day 17 of pregnancy, all fetuses were removed and examined for toxic phenomena (embryo-fetal toxicity) and for external, internal and skeletal malformations. A total of 285 pregnant mice were used in the present study. None of the dams treated with sildenafil citrate at any of the oral dose levels used in the present study died during the experimental period and all dams treated with the drug failed to reveal overt signs of maternal toxicity. Moreover, the results of the present study clearly demonstrate that none of the multiple oral dose levels of the drug at any time interval used has induced any external, internal or skeletal malformations in the fetuses obtained from treated females. However, the dose level of 40 mg/kg body weight of sildenafil citrate has a growth suppressing effect on alive fetuses when it was administered at all the time intervals used in the present study. Furthermore, the dose levels 26.0, 32.5 and 40 mg/kg of the drug have embryo-fetal toxicity when the drug is applied on days 13–15 of gestation. The possible mechanisms involved in the embryo-fetal toxicity and fetal growth suppressing effects of sildenafil citrate were discussed. The results of this study have important implications for the widespread use of this drug. PMID:23961116
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Developmental toxicity of orally administered sildenafil citrate (Viagra) in SWR/J mice.
Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy; Al-Meteri, Mokhlid Hamed
2011-04-01
Normal adult inbred SWR/J mice were used to investigate the teratogenic and other possible toxic effects of various dose levels of sildenafil citrate (Viagra) on fetuses. Multiple dose levels of 6.5, 13.0, 19.5, 26.0, 32.5 or 40.0 mg of sildenafil citrate/kg body weight (which correspond to the multiples of 1, 2, 3, 4, 5 or 6 of human 50 mg Viagra, respectively) were orally administered into pregnant mice on days 7-9, 10-12 or 13-15 of gestation. On day 17 of pregnancy, all fetuses were removed and examined for toxic phenomena (embryo-fetal toxicity) and for external, internal and skeletal malformations. A total of 285 pregnant mice were used in the present study. None of the dams treated with sildenafil citrate at any of the oral dose levels used in the present study died during the experimental period and all dams treated with the drug failed to reveal overt signs of maternal toxicity. Moreover, the results of the present study clearly demonstrate that none of the multiple oral dose levels of the drug at any time interval used has induced any external, internal or skeletal malformations in the fetuses obtained from treated females. However, the dose level of 40 mg/kg body weight of sildenafil citrate has a growth suppressing effect on alive fetuses when it was administered at all the time intervals used in the present study. Furthermore, the dose levels 26.0, 32.5 and 40 mg/kg of the drug have embryo-fetal toxicity when the drug is applied on days 13-15 of gestation. The possible mechanisms involved in the embryo-fetal toxicity and fetal growth suppressing effects of sildenafil citrate were discussed. The results of this study have important implications for the widespread use of this drug.
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Yoshida, Kenichi; Fukuoka, Hidenori; Odake, Yukiko; Nakajima, Shinsuke; Tachibana, Mariko; Ito, Jun; Hosokawa, Yusei; Yamada, Tomoko; Miura, Hiroshi; Suematsu, Natsu; Matsumoto, Ryusaku; Bando, Hironori; Suda, Kentaro; Nishizawa, Hitoshi; Iguchi, Genzo; Ogawa, Wataru; Takahashi, Yutaka
2017-01-01
Measuring salivary cortisol is both convenient and non-invasive for patients; however, its usefulness as a marker for monitoring medical therapy has not yet been established. The aim of this study was to assess the utility of multiple salivary cortisol measurements in patients with Cushing's syndrome (CS) during medical therapy. Six patients with CS (three with cortisol-secreting adrenocortical adenoma and three with ACTH-secreting pituitary adenoma) were recruited. Samples for morning serum cortisol, urinary free cortisol (UFC), and multiple salivary cortisol levels were collected before and during metyrapone treatment. The area under the curve (AUC) and mean value (MV) of daily salivary cortisol levels were calculated. In five out of six patients, UFC were normalized; however, multiple salivary cortisol measurements revealed an impaired diurnal cortisol rhythm in these patients. To verify the usefulness of multiple salivary cortisol measurements, we performed a prospective case study of a patient in whom the excess secretion of cortisol was not controlled (UFC 211 μg/day) with 2,250 mg/day in four divided doses of metyrapone. Multiple measurements of salivary cortisol revealed that cortisol levels elevated before the next administration. Accordingly, we shortened the interval by increasing the number of administration from four to five times per day, with a slight increment of daily dose of 2,500 mg. These optimizations resulted in a drastic improvement of diurnal pattern as well as UFC level (101 μg/day). Changes in both the MV and AUC of salivary cortisol levels were more correlated with those in UFC levels (Correlation coefficient 0.75, p = 0.007, and 0.70, p = 0.017) than those in the morning serum cortisol levels (0.42, p = 0.200), indicating that multiple salivary cortisol measurements reflect more precisely the excess secretion of cortisol. Our preliminary data suggest that multiple salivary cortisol measurements can be a useful tool to visualize the diurnal cortisol rhythm and to determine the dose and timing of metyrapone during the treatment in patients with CS.
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Using Population Dose to Evaluate Community-level Health Initiatives.
Harner, Lisa T; Kuo, Elena S; Cheadle, Allen; Rauzon, Suzanne; Schwartz, Pamela M; Parnell, Barbara; Kelly, Cheryl; Solomon, Loel
2018-05-01
Successful community-level health initiatives require implementing an effective portfolio of strategies and understanding their impact on population health. These factors are complicated by the heterogeneity of overlapping multicomponent strategies and availability of population-level data that align with the initiatives. To address these complexities, the population dose methodology was developed for planning and evaluating multicomponent community initiatives. Building on the population dose methodology previously developed, this paper operationalizes dose estimates of one initiative targeting youth physical activity as part of the Kaiser Permanente Community Health Initiative, a multicomponent community-level obesity prevention initiative. The technical details needed to operationalize the population dose method are explained, and the use of population dose as an interim proxy for population-level survey data is introduced. The alignment of the estimated impact from strategy-level data analysis using the dose methodology and the data from the population-level survey suggest that dose is useful for conducting real-time evaluation of multiple heterogeneous strategies, and as a viable proxy for existing population-level surveys when robust strategy-level evaluation data are collected. This article is part of a supplement entitled Building Thriving Communities Through Comprehensive Community Health Initiatives, which is sponsored by Kaiser Permanente, Community Health. Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.
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NASA Astrophysics Data System (ADS)
Lee, Jason J. S.; Tsai, Chia-Jung; Lo, Man-Kuok; Huang, Yung-Hui; Chen, Chien-Chuan; Wu, Jay; Tyan, Yeu-Sheng; Wu, Tung-Hsin
2008-05-01
A new type of normoxic polymer gel dosimeter, named MAGAT responses well to absorbed dose even when manufacturing in the presence of normal levels of oxygen. The aim of this study was to evaluate dose response, diffusion effect and cumulated dose response under multiple fractional irradiations of the MAGAT gel dosimeter using Multiple Spin-Echo (MSE) Magnetic Resonance (MR) sequence. Dose response was performed by irradiating MAGAT-gel-filled testing vials with a 6 MV linear accelerator and a linear relationship was present with doses from 0 to 6 Gy, but gradually, a bi-exponential function result was obtained with given doses up to 20 Gy. No significant difference in dose response was present between single and cumulated doses (p > 0.05). For study of diffusion effect, edge sharpness of the R2 map imaging between two split doses was smaller than 1 cm of dose profile penumbra between 20% and 80%. In conclusion, the MAGAT polymer gel dosimeter with MSE MR imaging is a promising method for dose verification in clinical radiation therapy practice.
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An analysis of collegiate band directors' exposure to sound pressure levels
NASA Astrophysics Data System (ADS)
Roebuck, Nikole Moore
Noise-induced hearing loss (NIHL) is a significant but unfortunate common occupational hazard. The purpose of the current study was to measure the magnitude of sound pressure levels generated within a collegiate band room and determine if those sound pressure levels are of a magnitude that exceeds the policy standards and recommendations of the Occupational Safety and Health Administration (OSHA), and the National Institute of Occupational Safety and Health (NIOSH). In addition, reverberation times were measured and analyzed in order to determine the appropriateness of acoustical conditions for the band rehearsal environment. Sound pressure measurements were taken from the rehearsal of seven collegiate marching bands. Single sample t test were conducted to compare the sound pressure levels of all bands to the noise exposure standards of OSHA and NIOSH. Multiple regression analysis were conducted and analyzed in order to determine the effect of the band room's conditions on the sound pressure levels and reverberation times. Time weighted averages (TWA), noise percentage doses, and peak levels were also collected. The mean Leq for all band directors was 90.5 dBA. The total accumulated noise percentage dose for all band directors was 77.6% of the maximum allowable daily noise dose under the OSHA standard. The total calculated TWA for all band directors was 88.2% of the maximum allowable daily noise dose under the OSHA standard. The total accumulated noise percentage dose for all band directors was 152.1% of the maximum allowable daily noise dose under the NIOSH standards, and the total calculated TWA for all band directors was 93dBA of the maximum allowable daily noise dose under the NIOSH standard. Multiple regression analysis revealed that the room volume, the level of acoustical treatment and the mean room reverberation time predicted 80% of the variance in sound pressure levels in this study.
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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.
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Vajda, Eric G; Logan, Douglas; Lasseter, Kenneth; Armas, Danielle; Plotkin, Diane J; Pipkin, J D; Li, Yong-Xi; Zhou, Rong; Klein, David; Wei, Xiaoxiong; Dilzer, Stacy; Zhi, Lin; Marschke, Keith B
2017-01-01
To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD-6972, in healthy subjects and subjects with type 2 diabetes (T2DM). In the single ascending dose study, LGD-6972 (2-480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD-6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD-6972 daily for 14 days. LGD-6972 had linear plasma pharmacokinetics consistent with once-daily dosing that was comparable in healthy and T2DM subjects. Dose-dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD-6972 also reduced plasma glucose in the postprandial state. Dose-dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD-6972 was well tolerated at the doses tested without dose-related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia. Inhibition of glucagon action by LGD-6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD-6972 after 14 days of dosing supports continued clinical development. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
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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
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Glatard, Anaïs; Berges, Aliénor; Sahota, Tarjinder
The no-observed-adverse-effect level (NOAEL) of a drug defined from animal studies is important for inferring a maximal safe dose in human. However, several issues are associated with its concept, determination and application. It is confined to the actual doses used in the study; becomes lower with increasing sample size or dose levels; and reflects the risk level seen in the experiment rather than what may be relevant for human. We explored a pharmacometric approach in an attempt to address these issues. We first used simulation to examine the behaviour of the NOAEL values as determined by current common practice; andmore » then fitted the probability of toxicity as a function of treatment duration and dose to data collected from all applicable toxicology studies of a test compound. Our investigation was in the context of an irreversible toxicity that is detected at the end of the study. Simulations illustrated NOAEL's dependency on experimental factors such as dose and sample size, as well as the underlying uncertainty. Modelling the probability as a continuous function of treatment duration and dose simultaneously to data from multiple studies allowed the estimation of the dose, along with its confidence interval, for a maximal risk level that might be deemed as acceptable for human. The model-based data integration also reconciled between-study inconsistency and explicitly provided maximised estimation confidence. Such alternative NOAEL determination method should be explored for its more efficient data use, more quantifiable insight to toxic doses, and the potential for more relevant animal-to-human translation. - Highlights: • Simulations revealed issues with NOAEL concept, determination and application. • Probabilistic modelling was used to address these issues. • The model integrated time-dose-toxicity data from multiple studies. • The approach uses data efficiently and may allow more meaningful human translation.« less
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Li, Xiaojiao; Liu, Chang; Wu, Min; Zhang, Hong; Sun, Yanfu; Cheng, Longmei; Chen, Hong; Liu, Chengjiao; Yang, Lizhi; Zhang, Qi; Cao, Yuchen; Gu, Jingkai; Ding, Yanhua
2016-08-01
Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.
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A case control study of multiple myeloma at four nuclear facilities.
Wing, S; Richardson, D; Wolf, S; Mihlan, G; Crawford-Brown, D; Wood, J
2000-04-01
Reported elevations of multiple myeloma among nuclear workers exposed to external penetrating ionizing radiation, based on small numbers of cases, prompted this multi-facility study of workers at US Department of Energy facilities. Ninety-eight multiple myeloma deaths and 391 age-matched controls were selected from the combined roster of 115,143 workers hired before 1979 at Hanford, Los Alamos National Laboratory, Oak Ridge National Laboratory, and the Savannah River site. These workers were followed for vital status through 1990 (1986 for Hanford). Demographic, work history, and occupational exposure data were derived from personnel, occupational medicine, industrial hygiene, and health physics records. Exposure-disease associations were evaluated using conditional logistic regression. Cases were disproportionately African American, male, and hired prior to 1948. Lifetime cumulative whole body ionizing radiation dose was not associated with multiple myeloma, however, there was a significant effect of age at exposure, with positive associations between multiple myeloma and doses received at older ages. Dose response associations increased in magnitude with exposure age (from 40 to 50) and lag assumption (from 5 to 15 years), while a likelihood ratio goodness of fit test reached the highest value for cumulative doses received at ages above 45 with a 5-year lag (X2=5.43,1 df; relative risk = 6.9% per 10 mSv). Dose response associations persisted with adjustment for potential confounders. Multiple myeloma was associated with low level whole body penetrating ionizing radiation doses at older ages. The exposure age effect is at odds with interpretations of A-bomb survivor studies but in agreement with several studies of cancer among nuclear workers.
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Xue, Xiaonan; Shore, Roy E; Ye, Xiangyang; Kim, Mimi Y
2004-10-01
Occupational exposures are often recorded as zero when the exposure is below the minimum detection level (BMDL). This can lead to an underestimation of the doses received by individuals and can lead to biased estimates of risk in occupational epidemiologic studies. The extent of the exposure underestimation is increased with the magnitude of the minimum detection level (MDL) and the frequency of monitoring. This paper uses multiple imputation methods to impute values for the missing doses due to BMDL. A Gibbs sampling algorithm is developed to implement the method, which is applied to two distinct scenarios: when dose information is available for each measurement (but BMDL is recorded as zero or some other arbitrary value), or when the dose information available represents the summation of a series of measurements (e.g., only yearly cumulative exposure is available but based on, say, weekly measurements). Then the average of the multiple imputed exposure realizations for each individual is used to obtain an unbiased estimate of the relative risk associated with exposure. Simulation studies are used to evaluate the performance of the estimators. As an illustration, the method is applied to a sample of historical occupational radiation exposure data from the Oak Ridge National Laboratory.
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Janssen, T J; Guelen, P J; Vree, T B; Botterblom, M H; Valducci, R
1988-01-01
The bioavailability of a new ambroxol sustained release preparation (75 mg) based on a dialyzing membrane for controlled release was studied in healthy volunteers after single and multiple oral dose in comparison with a standard sustained release formulation in a cross-over study under carefully controlled conditions. Plasma concentrations of ambroxol were measured by means of a HPLC method. Based on AUC data both preparations are found to be bioequivalent, but show different plasma concentration profiles. The test preparation showed a more pronounced sustained release profile than the reference preparation (single dose) resulting in significantly higher steady state plasma levels.
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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.
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The effects of grape seeds polyphenols on SKH-1 mice skin irradiated with multiple doses of UV-B.
Filip, Adriana; Daicoviciu, Doina; Clichici, Simona; Bolfa, Pompei; Catoi, Cornel; Baldea, Ioana; Bolojan, Laura; Olteanu, Diana; Muresan, Adriana; Postescu, I D
2011-11-03
The study investigated the protective activity of red grape seeds (Vitis vinifera L, Burgund Mare variety) (BM) extracts in vivo on multiple doses of ultraviolet radiation (UV)-B-induced deleterious effects in SKH-1 mice skin. Eighty 8-weeks-old female SKH-1 mice were divided into 8 groups: control, vehicle, UV-B irradiated, vehicle+UV-B irradiated, BM 2.5mg polyphenols (PF)/cm(2)+UV-B irradiated, BM 4 mg PF/cm(2)+UV-B irradiated, UV-B+BM 2.5mg PF/cm(2), UV-B+BM 4 mg PF/cm(2). The extract was applied topically before or after each UV-B exposure (240 mJ/cm(2)), for 10 days consecutively. The antioxidant activity of BM extract is higher than gallic acid (k(BM)=0.017, k(gallic acid)=0.013). Multiple doses of UV-B generated the formation of cyclobutane pyrimidine dimers (CPDs) and sunburn cells, increased glutathione peroxidase (GPx) and catalase (CAT) activities respectively glutathione (GSH) and IL-1β levels in skin. In group treated with 2.5mg PF/cm(2) before UV-B irradiation BM extract inhibited UV-B-induced sunburn cells, restored the superoxide dismutase (MnSOD) activity, increased insignificantly CAT and GPx activities and reduced IL-1β level. The BM 4.0 mg PF/cm(2) treatment decreased GSH level and reduced the percentage of CPDs positive cells in skin. Both doses of BM extract administered after UV-B irradiation increased the MnSOD and GPx activities and reduced the formation of sunburn cells in skin. Our results suggest that BM extract might be a potential chemo-preventive candidate in reducing the oxidative stress and apoptosis induced by multiple doses of UV-B in skin. Copyright © 2011 Elsevier B.V. All rights reserved.
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Barnewall, Roy E.; Comer, Jason E.; Miller, Brian D.; Gutting, Bradford W.; Wolfe, Daniel N.; Director-Myska, Alison E.; Nichols, Tonya L.; Taft, Sarah C.
2012-01-01
Repeated low-level exposures to biological agents could occur before or after the remediation of an environmental release. This is especially true for persistent agents such as B. anthracis spores, the causative agent of anthrax. Studies were conducted to examine aerosol methods needed for consistent daily low aerosol concentrations to deliver a low-dose (less than 106 colony forming units (CFU) of B. anthracis spores) and included a pilot feasibility characterization study, acute exposure study, and a multiple 15 day exposure study. This manuscript focuses on the state-of-the-science aerosol methodologies used to generate and aerosolize consistent daily low aerosol concentrations and resultant low inhalation doses to rabbits. The pilot feasibility characterization study determined that the aerosol system was consistent and capable of producing very low aerosol concentrations. In the acute, single day exposure experiment, targeted inhaled doses of 1 × 102, 1 × 103, 1 × 104, and 1 × 105 CFU were used. In the multiple daily exposure experiment, rabbits were exposed multiple days to targeted inhaled doses of 1 × 102, 1 × 103, and 1 × 104 CFU. In all studies, targeted inhaled doses remained consistent from rabbit-to-rabbit and day-to-day. The aerosol system produced aerosolized spores within the optimal mass median aerodynamic diameter particle size range to reach deep lung alveoli. Consistency of the inhaled dose was aided by monitoring and recording respiratory parameters during the exposure with real-time plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over multiple exposure days. PMID:22919662
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Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won
2015-10-01
The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose levels higher than 51 mg/m(2). Additional phase II trials are recommended at 250 mg/m(2).
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Erickson, Malathi; Hiebert, Linda M.; Carr, Anthony P.; Stickney, Jocelyn D.
2014-01-01
The effects of heparin administration, by the oral route, were evaluated in dogs. In single and multiple dose studies (single 7.5 mg/kg, multiple 3 × 7.5 mg/kg per 48 h), plasma, urine, and fecal samples were collected at various times up to 120 h after oral administration of unfractionated heparin. Changes in plasma and urine anti-Xa activity, plasma and urine anti-IIa activity, plasma activated partial thromboplastin time (APTT) and antithrombin (ATIII), and chemical heparin in urine and feces were examined with time. There was support for heparin absorption, with significant differences in APTT, heparin in plasma as determined by anti-Xa activity (Heptest) in the single dose study and plasma anti-Xa activity, anti-IIa activity and ATIII; and chemical heparin in urine in the multiple dose study. No clinical evidence of bleeding was detected in any dog during the studies. Oral heparin therapy may be applicable for thromboembolic disease in animals. Further studies are warranted to determine the effects of oral heparin at the endothelial level in the dog. PMID:24982550
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Escalating dose, multiple binge methamphetamine regimen does not impair recognition memory in rats.
Clark, Robert E; Kuczenski, Ronald; Segal, David S
2007-07-01
Rats exposed to methamphetamine (METH) in an acute high dose "binge" pattern have been reported to exhibit a persistent deficit in a novel object recognition (NOR) task, which may suggest a potential risk for human METH abusers. However, most high dose METH abusers initially use lower doses before progressively increasing the dose, only eventually engaging in multiple daily administrations. To simulate this pattern of METH exposure, we administered progressively increasing doses of METH to rats over a 14 day interval, then treated them with daily METH binges for 11 days. This treatment resulted in a persistent deficit in striatal dopamine (DA) levels of approximately 20%. We then tested them in a NOR task under a variety of conditions. We could not detect a deficit in their performance in the NOR task under any of the testing conditions. These results suggest that mechanisms other than or additional to the decrement in striatal DA associated with an acute METH binge are responsible for the deficit in the NOR task, and that neuroadaptations consequential to prolonged escalating dose METH pretreatment mitigate against these mechanisms.
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Balásházy, Imre; Farkas, Arpád; Madas, Balázs Gergely; Hofmann, Werner
2009-06-01
Cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive bronchial epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or support of the linear-non-threshold (LNT) hypothesis. In this study, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors at bronchial airway bifurcations, expressed as the ratio of local to average deposition densities, were determined to characterise the inhomogeneity of deposition and to elucidate their effect on resulting hit probabilities. The results obtained suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high, even at low average doses. Assuming a uniform distribution of activity there are practically no multiple hits and the hit probability as a function of dose exhibits a linear shape in the low dose range. The results are quite the opposite in the case of hot spots revealed by realistic deposition calculations, where practically all cells receive multiple hits and the hit probability as a function of dose is non-linear in the average dose range of 10-100 mGy.
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Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides.
Graham, Mark J; Lee, Richard G; Brandt, Teresa A; Tai, Li-Jung; Fu, Wuxia; Peralta, Raechel; Yu, Rosie; Hurh, Eunju; Paz, Erika; McEvoy, Bradley W; Baker, Brenda F; Pham, Nguyen C; Digenio, Andres; Hughes, Steven G; Geary, Richard S; Witztum, Joseph L; Crooke, Rosanne M; Tsimikas, Sotirios
2017-07-20
Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins. We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins. The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events. Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).
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Saito, Nobuo; Komori, Kazuhiro; Suzuki, Motoi; Kishikawa, Takayuki; Yasaka, Takahiro; Ariyoshi, Koya
2018-03-08
We investigated the negative effects of prior multiple vaccinations on influenza vaccine effectiveness (VE) and analysed the association of VE with prior vaccine doses. Patients aged 9-18 years presenting with influenza-like illness at a community hospital on a Japanese remote island during the 2011/12, 2012/13 and 2013/14 seasons were tested for influenza using a rapid diagnostic test (RDT). A test-negative case-control study design was used to estimate the VEs of trivalent inactivated influenza vaccine (TIV). Histories of vaccination and medically-attended influenza (MA-flu) A and B during three previous seasons were collected from registry systems. VE was calculated using multi-level mixed-effects logistic regression models adjusted for the history of RDT-confirmed MA-flu. During three influenza seasons, 1668 influenza-like illness episodes were analysed, including 421 and 358 episodes of MA-fluA and MA-fluB, respectively. The adjusted VE yielded significant dose-dependent attenuations by prior vaccinations against both MA-fluA [0 doses during previous three seasons: 96% (95% CI: 69%-100%), 1 dose: 48% (-7% to 74%), 2 doses: 52% (11%-74%), 3 doses: 21% (-25% to 51%); P for trend <0.05] and MA-fluB [0 doses: 66% (-5% to 89%), 1 dose: 48% (-14% to 76%), 2 doses: 34% (-33% to 67%), 3 doses: -7% (-83% to 37%); P for trend <0.05]. After excluding episodes of MA-flu during prior three seasons, similar trends were observed. Repeated previous vaccinations over multiple seasons had significant dose-dependent negative impacts on VE against both MA-fluA and MA-fluB. Further studies to confirm this finding are necessary.
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Isotretinoin kinetics after 80 to 320 mg oral doses.
Colburn, W A; Gibson, D M
1985-04-01
Twelve healthy male subjects received 80, 160, 240, and 320 mg doses of oral isotretinoin as multiples of 40 mg capsules separated by 2-week washout periods in a randomized, crossover design. Blood samples were drawn at specific times over a 72-hour period after dosing. Blood concentrations of isotretinoin as well as its major metabolite, 4-oxo-isotretinoin, were determined by a specific HPLC method. In addition to the normal laboratory battery of tests, serum triglyceride levels were determined before the first dose and again 72 hours after each of the four doses. Mean (+/- SD) maximum concentrations after 80 to 320 mg doses were 366 +/- 159, 820 +/- 474, 1056 +/- 547, and 981 +/- 381 ng/ml, whereas the respective AUC0-infinity values were 3690 +/- 1280, 7030 +/- 4140, 9780 +/- 6080, and 9040 +/- 2900 ng X hr/ml. The observed apparent elimination t1/2 remained approximately the same (14.7 hours) for each dose. The maximum concentration and AUC values for isotretinoin appear to be dose proportional from 80 to 240 mg but plateau at the 320 mg dose level. Therefore, because isotretinoin blood concentrations may not increase with higher doses in the fasting state, single, oral doses in excess of 240 mg should be used with caution. The data also suggest that elevated triglyceride levels are not a simple function of isotretinoin blood concentrations across the entire study population and dose range studied, but that in subjects with triglyceride levels in excess of the normal range triglyceride levels were positively related to isotretinoin blood concentrations.
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Okkerse, Pieter; Hay, Justin L; Versage, Eve; Tang, Yongqiang; Galluppi, Gerald; Ravina, Bernard; Verma, Ajay; Williams, Leslie; Aycardi, Ernesto; Groeneveld, Geert Jan
2016-07-01
BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica. This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ). Safety and efficacy assessments were used as endpoints. The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 μg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen. The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica. © 2016 The British Pharmacological Society.
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Bayesian Dose-Response Modeling in Sparse Data
NASA Astrophysics Data System (ADS)
Kim, Steven B.
This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a wrong parametric assumption. In this regard, we consider a robust experimental design which does not require any parametric assumption.
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Amin, Raid W; Guttmann, Rodney P; Harris, Quianna R; Thomas, Janesha W
2018-05-01
Vancomycin is a key antibiotic used in the treatment of multiple conditions including infections associated with cystic fibrosis and methicillin-resistant Staphylococcus aureus. The present study sought to develop a model based on empirical evidence of optimal vancomycin dose as judged by clinical observations that could accelerate the achievement of desired trough level in children with cystic fibrosis. Transformations of dose and trough were used to arrive at regression models with excellent fit for dose based on weight or age for a target trough. Results of this study indicate that the 2 proposed regression models are robust to changes in age or weight, suggesting that the daily dose on a per-kilogram basis is determined primarily by the desired trough level. The results show that to obtain a vancomycin trough level of 20 μg/mL, a dose of 80 mg/kg/day is needed. This analysis should improve the efficiency of vancomycin usage by reducing the number of titration steps, resulting in improved patient outcome and experience. © 2018, The American College of Clinical Pharmacology.
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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.
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Jia, Jing-ying; Zhao, Qian-hua; Liu, Yun; Gui, Yu-zhou; Liu, Gang-yi; Zhu, Da-yuan; Yu, Chen; Hong, Zhen
2013-01-01
Aim: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. Methods: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0–72 h and AUC0–∞ were calculated. Tolerance assessments were conducted throughout the study. Results: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76–0.82 h; the AUC0–72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. Conclusion: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers. PMID:23624756
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Zhang, Pei; Cui, Wanchang; Hankey, Kim G.; Gibbs, Allison M.; Smith, Cassandra P.; Taylor-Howell, Cheryl; Kearney, Sean R.; MacVittie, Thomas J.
2015-01-01
Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP, and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition respectively, suggesting possible crosstalk between spleen and other organs. Our data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs. PMID:26425899
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Safety and Pharmacokinetics of Multiple Dose myo-Inositol in Preterm Infants
Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Nolen, Tracy L.; Watterberg, Kristi L.; Oh, William; Goedecke, Michael; Ehrenkranz, Richard A.; Fennell, Timothy; Poindexter, Brenda B.; Cotten, C. Michael; Hallman, Mikko; Frantz, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; Lacy, Conra Backstrom; Walsh, Michele C.; Carlo, Waldemar A.; Sánchez, Pablo J.; Bell, Edward F.; Shankaran, Seetha; Carlton, David P.; Chess, Patricia R.; Higgins, Rosemary D.
2016-01-01
BACKGROUND Preterm infants with RDS given inositol had reduced BPD, death and severe ROP. We assessed the safety and pharmacokinetics(PK) of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS Infants ≤29wks GA (n=122, 14 centers) were randomized and treated with placebo or inositol at 10, 40 or 80mg/kg/day. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 weeks, 34weeks PMA or discharge. Serum collection employed a sparse sampling population PK design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS At 80mg/kg/day mean serum levels reached 140mg/L, similar to Hallman’s findings. Levels declined after 2 weeks, converging in all groups by 6 wks. Analyses showed a mean volume of distribution 0.657 L/kg, clearance 0.058 L/kg/hr, and half-life 7.90 hr. Adverse events and co-morbidities were fewer in the inositol groups, but not significantly so. CONCLUSIONS Multiple dose inositol at 80mg/kg/day was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a Phase 3 trial. PMID:27074126
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Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits
Cox, Daniel T. C.; Shanahan, Danielle F.; Hudson, Hannah L.; Fuller, Richard A.; Anderson, Karen; Hancock, Steven; Gaston, Kevin J.
2017-01-01
Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare. PMID:28208789
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Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits.
Cox, Daniel T C; Shanahan, Danielle F; Hudson, Hannah L; Fuller, Richard A; Anderson, Karen; Hancock, Steven; Gaston, Kevin J
2017-02-09
Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare.
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Tanaka, T.; Godin, B.; Bhavane, R.; Nieves-Alicea, R.; Gu, J.; Liu, X.; Chiappini, C.; Fakhoury, J. R.; Amra, S.; Ewing, A.; Li, Q.; Fidler, I.J.; Ferrari, M.
2010-01-01
Porous silicon (pSi) is being extensively studied as an emerging material for use in biomedical applications, including drug delivery, based on the biodegradability and versatile chemical and biophysical properties. We have recently introduced multistage nanoporous silicon microparticles (S1MP) designed as a cargo for nanocarrier drug delivery to enable the loaded therapeutics and diagnostics to sequential overcoming of the biological barriers to reach their target. In this first report on biocompatibility of intravenously administered pSi structures, we examined biocompatibility of negatively (−32.5±3.1mV) and positively (8.7±2.5mV) charged S1MP in acute single dose (107, 108, 5×108 S1MP/animal) and subchronic multiple dose (108 S1MP/animal/week for 4 weeks) administration schedules. Our data demonstrate that S1MP did not change plasma levels of renal (BUN and creatinine) and hepatic (LDH) biomarkers as well as23 plasma cytokines. LDH plasma levels of 145.2±23.6, 115.4±29.1 vs. 127.0±10.4; and 155.8±38.4, 135.5±52.3 vs. 178.4±74.6 were detected in mice treated with 108 negatively charged S1MP, 108 positively charged S1MP vs. saline control in single and multiple dose schedules, respectively. The S1MPs did not alter LDH levels in liver and spleen, nor lead to infiltration of leukocytes into the liver, spleen, kidney, lung, brain, heart, and thyroid. Collectively, these data provide evidence of a safe intravenous administration of S1MPs as a drug delivery carrier. PMID:20883755
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Deng, Shuhua; Huang, Wencan; Ni, Xiaojia; Zhang, Ming; Lu, Haoyang; Wang, Zhanzhang; Hu, Jinqing; Zhu, Xiuqing; Qiu, Chang; Shang, Dewei; Zhang, Yuefeng; Xiong, Linghui; Wen, Yuguan
2017-10-01
1. A new oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone is effective in improving the symptoms of common cold. The pharmacokinetic properties of the individual components were evaluated in a randomized, open-label, four-period study in 12 healthy Chinese volunteers following single and multiple doses. The data were compared with data for the individual ingredients in Antuss®. 2. In the single-dose period, exposure levels (AUC and C max ) for guaifenesin, pseudoephedrine and hydrocodone increased directly as the dose of the oral liquid formulation increased from 5 to 15 mL. Only minor amounts of guaifenesin and hydrocodone were excreted in urine (∼0.10% and 4.66%, respectively). Pseudoephedrine was mainly excreted unchanged, with 44.95% of the dose excreted in urine within 24 h. After multiple dosing, there was no obvious accumulation of any drug, as assessed by AUC. When considering C max , there was a trend toward accumulation of hydrocodone and pseudoephedrine. The pharmacokinetic profiles of guaifenesin and pseudoephedrine in the oral liquid formulation were similar to those in the branded preparation, Antuss®. 3. The newly developed oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone was safe and well tolerated and might provide a reliable alternative to the branded formulation for patients with common colds.
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Kazierad, D J; Bergman, A; Tan, B; Erion, D M; Somayaji, V; Lee, D S; Rolph, T
2016-08-01
To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia. © 2016 John Wiley & Sons Ltd.
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Body, Jean-Jacques; Facon, Thierry; Coleman, Robert E; Lipton, Allan; Geurs, Filip; Fan, Michelle; Holloway, Donna; Peterson, Mark C; Bekker, Pirow J
2006-02-15
Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.
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Demirol, Aygul; Gurgan, Timur
2009-08-01
To compare the efficacy of the microdose flare-up and multiple-dose antagonist protocols for poor-responder patients in intracytoplasmic sperm injection-ET cycles. A randomized, prospective study. Center for assisted reproductive technology in Turkey. Ninety patients with poor ovarian response in a minimum of two previous IVF cycles. All women were prospectively randomized into two groups by computer-assisted randomization. The patients in group 1 were stimulated according to the microdose flare-up protocol (n = 45), while the patients in group 2 were stimulated according to antagonist multiple-dose protocol (n = 45). The mean number of mature oocytes retrieved was the primary outcome measure, and fertilization rate, implantation rate per embryo, and clinical pregnancy rates were secondary outcome measures. The mean age of the women, the mean duration of infertility, basal FSH level, and the number of previous IVF cycles were similar in both groups. The total gonadotropin dose used was significantly higher in group 2, while the number of oocytes retrieved was significantly greater in group 1. Although the fertilization and clinical pregnancy rates were nonsignificantly higher in group 1 compared with group 2, the implantation rate was significantly higher in the microdose flare-up group than in the multiple-dose antagonist group (22% vs. 11%). The microdose flare-up protocol seems to have a better outcome in poor-responder patients, with a significantly higher mean number of mature oocytes retrieved and higher implantation rate.
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Defining unnecessary disinfection procedures for single-dose and multiple-dose vials.
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.
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Maddox, A M; Freireich, E J; Keating, M J; Haddox, M K
1988-03-01
Nine patients with hematological malignancies were treated with difluoromethylornithine and methylglyoxal bis(guanylhydrazone). The number of circulating blast cells decreased in all of the patients treated with DFMO and MGBG for longer than 1 wk. Morphological evidence of myeloid maturation was evident in four patients with leukemia and the circulating M Protein decreased in one patient with multiple myeloma. The polyamine content of the mononuclear cells in both the peripheral blood and bone marrow was transiently increased after the initial MGBG dose. During administration of DFMO decreases were achieved in the peripheral blood mononuclear cell putrescine levels in 7 patients, spermidine levels in 5 patients, and spermine levels in 4 patients. Alterations in bone marrow mononuclear cell polyamine levels were similar to those which occurred in the peripheral cells. An average of 9 days of DFMO treatment was required to lower mononuclear cell polyamine levels. Three of the 4 evaluable patients receiving multiple MGBG doses had an increased mononuclear cell content of MGBG after DFMO pretreatment. Enhancement of cellular MGBG levels was not directly correlated to the degree of cellular polyamine depletion.
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NASA Astrophysics Data System (ADS)
Wahi-Anwar, M. Wasil; Emaminejad, Nastaran; Hoffman, John; Kim, Grace H.; Brown, Matthew S.; McNitt-Gray, Michael F.
2018-02-01
Quantitative imaging in lung cancer CT seeks to characterize nodules through quantitative features, usually from a region of interest delineating the nodule. The segmentation, however, can vary depending on segmentation approach and image quality, which can affect the extracted feature values. In this study, we utilize a fully-automated nodule segmentation method - to avoid reader-influenced inconsistencies - to explore the effects of varied dose levels and reconstruction parameters on segmentation. Raw projection CT images from a low-dose screening patient cohort (N=59) were reconstructed at multiple dose levels (100%, 50%, 25%, 10%), two slice thicknesses (1.0mm, 0.6mm), and a medium kernel. Fully-automated nodule detection and segmentation was then applied, from which 12 nodules were selected. Dice similarity coefficient (DSC) was used to assess the similarity of the segmentation ROIs of the same nodule across different reconstruction and dose conditions. Nodules at 1.0mm slice thickness and dose levels of 25% and 50% resulted in DSC values greater than 0.85 when compared to 100% dose, with lower dose leading to a lower average and wider spread of DSC values. At 0.6mm, the increased bias and wider spread of DSC values from lowering dose were more pronounced. The effects of dose reduction on DSC for CAD-segmented nodules were similar in magnitude to reducing the slice thickness from 1.0mm to 0.6mm. In conclusion, variation of dose and slice thickness can result in very different segmentations because of noise and image quality. However, there exists some stability in segmentation overlap, as even at 1mm, an image with 25% of the lowdose scan still results in segmentations similar to that seen in a full-dose scan.
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Pharmacokinetics and pharmacodynamics of vildagliptin in healthy Chinese volunteers.
Hu, Pei; Yin, Qi; Deckert, Fabienne; Jiang, Ji; Liu, Dongyang; Kjems, Lise; Dole, William P; He, Yan-Ling
2009-01-01
Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled, time-lagged, parallel-group study in a total of 60 healthy Chinese participants. Single- and multiple-dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5-2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half-life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00-1.05 across the 25- to 200-mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose-proportional fashion (dose proportionality constant beta 1.00-1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near-complete (>95%) inhibition of DPP-4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon-like peptide-1 of up to 2- to 3-fold compared with placebo. The duration of DPP-4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose-lowering effects of vildagliptin occur in a glucose-dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose-proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP-4 activity with excellent tolerability at doses of up to and including 200 mg qd.
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Fluoxetine exposure impacts boldness in female Siamese fighting fish, Betta splendens.
Dzieweczynski, Teresa L; Kane, Jessica L; Campbell, Brennah A; Lavin, Lindsey E
2016-01-01
The present study examined the effects of the selective serotonin reuptake inhibitor, fluoxetine, on the behavior of female Siamese fighting fish, Betta splendens, in three different boldness assays (Empty Tank, Novel Environment, Social Tendency). When females were unexposed to fluoxetine, boldness was consistent within a context and correlated across assays. Fluoxetine exposure affected behavior within and among individuals on multiple levels. Exposure reduced overall boldness levels, made females behave in a less consistent manner, and significantly reduced correlations over time and across contexts. Fluoxetine exerted its effects on female Betta splendens behavior in a dose-dependent fashion and these effects persisted even after females were housed in clean water. If fluoxetine exposure impacts behaviors such as exploration that are necessary to an individual’s success, this may yield evolutionary consequences. In conclusion, the results show that fluoxetine exposure alters behavior beyond the level of overall response and highlights the importance of studying the behavioral effects of inadvertent pharmaceutical exposure in multiple contexts and with different dosing regimes.
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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.
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Dose as a Tool for Planning and Implementing Community-Based Health Strategies.
Kuo, Elena S; Harner, Lisa T; Frost, Madeline C; Cheadle, Allen; Schwartz, Pamela M
2018-05-01
A major challenge in community-based health promotion is implementing strategies that could realistically improve health at the population level. Population dose methodology was developed to help understand the combined impact of multiple strategies on population-level health behaviors. This paper describes one potential use of dose: as a tool for working collaboratively with communities to increase impact when planning and implementing community-level initiatives. Findings are presented from interviews conducted with 11 coordinators who used dose for planning and implementing local efforts with community coalitions. During early-stage planning, dose was used as a tool for strategic planning, and as a framework to build consensus among coalition partners. During implementation, a dose lens was used to revise strategies to increase their reach (the number of people exposed to the intervention) or strength (the relative change in behavior for each exposed person) to create population-level impact. A case study is presented, illustrating how some community coalitions and evaluators currently integrate dose into the planning and implementation of place-based healthy eating and active living strategies. Finally, a planning checklist was developed for program coordinators and evaluators. This article is part of a supplement entitled Building Thriving Communities Through Comprehensive Community Health Initiatives, which is sponsored by Kaiser Permanente, Community Health. Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.
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Vang, Sophia Ingeborg; Schmiegelow, Kjeld; Frandsen, Thomas; Rosthøj, Susanne; Nersting, Jacob
2015-05-01
High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils (P < 0.0001), Ery-MeMP (P < 0.0001) and Ery-6TGN (P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP (P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Ross, D.S.; Ridgway, E.C.; Daniels, G.H.
1984-10-01
Forty-five patients with solitary toxic thyroid adenomas received 131I (mean dose, 10.3 mCi) for treatment of hyperthyroidism and were followed for 4.9 +/- 3.2 years (range, 0.5 to 13.5). Seventy-seven percent were euthyroid by 2 months, 91% by 6 months, and 93% by 1 year. Only 3 patients did not respond to a single dose of 131I, but all responded to multiple doses. Late recurrent hyperthyroidism occurred in 3 patients at 4.5, 6, and 10 years after treatment with a single dose of 131I. No patient developed clinical hypothyroidism, and none had a low serum thyroxine level associated with anmore » elevated serum thyrotrophin level. Three patients developed minimal elevations in serum thyrotrophin levels: 1, 4, and 7.5 years after 131I treatment, their thyrotrophin levels were 8.4, 6.2, and 9.6 microU/mL, respectively. All 3 had normal serum thyroxine levels and were clinically euthyroid. Mean serum thyroxine concentrations of all patients were unchanged between 1 and more than 9 years of follow-up. These data suggest that solitary toxic adenomas may be treated with relatively low doses of 131I (5 to 15 mCi), and that post-treatment hypothyroidism is very unusual.« less
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Ma, Yanping; Liu, Wenhua; Zhang, Ling; Jia, Gu
2017-01-01
Background The aim of this study was to explore the impact of LBH589 alone or in combination with proteasome inhibitor bortezomib on multiple myeloma (MM) cell proliferation and its mechanism. Material/Methods MM cell line U266 and RRMM-BMMNC were treated with different concentrations of LBH589 alone or in combination with bortezomib. Cell proliferation was detected by MTT assay. Cell cycle and apoptosis was analyzed by flow cytometry. The protein and mRNA level of related genes was determined by Western blotting and qRT-PCR respectively. Results U266 cell and RRMM-BMMNC proliferation were inhibited by different concentrations of LBH589 (0, 10, 20, and 50 nmol/L) alone or 50 nmol/L of LBH589 in combination with bortezomib (10 and 20 nmol/L) in a dose- and time-dependent manner. LBH589 significantly induced G0/G1phase arrest and apoptosis in RRMM-BMMNC in a dose-dependent manner. The effects were significantly higher in all combined groups than in single-agent groups (all P<0.05). The mRNA level of Caspase3 and APAF1 were up-regulated gradually, while TOSO gene expression in RRMM-BMMNC was down-regulated gradually in a dose- and time-dependent manner. Moreover, LBH589 significantly induced hyperacetylation of histone H4, the protein level of PARP notably increased, and the level of Bcl-X decreased. Conclusions LBH589 can inhibit MM cell growth, block the cell cycle, and induce cell apoptosis, which has an anti-resistant effect on multidrug-resistant cells. LBH589 in combination with bortezomib has a synergistic effect on myeloma cells; its mechanism and reversal of drug resistance mechanism is involved in multiple changes in gene expression. PMID:29080899
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Cetkovic-Cvrlje, Marina; Thinamany, Sinduja; Bruner, Kylie A
2017-12-01
Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disorder characterized by destruction of insulin-producing pancreatic β-cells. Whereas epidemiological data implicate environmental factors in the increasing incidence of T1D, their identity remains unknown. Though exposure to bisphenol A (BPA) has been associated with several disorders, no epidemiologic evidence has linked BPA exposure and T1D. The goal of this study was to elucidate diabetogenic potentials of BPA and underlying mechanisms in the context of T-cell immunity, in a multiple low-dose streptozotocin (MLDSTZ)-induced autoimmune mouse T1D model. C57BL/6 mice were orally exposed to 1 or 10 mg BPA/L starting at 4 wk of age; diabetes was induced at 9 wk of age with STZ. T-cell composition, function, and insulitis levels were studied at Days 11 and 50 during diabetes development (i.e. post-first STZ injection). Results showed both BPA doses increased diabetes incidence and affected T-cell immunity. However, mechanisms of diabetogenic action appeared divergent based on dose. Low-dose BPA fits a profile of an agent that exhibits pro-diabetogenic effects via T-cell immunomodulation in the early stages of disease development, i.e. decreases in splenic T-cell subpopulations [especially CD4 + T-cells] along with a trend in elevation of splenic T-cell formation of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6). In contrast, high-dose BPA did not affect T-cell populations and led to decreased levels of IFN-γ and TNF-α. Both treatments did not affect insulitis levels at the disease early stage, but aggravated it later on. By the study end, besides decreasing T-cell proliferative capacity, low-dose BPA did not affect other T-cell-related parameters, including cytokine secretion, comparable to the effects of high-dose BPA. In conclusion, this study confirmed BPA as a potential diabetogenic compound with immunomodulatory mechanisms of action - in the context of T-cell immunity - that seemed to be dose dependent in the early immunopathogenesis of a MLDSTZ-induced model of T1D.
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NASA Technical Reports Server (NTRS)
Lushbaugh, C. C.
1974-01-01
The acute radiation syndrome in man is clinically bounded by death at high dose levels and by the prodromal syndrome of untoward physiological effects at minimal levels of clinically effective exposure. As in lower animals, man experiences principally three acute modes of death from radiation exposure (Bond et al., 1965). These are known collectively as the lethal radiation syndromes: central nervous system death, gastrointestinal death, and hematopoietic death. The effect of multiple exposure on lethality, the effect of multiple exposure on hematopoietic recovery, and quantitative aspects of cell and tissue repair are discussed.
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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
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Coelingh Bennink, Herjan J T; Verhoeven, Carole; Zimmerman, Yvette; Visser, Monique; Foidart, Jean-Michel; Gemzell-Danielsson, Kristina
2017-06-01
Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated. This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers. Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent. In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.
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Ji, Zhiying; LeBaron, Matthew J; Schisler, Melissa R; Zhang, Fagen; Bartels, Michael J; Gollapudi, B Bhaskar; Pottenger, Lynn H
2016-05-01
The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P < 0.05), indicating the systemic availability of MMS; however, the N7MeG DNA adduct, a target exposure biomarker, exhibited a non-linear dose-response in blood and liver tissues. Blood reticulocyte micronuclei (MN), a genotoxic effect biomarker, exhibited a clear no-observed-genotoxic-effect-level (NOGEL) of 5 mkd as a point of departure (PoD) for MMS. Two separate dose-response models, the Lutz and Lutz model and the stepwise approach using PROC REG both supported a bilinear/threshold dose-response for MN induction. Liver gene expression, a mechanistic endpoint, also exhibited a bilinear dose-response. Similarly, in MNU-treated rats, hepatic DNA adducts, gene expression changes and MN all exhibited clear PoDs, with a NOGEL of 1 mkd for MN induction, although dose-response modeling of the MNU-induced MN data showed a better statistical fit for a linear dose-response. In summary, these results provide in vivo data that support the existence of clear non-linear dose-responses for a number of biologically significant events along the pathway for genotoxicity induced by DNA-reactive agents. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat
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
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Mazumder, Upal Kanti; Gupta, Malaya; Pal, Dilipkumar; Bhattacharya, Shiladitya
2003-01-01
Methanol extract of Cuscuta reflexa Roxb. stem (MECR) contain flavonoids (0.2%) and Corchorus olitorius Linn. seed (MECO) was found to contain steroids and cardenolide glycosides. Effects of multiple weekly dose of MECR (25, 50, 75 mg/kg, i.p.) and MECO (15, 20, 25 mg/kg, i.p.) on liver and kidney functions and hematological parameters in mice were studied. No significant alteration of RBC count and hemoglobin content was observed in all dose level of treatment in MECR and MECO treated mice whereas significant increase of clotting time was seen in moderate and high doses in both case. MECR and MECO both caused significant increase in WBC count only in high dose level of treatment. Both the extracts in medium and high dose level increased SGOT, SGPT, NPN and plasma cholesterol significantly. Serum alkaline phosphatase and total bilirubin were also increased by both moderate and high dose level of treatments in MECR and MECO treated mice respectively. Low dose of both the extract did not exhibit any significant change of creatinine and serum protein level. But high dose level of MECR and MECO significantly increased creatinine level. Increase in plasma cholesterol may be due to decrease in cholesterol catabolism owing to liver dysfunction of due to the intake of MECO itself as it was found to be steroid in nature. Elevated level of SGOT, SGPT and serum alkaline phosphatase activity in moderate and high dose level of weekly treated mice may be due to improper liver function following the treatment. Increased urea, non protein nitrogen and creatinine content in blood have been observed with impaired renal function. The slightly higher toxicity in case of MECO treated mice may be due to the presence of cardenolide glycosides in the ME of C. olitorius seed. However, low doses of MECR and MECO (25 and 15 mg/kg, i.p. respectively) did not exhibit any remarkable change on liver and kidney functions and hematological parameters.
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Similarity of Bisphenol A Pharmacokinetics in Rhesus Monkeys and Mice: Relevance for Human Exposure
Taylor, Julia A.; vom Saal, Frederick S.; Welshons, Wade V.; Drury, Bertram; Rottinghaus, George; Hunt, Patricia A.; Toutain, Pierre-Louis; Laffont, Céline M.; VandeVoort, Catherine A.
2011-01-01
Objective Daily adult human exposure to bisphenol A (BPA) has been estimated at < 1 μg/kg, with virtually complete first-pass conjugation in the liver in primates but not in mice. We measured unconjugated and conjugated BPA levels in serum from adult female rhesus monkeys and adult female mice after oral administration of BPA and compared findings in mice and monkeys with prior published data in women. Methods Eleven adult female rhesus macaques were fed 400 μg/kg deuterated BPA (dBPA) daily for 7 days. Levels of serum dBPA were analyzed by isotope-dilution liquid chromatography–mass spectrometry (0.2 ng/mL limit of quantitation) over 24 hr on day 1 and on day 7. The same dose of BPA was fed to adult female CD-1 mice; other female mice were administered 3H-BPA at doses ranging from 2 to 100,000 μg/kg. Results In monkeys, the maximum unconjugated serum dBPA concentration of 4 ng/mL was reached 1 hr after feeding and declined to low levels by 24 hr, with no significant bioaccumulation after seven daily doses. Mice and monkeys cleared unconjugated serum BPA at virtually identical rates. We observed a linear (proportional) relationship between administered dose and serum BPA in mice. Conclusions BPA pharmacokinetics in women, female monkeys, and mice is very similar. By comparison with approximately 2 ng/mL unconjugated serum BPA reported in multiple human studies, the average 24-hr unconjugated serum BPA concentration of 0.5 ng/mL in both monkeys and mice after a 400 μg/kg oral dose suggests that total daily human exposure is via multiple routes and is much higher than previously assumed. PMID:20855240
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Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule
Awada, A; Punt, C J A; Piccart, M J; Tellingen, O Van; Manen, L Van; Kerger, J; Groot, Y; Wanders, J; Verweij, J; Wagener, D J Th
1999-01-01
Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min IV infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1–5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 μg m−2. According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 μg m−2, the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 μg m−2. From the dose level 170 μg m−2, the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 μg m−2. The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml−1) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values. © 1999 Cancer Research Campaign PMID:10188890
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Grover, Anita; Benet, Leslie Z.
2013-01-01
Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives. PMID:21499748
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Faught, Austin M; Davidson, Scott E; Fontenot, Jonas; Kry, Stephen F; Etzel, Carol; Ibbott, Geoffrey S; Followill, David S
2017-09-01
The Imaging and Radiation Oncology Core Houston (IROC-H) (formerly the Radiological Physics Center) has reported varying levels of agreement in their anthropomorphic phantom audits. There is reason to believe one source of error in this observed disagreement is the accuracy of the dose calculation algorithms and heterogeneity corrections used. To audit this component of the radiotherapy treatment process, an independent dose calculation tool is needed. Monte Carlo multiple source models for Elekta 6 MV and 10 MV therapeutic x-ray beams were commissioned based on measurement of central axis depth dose data for a 10 × 10 cm 2 field size and dose profiles for a 40 × 40 cm 2 field size. The models were validated against open field measurements consisting of depth dose data and dose profiles for field sizes ranging from 3 × 3 cm 2 to 30 × 30 cm 2 . The models were then benchmarked against measurements in IROC-H's anthropomorphic head and neck and lung phantoms. Validation results showed 97.9% and 96.8% of depth dose data passed a ±2% Van Dyk criterion for 6 MV and 10 MV models respectively. Dose profile comparisons showed an average agreement using a ±2%/2 mm criterion of 98.0% and 99.0% for 6 MV and 10 MV models respectively. Phantom plan comparisons were evaluated using ±3%/2 mm gamma criterion, and averaged passing rates between Monte Carlo and measurements were 87.4% and 89.9% for 6 MV and 10 MV models respectively. Accurate multiple source models for Elekta 6 MV and 10 MV x-ray beams have been developed for inclusion in an independent dose calculation tool for use in clinical trial audits. © 2017 American Association of Physicists in Medicine.
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Ultra-accelerated natural sunlight exposure testing
Jorgensen, Gary J.; Bingham, Carl; Goggin, Rita; Lewandowski, Allan A.; Netter, Judy C.
2000-06-13
Process and apparatus for providing ultra accelerated natural sunlight exposure testing of samples under controlled weathering without introducing unrealistic failure mechanisms in exposed materials and without breaking reciprocity relationships between flux exposure levels and cumulative dose that includes multiple concurrent levels of temperature and relative humidity at high levels of natural sunlight comprising: a) concentrating solar flux uniformly; b) directing the controlled uniform sunlight onto sample materials in a chamber enclosing multiple concurrent levels of temperature and relative humidity to allow the sample materials to be subjected to accelerated irradiance exposure factors for a sufficient period of time in days to provide a corresponding time of about at least a years worth of representative weathering of the sample materials.
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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.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Marty, M. S.; Domoradzki, J. Y.; Hansen, S. C.
2007-12-01
There is a paucity of data on neonatal systemic exposure using different dosing paradigms. Male CD (Sprague-Dawley derived) rats at postnatal day (PND) 5 were dosed with chlorpyrifos (CPF, 1 mg/kg) using different routes of exposure, vehicles, and single vs. divided doses. Blood concentrations of CPF and its primary metabolite, trichloropyridinol (TCP), were measured at multiple times through 24 h. Groups included: single gavage bolus vs. divided gavage doses in corn oil (1 vs 3 times in 24 h), single gavage bolus vs. divided gavage doses in rat milk, and subcutaneous administration in DMSO. These data were compared with lactationalmore » exposure of PND 5 pups from dams exposed to CPF in the diet at 5 mg/kg/day for four weeks or published data from dams exposed to daily gavage with CPF at 5 mg/kg/day. Maternal blood CPF levels were an order of magnitude lower from dietary exposure than gavage (1.1 vs 14.8 ng/g), and blood CPF levels in PND 5 pups that nursed dietary-exposed or gavage-exposed dams were below the limit of detection. Single gavage doses of 1 mg/kg CPF in corn oil vehicle in pups resulted in CPF blood levels of 49 ng/g, and in milk vehicle about 9 ng/g. Divided doses led to lower peak CPF levels. A bolus dose of 1 mg/kg CPF in DMSO administered sc appeared to have substantially altered pharmacokinetics from orally administered chlorpyrifos. To be meaningful for risk assessment, neonatal studies require attention to the exposure scenario, since route, vehicle, dose and frequency of administration result in different systemic exposure to the test chemical and its metabolites.« less
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Bruera, Gemma; Massacese, Silvia; Galvano, Antonio; Mas, Antonella Dal; Guadagni, Stefano; Calvisi, Giuseppe; Ciacco, Eugenio; Russo, Antonio; Ricevuto, Enrico
2018-04-17
Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m 2 /d 1-2, 8-9, 15-16, 22-23, with 100 mg/m 2 /d increase for dose level; DTX 50 mg/m 2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m 2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m 2 /d and 80 mg/m 2 , respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy.
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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. .
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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.
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Waters, E K; Sigh, J; Friedrich, U; Hilden, I; Sørensen, B B
2017-09-01
Concizumab, a humanized monoclonal antibody against tissue factor pathway inhibitor (TFPI), is being developed as a subcutaneously (s.c.) administered treatment for haemophilia. It demonstrated a concentration-dependent procoagulant effect in functional TFPI assays; however, global haemostatic assays, such as the thrombin generation assay (TGA), offer a more complete picture of coagulation. We investigated how concizumab affects thrombin generation following ex vivo spiking in plasma from haemophilia patients using the TGA, and if the assay can detect the effect of multiple s.c. concizumab doses in healthy subjects. For the ex vivo spiking study, platelet-poor plasma (PPP) from 18 patients with severe haemophilia was spiked with 0.001-500 nm concizumab. For the multiple-dosing study, four healthy males received concizumab 250 μg kg -1 s.c. every other day for eight doses; blood was collected before and after dosing and processed into PPP. In both studies, thrombin generation was measured using a Calibrated Automated Thrombogram ® system with 1 pm tissue factor. In spiked samples from haemophilia patients, peak thrombin and endogenous thrombin potential (ETP) increased concentration dependently, reaching near-normal levels at concizumab concentrations >10 nm. Repeated s.c. doses of concizumab in healthy subjects increased both peak thrombin and ETP; these effects were sustained throughout the dosing interval. Thrombin generation assay demonstrated increased thrombin generation with concizumab after ex vivo spiking of haemophilia plasma and multiple s.c. doses in healthy subjects, supporting both the utility of the TGA in evaluating concizumab treatment and the potential of s.c. concizumab as a novel haemophilia therapy. © 2017 The Authors. Haemophilia Published by John Wiley & Sons Ltd.
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Sandborn, W J; Bhandari, B R; Fogel, R; Onken, J; Yen, E; Zhao, X; Jiang, Z; Ge, D; Xin, Y; Ye, Z; French, D; Silverman, J A; Kanwar, B; Subramanian, G M; McHutchison, J G; Lee, S D; Shackelton, L M; Pai, R K; Levesque, B G; Feagan, B G
2016-07-01
Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis. © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.
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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.
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Salicylate-induced enzymuria: comparison with other anti-inflammatory agents.
Proctor, R A; Kunin, C M
1978-12-01
N-acetyl-beta glucosaminidase (NAG) enzymuria was used as a marker of renal injury in patients with rheumatic disease. An elevated NAG level was particularly common in patients receiving gold or aspirin therapy. The multiplicity of drugs received and the unknown role of underlying disease in these patients led to a study in healthy volunteers. Customary therapeutic doses of aspirin, choline salicylate, ibuprofen, indomethacin and acetaminophen did not produce enzymuria. Large single doses of salicylates equivalent to 6 tablets of aspirin consistently did produce enzymuria. The size of the individual dose in relation to body weight was more important than the total daily dose. NAG enzymuria appears to be a sensitive tool for identifying potentially nephrotoxic drugs.
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Kumar, Shaji K; Laubach, Jacob P; Giove, Thomas J; Quick, Maureen; Neuwirth, Rachel; Yung, Godwin; Rajkumar, S Vincent; Richardson, Paul G
2017-09-01
Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules. © 2017 John Wiley & Sons Ltd.
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Conformity of commercial oral single solid unit dose packages in hospital pharmacy practice.
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.
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Peruzzo Cornetto, Andrea; Aimonetto, Stefania; Pisano, Francesco; Giudice, Marcello; Sicuro, Marco; Meloni, Teodoro; Tofani, Santi
2016-01-01
This study evaluates per-procedure, collective and per capita effective dose to the population by interventional cardiology (IC) procedures performed during 2002–11 at the main hospital of Aosta Valley Region that can be considered as representative of the health-care level I countries, as defined by the UNSCEAR, based on its socio-demographic characteristics. IC procedures investigated were often multiple procedures in patients older than 60 y. The median extreme dose-area product values of 300 and 22 908 cGycm2 were found for standard pacemaker implantation and coronary angioplasty, respectively, while the relative mean per-procedure effective dose ranged from 0.7 to 47 mSv. A 3-fold increase in frequency has been observed together with a correlated increase in the delivered per capita dose (0.05–0.27 mSv y−1) and the collective dose (5.8–35 man Sv y−1). Doses increased particularly from 2008 onwards mainly because of the introduction of coronary angioplasty procedures in the authors’ institution. IC practice contributed remarkably in terms of effective dose to the population, delivering ∼10 % of the total dose by medical ionising radiation examination categories. PMID:26012484
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Faught, Austin M; Davidson, Scott E; Popple, Richard; Kry, Stephen F; Etzel, Carol; Ibbott, Geoffrey S; Followill, David S
2017-09-01
The Imaging and Radiation Oncology Core-Houston (IROC-H) Quality Assurance Center (formerly the Radiological Physics Center) has reported varying levels of compliance from their anthropomorphic phantom auditing program. IROC-H studies have suggested that one source of disagreement between institution submitted calculated doses and measurement is the accuracy of the institution's treatment planning system dose calculations and heterogeneity corrections used. In order to audit this step of the radiation therapy treatment process, an independent dose calculation tool is needed. Monte Carlo multiple source models for Varian flattening filter free (FFF) 6 MV and FFF 10 MV therapeutic x-ray beams were commissioned based on central axis depth dose data from a 10 × 10 cm 2 field size and dose profiles for a 40 × 40 cm 2 field size. The models were validated against open-field measurements in a water tank for field sizes ranging from 3 × 3 cm 2 to 40 × 40 cm 2 . The models were then benchmarked against IROC-H's anthropomorphic head and neck phantom and lung phantom measurements. Validation results, assessed with a ±2%/2 mm gamma criterion, showed average agreement of 99.9% and 99.0% for central axis depth dose data for FFF 6 MV and FFF 10 MV models, respectively. Dose profile agreement using the same evaluation technique averaged 97.8% and 97.9% for the respective models. Phantom benchmarking comparisons were evaluated with a ±3%/2 mm gamma criterion, and agreement averaged 90.1% and 90.8% for the respective models. Multiple source models for Varian FFF 6 MV and FFF 10 MV beams have been developed, validated, and benchmarked for inclusion in an independent dose calculation quality assurance tool for use in clinical trial audits. © 2017 American Association of Physicists in Medicine.
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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.
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Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne
2015-01-01
Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra/rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept [corrected]. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.
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Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne
2015-01-01
Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra, rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs. PMID:26356639
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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.
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Butterworth, K T; Coulter, J A; Jain, S; Forker, J; McMahon, S J; Schettino, G; Prise, K M; Currell, F J; Hirst, D G
2010-01-01
High atomic number (Z) materials such as gold preferentially absorb kilovoltage x-rays compared to soft tissue and may be used to achieve local dose enhancement in tumours during treatment with ionizing radiation. Gold nanoparticles have been demonstrated as radiation dose enhancing agents in vivo and in vitro. In the present study, we used multiple endpoints to characterize the cellular cytotoxic response of a range of cell lines to 1.9 nm gold particles and measured dose modifying effects following transient exposure at low concentrations. Gold nanoparticles caused significant levels of cell type specific cytotoxicity, apoptosis and increased oxidative stress. When used as dose modifying agents, dose enhancement factors varied between the cell lines investigated with the highest enhancement being 1.9 in AGO-1522B cells at a nanoparticle concentration of 100 μg ml−1. This study shows exposure to 1.9 nm gold particles to induce a range of cell line specific responses including decreased clonogenic survival, increased apoptosis and induction of DNA damage which may be mediated through the production of reactive oxygen species. This is the first study involving 1.9 nm nanometre sized particles to report multiple cellular responses which impact on the radiation dose modifying effect. The findings highlight the need for extensive characterization of responses to gold nanoparticles when assessing dose enhancing potential in cancer therapy. PMID:20601762
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Experimental Design for Multi-drug Combination Studies Using Signaling Networks
Huang, Hengzhen; Fang, Hong-Bin; Tan, Ming T.
2017-01-01
Summary Combinations of multiple drugs are an important approach to maximize the chance for therapeutic success by inhibiting multiple pathways/targets. Analytic methods for studying drug combinations have received increasing attention because major advances in biomedical research have made available large number of potential agents for testing. The preclinical experiment on multi-drug combinations plays a key role in (especially cancer) drug development because of the complex nature of the disease, the need to reduce development time and costs. Despite recent progresses in statistical methods for assessing drug interaction, there is an acute lack of methods for designing experiments on multi-drug combinations. The number of combinations grows exponentially with the number of drugs and dose-levels and it quickly precludes laboratory testing. Utilizing experimental dose-response data of single drugs and a few combinations along with pathway/network information to obtain an estimate of the functional structure of the dose-response relationship in silico, we propose an optimal design that allows exploration of the dose-effect surface with the smallest possible sample size in this paper. The simulation studies show our proposed methods perform well. PMID:28960231
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An airport community noise-impact assessment model
NASA Technical Reports Server (NTRS)
Deloach, R.
1980-01-01
A computer model was developed to assess the noise impact of an airport on the community which it serves. Assessments are made using the Fractional Impact Method by which a single number describes the community aircraft noise environment in terms of exposed population and multiple event noise level. The model is comprised of three elements: a conventional noise footprint model, a site specific population distribution model, and a dose response transfer function. The footprint model provides the noise distribution for a given aircraft operating scenario. This is combined with the site specific population distribution obtained from a national census data base to yield the number of residents exposed to a given level of noise. The dose response relationship relates noise exposure levels to the percentage of individuals highly annoyed by those levels.
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Gray, Leon Earl; Barlow, Norman J.; Howdeshell, Kembra L.; Ostby, Joseph S.; Furr, Johnathan R.; Gray, Clark L.
2009-01-01
In the rat, some phthalates alter sexual differentiation at relatively low dosage levels by altering fetal Leydig cell development and hormone synthesis, thereby inducing abnormalities of the testis, gubernacular ligaments, epididymis, and other androgen-dependent tissues. In order to define the dose-response relationship between di(2-ethylhexyl) phthalate (DEHP) and the Phthalate Syndrome of reproductive alterations in F1 male rats, Sprague-Dawley (SD) rat dams were dosed by gavage from gestational day 8 to day 17 of lactation with 0, 11, 33, 100, or 300 mg/kg/day DEHP (71–93 males per dose from 12 to 14 litters per dose). Some of the male offspring continued to be exposed to DEHP via gavage from 18 days of age to necropsy at 63–65 days of age (PUB cohort; 16–20/dose). Remaining males were not exposed after postnatal day 17 (in utero-lactational [IUL] cohort) and were necropsied after reaching full maturity. Anogenital distance, sperm counts and reproductive organ weights were reduced in F1 males in the 300 mg/kg/day group and they displayed retained nipples. In the IUL cohort, seminal vesicle weight also was reduced at 100 mg/kg/day. In contrast, serum testosterone and estradiol levels were unaffected in either the PUB or IUL cohorts at necropsy. A significant percentage of F1 males displayed one or more Phthalate Syndrome lesions at 11 mg/kg/day DEHP and above. We were able to detect effects in the lower dose groups only because we examined all the males in each litter rather than only one male per litter. Power calculations demonstrate how using multiple males versus one male/litter enhances the detection of the effects of DEHP. The results at 11 mg/kg/day confirm those reported from a National Toxicology Program multigenerational study which reported no observed adverse effect levels-lowest observed adverse effect levels of 5 and 10 mg/kg/day DEHP, respectively, via the diet. PMID:19482887
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Modeling Rabbit Responses to Single and Multiple Aerosol ...
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
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Tierney, Rob; Nakai, Toru; Parkins, Christopher J; Caposio, Patrizia; Fairweather, Neil F; Sesardic, Dorothea; Jarvis, Michael A
2012-04-26
The current commercially available vaccine used to prevent tetanus disease following infection with the anaerobic bacterium Clostridium tetani is safe and effective. However, tetanus remains a major source of mortality in developing countries. In 2008, neonatal tetanus was estimated to have caused >59,000 deaths, accounting for 1% of worldwide infant mortality, primarily in poorer nations. The cost of multiple vaccine doses administered by injection necessary to achieve protective levels of anti-tetanus toxoid antibodies is the primary reason for low vaccine coverage. Herein, we show that a novel vaccine strategy using a cytomegalovirus (CMV)-based vaccine platform induces protective levels of anti-tetanus antibodies that are durable (lasting >13 months) in mice following only a single dose. This study demonstrates the ability of a 'single-dose' CMV-based vaccine strategy to induce durable protection, and supports the potential for a tetanus vaccine based on CMV to impact the incidence of tetanus in developing countries. Copyright © 2012 Elsevier Ltd. All rights reserved.
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NASA Astrophysics Data System (ADS)
Nur Laily Kurniawati, Alfin; Aulanni'am; Srihardyastutie, Arie; Safitri, Anna
2018-01-01
The aim of this research is to study antidiabetic activity of root extract of Ruellia tuberosa L on rats (Rattus novergicus) induced by multiple-low dose streptozotocin as animal diabetic models. The parameters investigated were blood glucose levels, free radicals (MDA, malondialdehyde) levels and hepatic histopathology. The main materials used were n-hexane root extracts from Ruellia tuberosa L. Three groups of rats, including control group (group I), diabetic group (group II), and therapy group with Ruellia tuberosa L (group III), were used. Streptozotocin was given at multiple-low dose of 20 mg/kg of body weight for 5 times in 5 consecutive days i.p. to rats in groups II and III. The Ruellia tuberosa L extracts were then given orally for group III in the dose of 250 mg/kg of body weight per day for 3 weeks. Results of the current work showed that root extract Ruellia tuberosa L had lowered blood glucose levels on rats in group III by 60.3%, from 299.7 ± 24.7 mg/dL up to 119.0 ± 26.6 mg/dL. Moreover, the antidiabetic activity of Ruellia tuberosa L extracts also deduced from decrease of MDA levels in group III, from 3.5 ± 0.3 μg/mL up to 1.7 ± 0.4 μg/mL. The recovery of hepatic organ from treatment group has also been proven from the its histology profiles stained with hematoxylin-eosin.
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Prashanth, S.; Kumar, A. Anil; Madhu, B.; Rama, N.; Sagar, J. Vidya
2011-01-01
Aims: To find out the pharmacokinetic and pharmacodynamic drug interaction of carbamazepine, a protype drug used to treat painful diabetic neuropathy with glibenclamide in healthy albino Wistar rats following single and multiple dosage treatment. Materials and Methods: Therapeutic doses (TD) of glibenclamide and TD of carbamazepine were administered to the animals. The blood glucose levels were estimated by GOD/POD method and the plasma glibenclamide concentrations were estimated by a sensitive RP HPLC method to calculate pharmacokinetic parameters. Results: In single dose study the percentage reduction of blood glucose levels and glibenclamide concentrations of rats treated with both carbamazepine and glibenclamide were significantly increased when compared with glibenclamide alone treated rats and the mechanism behind this interaction may be due to inhibition of P-glycoprotein mediated transport of glibenclamide by carbamazepine, but in multiple dose study the percentage reduction of blood glucose levels and glibenclamide concentrations were reduced and it may be due to inhibition of P-glycoprotein mediated transport and induction of CYP2C9, the enzyme through which glibenclamide is metabolised. Conclusions: In the present study there is a pharmacokinetic and pharmacodynamic interaction between carbamazepine and glibenclamide was observed. The possible interaction involves both P-gp and CYP enzymes. To investigate this type of interactions pre-clinically are helpful to avoid drug-drug interactions in clinical situation. PMID:21701639
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Yahya, Noorazrul; Ebert, Martin A; Bulsara, Max; House, Michael J; Kennedy, Angel; Joseph, David J; Denham, James W
2015-11-01
This study aimed to compare urinary dose-symptom correlates after external beam radiotherapy of the prostate using commonly utilised peak-symptom models to multiple-event and event-count models which account for repeated events. Urinary symptoms (dysuria, haematuria, incontinence and frequency) from 754 participants from TROG 03.04-RADAR trial were analysed. Relative (R1-R75 Gy) and absolute (A60-A75Gy) bladder dose-surface area receiving more than a threshold dose and equivalent uniform dose using exponent a (range: a ∈[1 … 100]) were derived. The dose-symptom correlates were analysed using; peak-symptom (logistic), multiple-event (generalised estimating equation) and event-count (negative binomial regression) models. Stronger dose-symptom correlates were found for incontinence and frequency using multiple-event and/or event-count models. For dysuria and haematuria, similar or better relationships were found using peak-symptom models. Dysuria, haematuria and high grade (⩾ 2) incontinence were associated to high dose (R61-R71 Gy). Frequency and low grade (⩾ 1) incontinence were associated to low and intermediate dose-surface parameters (R13-R41Gy). Frequency showed a parallel behaviour (a=1) while dysuria, haematuria and incontinence showed a more serial behaviour (a=4 to a ⩾ 100). Relative dose-surface showed stronger dose-symptom associations. For certain endpoints, the multiple-event and event-count models provide stronger correlates over peak-symptom models. Accounting for multiple events may be advantageous for a more complete understanding of urinary dose-symptom relationships. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.
Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg
2018-05-01
Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.
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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
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76 FR 20513 - Revision of the Requirements for Constituent Materials
Federal Register 2010, 2011, 2012, 2013, 2014
2011-04-13
... in multiple-dose containers must contain a preservative, except that a preservative need not be added... contamination of multiple-dose containers of vaccines that did not contain a preservative.\\2\\ As discussed... Workshop on Thimerosal Vaccines,'' p. 24, August 11, 1999. Preservatives in multiple-dose containers have a...
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Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes.
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.
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Anticholinergics and Central Nervous System Effects: Are We Confused?
Staskin, David R; Zoltan, Edward
2007-01-01
The central nervous system (CNS) effects of anticholinergic agents have been documented in various patient populations and to varying degrees in case reports, brain-activity surrogates, and computerized cognitive testing. The older patient population with overactive bladder represents a group at increased risk of cognitive impairment and other CNS side effects associated with antimuscarinic agents. The complexity of the effect of anticholinergic agents on CNS function requires an increased level of careful investigation. Studies need to be performed in the at-risk population with multiple, validated tests at clinically prescribed doses in acute and chronic situations. These studies need to take into account the effect of commonly prescribed dosing regimens, with doses selected to represent with equivalent bladder potency. The alterations in the serum levels and parent/metabolite effects contributed by metabolic issues or drug delivery systems require special attention. PMID:18231615
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Ouyang, L; Folkerts, M; Lee, H
2015-06-15
Purpose: To perform a dosimetric evaluation on a new developed volumetric modulated arc therapy based total body irradiation (VMAT-TBI). Methods: Three patients were CT scanned with an indexed rotatable body frame to get whole body CT images. Concatenated CT images were imported in Pinnacle treatment planning system and whole body and lung were contoured as PTV and organ at risk, respectively. Treatment plans were generated by matching multiple isocenter volumetric modulated arc (VMAT) fields of the upper body and multiple isocenter parallel-opposed fields of the lower body. For each plan, 1200 cGy in 8 fractions was prescribed to the wholemore » body volume and the lung dose was constrained to a mean dose of 750 cGy. Such a two-level dose plan was achieved by inverse planning of the torso VMAT fields. For comparison, conventional standing TBI (cTBI) plans were generated on the same whole body CT images at an extended SSD (550cm).The shape of compensators and lung blocks are simulated using body segments and lung contours Compensation was calculated based on the patient CT images, in mimic of the standing TBI treatment. The whole body dose distribution of cTBI plans were calculated with a home-developed GPU Monte Carlo dose engine. Calculated cTBI dose distribution was prescribed to the mid-body point at umbilical level. Results: The VMAT-TBI treatment plans of three patients’ plans achieved 80.2%±5.0% coverage of the total body volume within ±10% of the prescription dose, while cTBI treatment plans achieved 72.2%±4.0% coverage of the total body volume. The averaged mean lung dose of all three patients is lower for VMAT-TBI (7.48 cGy) than for cTBI (8.96 cGy). Conclusion: The proposed patient comfort-oriented VMAT-TBI technique provides for a uniform dose distribution within the total body while reducing the dose to the lungs.« less
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Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul
2010-07-01
Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1-4, prednisone at a dose of 1.5 mg/kg also on days 1-4 and thalidomide at a dose of 50-100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1-4 and 1.6, 3.2, or 4.8 g on days 5-35. Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3-4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1-4 followed by 4.8 g p.o. on days 5-35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs.
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Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul
2010-01-01
Background Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. Design and Methods This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1–4, prednisone at a dose of 1.5 mg/kg also on days 1–4 and thalidomide at a dose of 50–100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1–4 and 1.6, 3.2, or 4.8 g on days 5–35. Results Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3–4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. Conclusions This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1–4 followed by 4.8 g p.o. on days 5–35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs (ClinicalTrials.gov Identifier: NCT00406978). PMID:20053869
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Multi-level effects of low dose rate ionizing radiation on southern toad, Anaxyrus [Bufo] terrestris
Stark, Karolina; Scott, David E.; Tsyusko, Olga; ...
2015-04-30
Despite their potential vulnerability to contaminants from exposure at multiple life stages, amphibians are one of the least studied groups of vertebrates in ecotoxicology, and research on radiation effects in amphibians is scarce. We used multiple endpoints to assess the radiosensitivity of the southern toad ( Anaxyrus [Bufo] terrestris) during its pre-terrestrial stages of development –embryonic, larval, and metamorphic. Toads were exposed, from several hours after oviposition through metamorphosis (up to 77 days later), to four low dose rates of ¹³⁷Cs at 0.13, 2.4, 21, and 222 mGy d⁻¹, resulting in total doses up to 15.8 Gy. Radiation treatments didmore » not affect hatching success of embryos, larval survival, or the length of the larval period. The individual family variation in hatching success of embryos was larger than the radiation response. In contrast, newly metamorphosed individuals from the higher dose-rate treatments had higher mass and mass/length body indices, a measure which may relate to higher post-metamorphic survival. The increased mass and index at higher dose rates may indicate that the chronic, low dose rate radiation exposures triggered secondary responses. Additionally, the increases in growth were linked to a decrease in DNA damage (as measured by the Comet Assay) in red blood cells at a dose rate of 21mGy d⁻¹ and a total dose of 1.1 Gy. In conclusion, the complex effects of low dose rates of ionizing radiation may trigger growth and cellular repair mechanisms in amphibian larvae.« less
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Whitehead, Gregory S; Thomas, Seddon Y; Cook, Donald N
2014-01-01
Humans with asthma display considerable heterogeneity with regard to T helper (Th) 2-associated eosinophilic and Th17-associated neutrophilic inflammation, but the impact of the environment on these different forms of asthma is poorly understood. We studied the nature and longevity of asthma-like responses triggered by inhalation of allergen together with environmentally relevant doses of inhaled lipopolysaccharide (LPS). Ovalbumin (OVA) was instilled into the airways of mice together with a wide range of LPS doses. Following a single OVA challenge, or multiple challenges, animals were assessed for pulmonary cytokine production, airway inflammation, and airway hyperresponsiveness (AHR). Mice instilled with OVA together with very low doses (≤10⁻³ μg) of LPS displayed modest amounts of Th2 cytokines, with associated airway eosinophilia and AHR after a single challenge, and these responses were sustained after multiple OVA challenges. When the higher but still environmentally relevant dose of 10⁻¹ μg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia. After multiple OVA challenges, however, the 10⁻¹ μg LPS animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells with high levels of inducible co-stimulatory molecule (ICOS). As a result, asthma-like features in these mice were shorter-lived than in mice sensitized using lower doses of LPS. The nature and longevity of Th2, Th17, and Treg immune responses to inhaled allergen are dependent on the quantity of LPS inhaled at the time of allergic sensitization. These findings might account in part for the heterogeneity of inflammatory infiltrates seen in lungs of asthmatics.
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2012-01-01
Introduction Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Methods In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. Results Seventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. Conclusions The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies. PMID:22340283
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A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors
Rini, Brian I.; Garcia, Jorge A.; Cooney, Matthew M.; Elson, Paul; Tyler, Allison; Beatty, Kristi; Bokar, Joseph; Mekhail, Tarek; Bukowski, R.M.; Budd, G. Thomas; Triozzi, Pierre; Borden, Ernest; Ivy, Percy; Chen, Helen X.; Dolwati, Afshin; Dreicer, Robert
2009-01-01
Purpose Bevacizumab is an antibody against vascular endothelial growth factor (VEGF); sunitinib is an inhibitor of VEGF and related receptors. The safety and maximum tolerated dose (MTD) of sunitinib plus bevacizumab was assessed in this phase I trial. Experimental Design Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level 5 mg/kg) on days 1, 15 and 29 of a 42-day cycle. Dose-limiting toxicities (DLTs) during the first 6-week cycle were used to determine the MTD. Results Thirty-eight patients were enrolled. Pts received a median of 3 cycles of treatment (range, 1–17+). There was one DLT (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed RECIST-defined PR (18%; 95% confidence interval: 8–34%). Nineteen of the 32 patients with a post-baseline scan (59%) had at least some reduction in overall tumor burden (median 32%, range 3–73%). Conclusions The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Anti-tumor activity was observed across multiple solid tumors. PMID:19773375
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Datta, R K; Johnson, E A; Bhattacharjee, G; Stenger, R J
1976-03-01
Administration of a single acute dose (20 mg/kg body weight) of methadone hydrochloride to both male and female mice increased the specific activity of NADPH-cytochrome c reductase and did not change much the content of cytochrome P-450 of their liver microsomes. Administration of multiple acute doses of methadone in male mice increased the specific activity of cytochrome c reductase and the content of cytochrome P-450 of their liver microsomes. Chronic administration of progressively increasing doses of methadone (up to 40 mg/kg body weight) to male mice increased the specific activity of c reductase. Similar chronic administration of methadone up to 28 mg/kg body weight also increased the microsomal content of P-450, but with higher doses of methadone, the content of P-450 declined and finally dropped slightly below control levels. The levels of c reductase activity and P-450 content returned to normal about two weeks after discontinuation of methadone administration.
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NASA Astrophysics Data System (ADS)
Abba, Habu Tela; Hassan, Wan Muhamad Saridan Wan; Saleh, Muneer Aziz; Aliyu, Abubakar Sadiq; Ramli, Ahmad Termizi
2017-11-01
In- situ measurement of terrestrial gamma radiation dose rates (TGRD) was conducted in northern zone of Jos Plateau and a statistical relationship between the TGRD and the underlying geological formations was investigated. The TGRD rates in all the measurements ranged from 40 to 1265 nGy h-1 with a mean value of 250 nGy h-1. The maximum TGDR was recorded on geological type G8 (Younger Granites) at Bisitchi, and the lowest TGDR was recorded on G6 (Basaltic rocks) at Gabia. One way analysis of variance (ANOVA) statistical test was used to compared the data. Significantly, the results of this study inferred a strong relationship between TGRD levels with geological structures of a place. An isodose map was plotted to represent exposure rates due to TGRD. The results of this investigation could be useful for multiple public interest such as evaluating public dose for the area.
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Shamim, Rafat; Srivastava, Shashi; Rastogi, Amit; Kishore, Kamal; Srivastava, Aneesh
2017-01-01
Clonidine, opioids, β-blockers, and dexmedetomidine have been tried to attenuate stress responses during laparoscopic surgery. We evaluated the efficacy of dexmedetomidine in two different doses in attenuating stress responses on patients undergoing laparoscopic pyeloplasty. Ninety patients were assigned to one of the three groups: Group A, Group B, and Group C. Group B received dexmedetomidine 1 mcg/kg as loading dose, followed by 0.7 mcg/kg/h for maintenance; Group C received dexmedetomidine 0.7 mcg/kg as a loading dose, followed by 0.5 mcg/kg/h for maintenance. Group A received normal saline. Stress responses were assessed by the variations in heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels. One-way analysis of variance test was applied. Multiple comparisons between groups were done with post hoc Bonferroni test. The HR and MAP were found to be higher in Group A. The difference was statistically significant ( P < 0.05) during intubation, carbon dioxide insufflation, and extubation when compared with Groups B and C. Blood glucose levels at postintubation and at extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. Serum cortisol levels at postintubation, during midsurgery, and 2 h after extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. However, HR, MAP, blood glucose levels, and serum cortisol levels were similar in dexmedetomidine groups. Dexmedetomidine decreases stress response and provides good condition for maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B.
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Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.
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 .).
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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.
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Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band
2015-02-25
Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. We provide evidence-decreased concomitant heroin use-of low-dose add-on DM's efficacy for treating opioid-dependent patients undergoing MMT. © The Author 2015. Published by Oxford University Press on behalf of CINP.
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Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong
2015-01-01
Background: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Methods: Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Results: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. Conclusions: We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT. PMID:25716777
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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.
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The effects of cannabinoids on serum cortisol and prolactin in humans
Ranganathan, Mohini; Braley, Gabriel; Pittman, Brian; Cooper, Thomas; Perry, Edward; Krystal, John; D’Souza, Deepak Cyril
2010-01-01
Background Cannabis is one of the most widely used illicit substances, and there is growing interest in the therapeutic applications of cannabinoids. While known to modulate neuroendocrine function, the precise acute and chronic dose-related effects of cannabinoids in humans are not well-known. Furthermore, the existing literature on the neuroendocrine effects of cannabinoids is limited by small sample sizes (n=6–22), heterogeneous samples with regard to cannabis exposure (lumping users and nonusers), lack of controlling for chronic cannabis exposure, differing methodologies, and limited dose–response data. Delta-9-tetrahydrocannabinol (Δ-9-THC) was hypothesized to produce dose-related increases in plasma cortisol levels and decreases in plasma prolactin levels. Furthermore, relative to controls, frequent users of cannabis were hypothesized to show altered baseline levels of these hormones and blunted Δ-9-THC-induced changes of these hormones. Materials and methods Pooled data from a series of laboratory studies with multiple doses of intravenous Δ-9-THC in healthy control subjects (n=36) and frequent users of cannabis (n=40) was examined to characterize the acute, chronic, and acute on chronic effects of cannabinoids on plasma cortisol and prolactin levels. Hormone levels were measured before (baseline) and 70 min after administration of each dose of Δ-9-THC. Data were analyzed using linear mixed models with +70 min hormonal levels as the dependant variable and baseline hormonal level as the covariate. Results At socially relevant doses, Δ-9-THC raised plasma cortisol levels in a dose-dependent manner but frequent users showed blunted increases relative to healthy controls. Frequent users also had lower baseline plasma prolactin levels relative to healthy controls. Conclusions These group differences may be related to the development of tolerance to the neuroendocrine effects of cannabinoids. Alternatively, these results may reflect inherent differences in neuroendocrine function in frequent users of cannabis and not a consequence of cannabis use. PMID:19083209
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Cornfeld, Daniel; Israel, Gary; Detroy, Ezra; Bokhari, Jamal; Mojibian, Hamid
2011-03-01
The purpose of the study was to quantify the radiation dose reduction achieved when imaging the aorta using Adaptive Statistical Iterative Reconstruction (ASIR) and to determine if this has an effect on image quality. We retrospectively reviewed 31 CT angiography examinations of the thoracic and abdominal aorta performed with ASIR and 32 consecutive similar examinations performed without ASIR. Volume CT dose index (CTDI(vol)), dose-length product (DLP), aortic enhancement at multiple levels, aorta-to-muscle contrast-to-noise ratio at multiple levels, and subjective image quality were compared between the two groups. The mean CTDI(vol) and DLP were significantly lower for the studies performed with ASIR versus studies without ASIR (15.6 vs 21.5 mGy, with an average difference of 5.8 mGy [95% CI 2.3-9.4 mGy] and 818 vs 1075 mGy × cm with an average difference of -257 mGy × cm [54-460 mGy × cm], respectively). Aortic enhancement, aortic signal-to-noise ratio, and aortic to muscle contrast-to-noise ratio were not different between the two groups. Subjectively, one reviewer preferred the non-ASIR images and one found the images equivalent. Both reviewers believed the images were of diagnostic quality. A 29% decrease in CTDI(vol) and a 20% decrease in DLP were obtained in scans with ASIR compared with scans without ASIR, without a quantitative loss of image quality.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Szrom, Fran; Falo, Gerald A.; Lodde, Gordon M.
2009-03-01
Depleted uranium (DU) intake rates and subsequent dose rates were estimated for personnel entering armored combat vehicles perforated with DU penetrators (level II and level III personnel) using data generated during the Capstone Depleted Uranium (DU) Aerosol Study. Inhalation intake rates and associated dose rates were estimated from cascade impactors worn by sample recovery personnel and from cascade impactors that served as area monitors. Ingestion intake rates and associated dose rates were estimated from cotton gloves worn by sample recovery personnel and from wipe test samples from the interior of vehicles perforated with large caliber DU munitions. The mean DUmore » inhalation intake rate for level II personnel ranged from 0.447 mg h-1 based on breathing zone monitor data (in and around a perforated vehicle) to 14.5 mg h-1 based on area monitor data (in a perforated vehicle). The mean DU ingestion intake rate for level II ranged from 4.8 mg h-1 to 38.9 mg h-1 based on the wipe test data including surface to glove transfer factors derived from the Capstone data. Based on glove contamination data, the mean DU ingestion intake rates for level II and level III personnel were 10.6 mg h-1 was and 1.78 mg h-1, respectively. Effective dose rates and peak kidney uranium concentration rates were calculated based on the intake rates. The peak kidney uranium concentration rate cannot be multiplied by the total exposure duration when multiple intakes occur because uranium will clear from the kidney between the exposures.« less
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21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.
Code of Federal Regulations, 2011 CFR
2011-04-01
... vivo bioavailability study. 320.27 Section 320.27 Food and Drugs FOOD AND DRUG ADMINISTRATION... Guidelines on the design of a multiple-dose in vivo bioavailability study. (a) Basic principles. (1) In... labeling of the test product. (3) A multiple-dose study may be required to determine the bioavailability of...
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A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray.
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.
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Elias, A D; Wheeler, C; Ayash, L J; Schwartz, G; Ibrahim, J; Mills, L; McCauley, M; Coleman, N; Warren, D; Schnipper, L; Antman, K H; Teicher, B A; Frei, E
1998-06-01
Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain, predominantly in stocking glove distribution, occurring between day -3 and day 0, and a sensory peripheral neuropathy with similar distribution peaking around day +60. The maximal achievable dose of etanidazole (16 g/m2 dose level) resulted in a mean serum level of 38 micrograms/ml (25-55 micrograms/ml). Etanidazole significantly enhanced host toxicity of high-dose ICE. Effective modulatory doses of etanidazole could not be given with acceptable toxicity using this schedule.
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Lublin, Fred D; Bowen, James D; Huddlestone, John; Kremenchutzky, Marcelo; Carpenter, Adam; Corboy, John R; Freedman, Mark S; Krupp, Lauren; Paulo, Corri; Hariri, Robert J; Fischkoff, Steven A
2014-11-01
Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection. PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
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Porter, W P; Jaeger, J W; Carlson, I H
1999-01-01
This paper describes the results of 5 years of research on interactive effects of mixtures of aldicarb, atrazine, and nitrate on endocrine, immune, and nervous system function. The concentrations of chemicals used were the same order of magnitude as current maximum contaminant levels (MCLs) for all three compounds. Such levels occur in groundwater across the United States. Dosing was through voluntary consumption of drinking water. We used fractional and full factorial designs with center replicates to determine multifactor effects. We used chronic doses in experiments that varied in duration from 22 to 103 days. We tested for changes in thyroid hormone levels, ability to make antibodies to foreign proteins, and aggression in wild deer mice, Peromyscus maniculatus, and white outbred Swiss Webster mice, Mus musculus, ND4 strain. Endocrine, immune, and behavior changes occurred due to doses of mixtures, but rarely due to single compounds at the same concentrations. Immune assay data suggest the possibility of seasonal effects at low doses. We present a multiple-level model to help interpret the data in the context of human health and biological conservation concerns. We discuss six testing deficiencies of currently registered pesticides, and suggest areas of human health concerns if present trends in pesticide use continue.
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Glue, Paul; Cape, Gavin; Tunnicliff, Donna; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, C Tak; Harland, Sarah; Devane, Jane; Crockett, R S; Howes, John; Darpo, Borje; Zhou, Meijian; Weis, Holger; Friedhoff, Lawrence
2016-11-01
Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and C max and was slowly eliminated (mean t 1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues. © 2016, The American College of Clinical Pharmacology.
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Whitehead, Gregory S.; Thomas, Seddon Y.
2013-01-01
Background: Humans with asthma display considerable heterogeneity with regard to T helper (Th) 2–associated eosinophilic and Th17-associated neutrophilic inflammation, but the impact of the environment on these different forms of asthma is poorly understood. Objective: We studied the nature and longevity of asthma-like responses triggered by inhalation of allergen together with environmentally relevant doses of inhaled lipopolysaccharide (LPS). Methods: Ovalbumin (OVA) was instilled into the airways of mice together with a wide range of LPS doses. Following a single OVA challenge, or multiple challenges, animals were assessed for pulmonary cytokine production, airway inflammation, and airway hyperresponsiveness (AHR). Results: Mice instilled with OVA together with very low doses (≤ 10–3 μg) of LPS displayed modest amounts of Th2 cytokines, with associated airway eosinophilia and AHR after a single challenge, and these responses were sustained after multiple OVA challenges. When the higher but still environmentally relevant dose of 10–1 μg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia. After multiple OVA challenges, however, the 10–1 μg LPS animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells with high levels of inducible co-stimulatory molecule (ICOS). As a result, asthma-like features in these mice were shorter-lived than in mice sensitized using lower doses of LPS. Conclusions: The nature and longevity of Th2, Th17, and Treg immune responses to inhaled allergen are dependent on the quantity of LPS inhaled at the time of allergic sensitization. These findings might account in part for the heterogeneity of inflammatory infiltrates seen in lungs of asthmatics. Citation: Whitehead GS, Thomas SY, Cook DN. 2014. Modulation of distinct asthmatic phenotypes in mice by dose-dependent inhalation of microbial products. Environ Health Perspect 122:34–42; http://dx.doi.org/10.1289/ehp.1307280 PMID:24168764
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Amirshahrokhi, K; Ghazi-Khansari, M
2012-11-01
Thalidomide is an immunomodulatory and anti-inflammatory agent and is used in autoimmune disorders. It has been shown that thalidomide inhibits proinflammatory cytokines production. The purpose of this study was to investigate the effect of thalidomide on the prevention of autoimmune diabetes in mice. Diabetes was induced by multiple low-dose of streptozotocin (MLDS) injection. Mice were treated with thalidomide (300 mg/kg/day orally) for 21 days. Plasma levels of glucose, insulin and nitrate/nitrite as well as pancreatic cytokine levels were measured. Pathological examinations of the pancreas revealed that thalidomide reduced the islet inflammation (insulitis) and destruction of beta cells. Thalidomide treatment prevented hyperglycemia and preserved pancreatic insulin secretion in the diabetic mice. Thalidomide treatment also significantly decreased plasma levels of nitric oxide and pancreatic proinflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-12, IL-17 and interferon (IFN)-γ)] while increased anti-inflammatory cytokine IL-10. In conclusion, these findings indicate that thalidomide may have a protective effect against the autoimmune destruction of the pancreatic beta-cells during the development of MLDS-induced type 1 diabetes in mice. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Pozolotina, Vera N; Antonova, Elena V
2017-03-01
The multiple stressors, in different combinations, may impact differently upon seed quality, and low-level doses of radiation may enhance synergistic or antagonistic effects. During 1991-2014 we investigated the quality of the dandelion (Taraxacum officinale s.l.) seed progeny growing under low-level radiation exposure at the East-Ural Radioactive Trace (EURT) area (result of the Kyshtym accident, Russia), and in plants from areas exposed to background radiation. The viability of the dandelion seed progeny was assessed according to chronic radiation exposure, accounting for the variability of weather conditions among years. Environmental factors (temperature, precipitation, and their ratio in different months) can modify the radiobiological effects. We found a wide range of possible responses to multiple stressors: inhibition, stimulation, and indifferent effects in different seasons. The intraspecific variability of the quality of dandelion seed progeny was greatly increased under conditions of low doses of chronic irradiation. Temperature was the most significant factor for seed progeny formation in the EURT zone, whereas the sums of precipitation and ratios of precipitation to temperature dominantly affected organisms from the background population.
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Gilbert, J; Baker, S D; Bowling, M K; Grochow, L; Figg, W D; Zabelina, Y; Donehower, R C; Carducci, M A
2001-08-01
Phenylbutyrate (PB) is an aromatic fatty acid with multiple mechanisms of action including histone deacetylase inhibition. Preclinically, PB demonstrates both cytotoxic and differentiating effects at a concentration of 0.5 mM. We conducted a Phase I trial of p.o. PB patients with refractory solid tumor malignancies to evaluate toxicity, pharmacokinetic parameters, and feasibility of p.o. administration. Twenty-eight patients with refractory solid tumor malignancies were enrolled on this dose-escalation to maximally tolerated dose trial. Five dose levels of PB were studied: 9 g/day (n = 4), 18 g/day (n = 4), 27 g/day (n = 4), 36 g/day (n = 12), and 45 g/day (n = 4). Pharmacokinetic studies were performed and included an p.o. bioavailability determination. Compliance data were also collected. The recommended Phase II dose is 27 g/day. Overall the drug was well tolerated with the most common toxicities being grade 1-2 dyspepsia and fatigue. Nonoverlapping dose-limiting toxicities of nausea/vomiting and hypocalcemia were seen at 36 g/day. The p.o. bioavailability of PB was 78% for all dose levels, and the biologically active concentration of 0.5 mM was achieved at all dose levels. Compliance was excellent with 93.5% of all possible doses taken. No partial remission or complete remission was seen, but 7 patients had stable disease for more than 6 months while on the drug. PB (p.o.) is well tolerated and achieves the concentration in vivo that has been shown to have biological activity in vitro. PB may have a role as a cytostatic agent and should be additionally explored in combination with cytotoxics and other novel drugs.
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Ten-year oral toxicity study with Norlestrin in rhesus monkeys.
Fitzgerald, J; de la Iglesia, F; Goldenthal, E I
1982-12-01
The long term effects of the oral contraceptive, Norlestrin, were evaluated in sexually mature female rhesus (Macaca mulatta) monkeys over a 10 year period. Norlestrin, a combination of norethindrone acetate and ethinylestradiol (50:1) was given orally on a continuous cyclic regimen of 21 d of dosing followed by 7 d without treatment. Groups of 16 monkeys each received the drug at dose levels of 0.05, 0.51, and 2.55 mg/kg representing multiples of 1, 10, and 50 times the human dose, respectively. A comparable group of 16 animals remained untreated and served as controls. Selected clinical and laboratory parameters were monitored throughout the study and all animals were necropsied and evaluated for gross and histopathologic changes. All dose levels were well tolerated and survival was not affected. There were no consistent treatment-related alterations in coagulation or other clinical laboratory parameters. Ophthalmologically, macular pigmentary anomalies were observed in all groups. Treatment-associated pathologic findings, representing exaggerated pharmacological responses with superimposed senile changes, including ovarian and uterine atrophy and dilatation of acini and ducts in the mammary gland. Periodic vaginal cytologic examination and mammary gland palpation did not demonstrate drug related changes. A small number of neoplasms was seen in all groups and a granulosa cell carcinoma of the ovary occurred in a control animal. The benign tumors consisted of three cutaneous papillomas: one in a low dose and one in a high dose animal, a uterine leiomyoma in one high dose animal, and a pancreatic duct adenoma in one low dose animal. The results of this study indicate that Norlestrin had no significant toxic manifestations or tumorigenic potential when administered on a cyclic regimen to female rhesus monkeys at levels up to 50 times the human dose for ten yr.
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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
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Parkinson, Craig; Burman, Pia; Messig, Michael; Trainer, Peter J
2007-01-01
To effectively normalize IGF-I in patients with acromegaly, various covariates may affect dosing and plasma concentrations of pegvisomant. We assessed whether sex, age, weight, and previous radiotherapy influence dosing of pegvisomant in patients with active disease. Data from 69 men and 49 women participating in multicenter, open-label trials of pegvisomant were retrospectively evaluated using multiple regression techniques. Sixty-nine subjects (39 men, 30 women) had undergone external beam pituitary radiotherapy. Serum IGF-I was at least 30% above age-related upper limit of normal in all patients at study entry. After a loading dose of pegvisomant (80 mg), patients were commenced on 10 mg/d. Pegvisomant dose was adjusted by 5 mg every eighth week until serum IGF-I was normalized. At baseline, men had significantly higher mean serum IGF-I levels than women despite similar GH levels. After treatment with pegvisomant, IGF-I levels were similar in men and women. A significant correlation between baseline GH, IGF-I, body weight, and the dose of pegvisomant required to normalize serum IGF-I was observed (all P < 0.001). Women required an average of 0.04 mg/kg more pegvisomant than men and a mean weight-corrected dose of 19.2 mg/d to normalize serum IGF-I [14.5 mg/d (men); P < 0.001]. Patients treated with radiotherapy required less pegvisomant to normalize serum IGF-I despite similar baseline GH/IGF-I levels (15.2 vs. 18.5 mg/d for no previous radiotherapy; P = 0.002). Sex, body weight, previous radiotherapy, and baseline GH/IGF-I influence the dose of pegvisomant required to normalize serum IGF-I in patients with active acromegaly.
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Kahraman, Korhan; Berker, Bulent; Atabekoglu, Cem Somer; Sonmezer, Murat; Cetinkaya, Esra; Aytac, Rusen; Satiroglu, Hakan
2009-06-01
To compare the efficacy of microdose GnRH agonist (GnRH-a) flare-up and multiple dose GnRH antagonist protocols in patients who have a poor response to a long luteal GnRH-a protocol. Prospective, randomized, clinical study. University hospital. Forty-two poor responder patients undergoing intracytoplasmic sperm injection (ICSI)-embryo transfer cycle. Twenty-one patients received microdose leuprolide acetate (LA) (50 microg twice daily) starting on the second day of withdrawal bleeding. The other 21 patients received 0.25 mg of cetrorelix daily when the leading follicle reached 14 mm in diameter. Serum E(2) levels, number of growing follicles and mature oocytes, embryo quality, dose of gonadotropin used, cancellation, fertilization, implantation rate and pregnancy rate (PR). The mean serum E(2) concentration on the day of hCG administration was significantly higher in the microdose GnRH-a group than in the GnRH antagonist group (1,904 vs. 1,362 pg/mL). The clinical PRs per started cycle of microdose GnRH-a and GnRH antagonist groups were 14.2% and 9.5%, respectively. There were no statistically significant differences in the other ovulation induction characteristics, fertilization and implantation rates. Microdose GnRH-a flare-up protocol and multiple dose GnRH antagonist protocol seem to have similar efficacy in improving treatment outcomes of poor responder patients.
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Acharya, Santhosh; Bhat, N N; Joseph, Praveen; Sanjeev, Ganesh; Sreedevi, B; Narayana, Y
2011-05-01
The effects of single pulses and multiple pulses of 7 MV electrons on micronuclei (MN) induction in cytokinesis-blocked human peripheral blood lymphocytes (PBLs) were investigated over a wide range of dose rates per pulse (instantaneous dose rate). PBLs were exposed to graded doses of 2, 3, 4, 6, and 8 Gy of single electron pulses of varying pulse widths at different dose rates per pulse, ranging from 1 × 10(6) Gy s(-1) to 3.2 × 10(8) Gy s(-1). Different dose rates per pulse were achieved by changing the dose per electron pulse by adjusting the beam current and pulse width. MN yields per unit absorbed dose after irradiation with single electron pulses were compared with those of multiple pulses of electrons. A significant decrease in the MN yield with increasing dose rates per pulse was observed, when dose was delivered by a single electron pulse. However, no reduction in the MN yield was observed when dose was delivered by multiple pulses of electrons. The decrease in the yield at high dose rates per pulse suggests possible radical recombination, which leads to decreased biological damage. Cellular response to the presence of very large numbers of chromosomal breaks may also alter the damage.
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Wu, Lin-Lin; Gong, Wei; Shen, Si-Peng; Wang, Zhong-He; Yao, Jia-Xi; Wang, Jun; Yu, Jing; Gao, Rong; Wu, Gang
2017-09-01
Excessive metal exposure has been recognized as one of the detrimental factors for brain damage. However, the potential adverse effects induced by heavy metals on monoamine neurotransmitter pathways remains poorly understood. Our study aimed to investigate the possible association between metal exposure and neurotransmitter metabolism. By a cross-sectional investigation, 224 electroplating workers and 213 non-electroplating exposure workers were recruited in the exposure and control groups. Metal exposure levels were analyzed using inductively-coupled plasma mass spectrometry and monoamine neurotransmitter pathway metabolites were measured by ultra-performance liquid chromatography tandem mass spectrometry in human urine samples. Multivariate linear regression model was used to assess the dose-response relationships of urinary metals and neurotransmitter pathway metabolites. Significant dose-dependent trends of urinary vanadium quartiles with all metabolites were observed, and the trends demonstrated significance after multiple testing correction. It also showed that urinary chromium levels were significantly associated with decreased serotonin level and cadmium was positively associated with norepinephrine and epinephrine. In addition, arsenic was positively associated with tryptophan, serotonin, dopamine and norepinephrine. Iron was positively associated with increased homovanillic acid (HVA) and epinephrine while nickel was negatively associated with increased epinephrine levels. Zinc was positively related to tryptophan, kynurenin (KYN), 5-hydroxyindole acetic acid (5-HIAA), dopamine, HVA and norepinephrine. There was no significant association between urinary copper with any other metabolites after adjusting of multiple metal models. Metal exposure may be associated with neurotransmitter metabolism disturbances. The present work is expected to provide some support in the prevention and management of metal-associated neurological diseases. Copyright © 2017. Published by Elsevier Ltd.
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Rao, C V; Rivenson, A; Kelloff, G J; Reddy, B S
1995-01-01
The chemopreventive effect of 40 and 80% maximum tolerated dose (MTD) levels of ascorbylpalmitate (AP), carbenoxolone (CBX), dimethylfumarate (DMF) and p-methoxyphenol (p-MP) administrated in the diet before and during initiation and postinitiation phases of azoxymethane (AOM)-induced colon carcinogenesis was studied in male F344 rats. The MTD levels of AP, CBX, DMF and p-MP were determined in male F344 rats and found to be 5000 1500, 1000 and 1000 ppm, respectively, in modified AIN-76A diet. Based on these MTD values, 40 and 80% MTD levels of each agent was tested for their efficacy in color carcinogenesis. At 5 weeks of age, groups of animals were fed the control (modified AIN-76A diet or diets containing 40 and 80% MTD levels of each AP, CBX, DMF and p-MP. At 7 weeks of age, all animals, except those in the vehicle (normal saline)-treated groups, were given two weekly s.c. injections of AOM at a dose rate of 15 mg/kg body weight/week. All groups were continued on their respective dietary regimen until the termination of the experiment 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. The results indicate that dietary administration of 40% MTD of AP significantly inhibited multiplicities (tumor/animal) of noninvasive and total (invasive plus noninvasive) adenocarcinoma of the colon (P < 0.05) and 80% MTD of AP significantly inhibited the incidence (% animals with tumors) and the multiplicities of invasive and total adenocarcinomas of the colon (P < 0.01). Dietary CBX at 40 and 80% MTD levels suppressed the incidence and multiplicities of invasive and total adenocarcinomas (P < 0.05 to 0.001) whereas 40 and 80% MTD of DMF and p-MP had significantly inhibited invasive adenocarcinoma incidence and multiplicity (P < 0.05 to 0.001). However, DMF and p-MP had no significant effect on noninvasive and total adenocarcinoma incidence and multiplicity (P > 0.05). These results suggest that AP and CBX possess potential chemopreventive properties against colon cancer.
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Measurement of skin dose from cone-beam computed tomography imaging.
Akyalcin, Sercan; English, Jeryl D; Abramovitch, Kenneth M; Rong, Xiujiang J
2013-10-09
To measure surface skin dose from various cone-beam computed tomography (CBCT) scanners using point-dosimeters. A head anthropomorphic phantom was used with nanoDOT optically stimulated luminescence (OSL) dosimeters (Landauer Corp., Glenwood, IL) attached to various anatomic landmarks. The phantom was scanned using multiple exposure protocols for craniofacial evaluations in three different CBCT units and a conventional x-ray imaging system. The dosimeters were calibrated for each of the scan protocols on the different imaging systems. Peak skin dose and surface doses at the eye lens, thyroid, submandibular and parotid gland levels were measured. The measured skin doses ranged from 0.09 to 4.62 mGy depending on dosimeter positions and imaging systems. The average surface doses to the lens locations were ~4.0 mGy, well below the threshold for cataractogenesis (500 mGy). The results changed accordingly with x-ray tube output (mAs and kV) and also were sensitive to scan field of view (SFOV). As compared to the conventional panoramic and cephalometric imaging system, doses from all three CBCT systems were at least an order of magnitude higher. Peak skin dose and surface doses at the eye lens, thyroid, and salivary gland levels measured from the CBCT imaging systems were lower than the thresholds to induce deterministic effects. However, our findings do not justify the routine use of CBCT imaging in orthodontics considering the lifetime-attributable risk to the individual.
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Measurement of skin dose from cone-beam computed tomography imaging
2013-01-01
Objective To measure surface skin dose from various cone-beam computed tomography (CBCT) scanners using point-dosimeters. Materials & methods A head anthropomorphic phantom was used with nanoDOT optically stimulated luminescence (OSL) dosimeters (Landauer Corp., Glenwood, IL) attached to various anatomic landmarks. The phantom was scanned using multiple exposure protocols for craniofacial evaluations in three different CBCT units and a conventional x-ray imaging system. The dosimeters were calibrated for each of the scan protocols on the different imaging systems. Peak skin dose and surface doses at the eye lens, thyroid, submandibular and parotid gland levels were measured. Results The measured skin doses ranged from 0.09 to 4.62 mGy depending on dosimeter positions and imaging systems. The average surface doses to the lens locations were ~4.0 mGy, well below the threshold for cataractogenesis (500 mGy). The results changed accordingly with x-ray tube output (mAs and kV) and also were sensitive to scan field of view (SFOV). As compared to the conventional panoramic and cephalometric imaging system, doses from all three CBCT systems were at least an order of magnitude higher. Conclusions Peak skin dose and surface doses at the eye lens, thyroid, and salivary gland levels measured from the CBCT imaging systems were lower than the thresholds to induce deterministic effects. However, our findings do not justify the routine use of CBCT imaging in orthodontics considering the lifetime-attributable risk to the individual. PMID:24192155
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Weed, Michael R; Wilcox, Kristin M; Ator, Nancy A; Hienz, Robert D
2008-06-01
Alcohol abuse is a major public health burden that can lead to many adverse health effects such as impaired hepatic, gastrointestinal, central nervous system and immune system function. Preclinical animal models of alcohol abuse allow for experimental control over variables often difficult to control in human clinical studies (e.g., ethanol exposure before or during the study, history of other drug use, access to medical care, nutritional status, etc). Nonhuman primate models in particular provide increased genetic, anatomic and physiologic similarity to humans, relative to rodent models. A small percentage of macaques will spontaneously consume large quantities of ethanol; however, most nonhuman primate models of "voluntary" ethanol intake produce relatively low daily ethanol intake in the majority of monkeys. To facilitate study of chronic exposure to high levels of ethanol intake, a macaque model has been developed that induces consistent, daily high-level ethanol consumption. This multiple-session procedure employed 4 drinking sessions per day, with sessions occurring once every 6 hours. The group average alcohol consumption was 4.6 g/kg/d (SEM 0.4), roughly twice the group average consumption of previous reports. Ethanol drinking sessions produced group mean blood ethanol levels of 95 mg/dl after 60 minutes, and fine motor control was impaired up to 90 minutes after a drinking session. This model of multiple-session, limited access, oral ethanol self-dosing produced consistent, high-level ethanol consumption with each session qualifying as a "binge" drinking session using the definition of "binge" provided by the NIAAA (>80 mg/dl/session). This model of ethanol drinking in macaques will be of great utility in the study of immunological, physiological and behavioral effects of ethanol in nonhuman primates.
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Toye, Warren; Das, Ram; Kron, Tomas; Franich, Rick; Johnston, Peter; Duchesne, Gillian
2009-05-01
To develop an in vivo dosimetry based investigative action level relevant for a corrective protocol for HDR brachytherapy boost treatment. The dose delivered to points within the urethra and rectum was measured using TLD in vivo dosimetry in 56 patients. Comparisons between the urethral and rectal measurements and TPS calculations showed differences, which are related to the relative position of the implant and TLD trains, and allowed shifts of implant position relative to the prostate to be estimated. Analysis of rectal dose measurements is consistent with implant movement, which was previously only identified with the urethral data. Shift corrected doses were compared with results from the TPS. Comparison of peak doses to the urethra and rectum has been assessed against the proposed corrective protocol to limit overdosing these critical structures. An initial investigative level of 20% difference between measured and TPS peak dose was established, which corresponds to 1/3 of patients which was practical for the caseload. These patients were assessed resulting in corrective action being applied for one patient. Multiple triggering for selective investigative action is outlined. The use of a single in vivo measurement in the first fraction optimizes patient benefit at acceptable cost.
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A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats.
Cancel, Aida M; Dillberger, John E; Kelly, Catherine M; Bolte, Henry F; Creasy, Dianne M; Sokal, David C
2010-03-01
This study investigated if quinacrine can induce a tumorigenic response in rats when administered in a manner similar to the intended human use for female non-surgical sterilization. Young sexually mature female rats received two doses of quinacrine (or 1% methylcellulose control) into each uterine horn approximately 21 days apart, and were observed for 23 months after the second dose administration. Dose levels were 0/0, 0/0, 10/10, 70/70, and 70/250-350 mg/kg (first dose/second dose), which represent local doses in the uterus at approximate multiples of 1x, 8x and 40x the human dose (mg quinacrine/g uterine weight) used for female non-surgical sterilization. Rats were observed for viability, clinical signs of toxicity, and changes in body weight and food consumption. At necropsy, selected organs were weighed, macroscopic observations were recorded, and tissues were collected, fixed, processed, and examined for microscopic pathologic findings. Acute quinacrine toxicity was evident during the dosing period but did not affect long-term survival. Non-neoplastic findings were more common in treated animals than controls, providing evidence of the appropriateness of the bioassay. The incidence of uncommon tumors of the reproductive tract was similar to controls at doses of 10/10mg/kg but increased with dose level and was significantly greater than controls at >or=70/70 mg/kg. We conclude that two doses of quinacrine administered approximately 21 days apart into the uterus of young sexually mature rats at a local dose approximately 8 times the human dose used for non-surgical female sterilization increased the lifetime risk of tumor development in the reproductive tract. (c) 2009 Elsevier Inc. All rights reserved.
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Intermittent preventive treatment of malaria during pregnancy in central Mozambique.
Brentlinger, Paula E; Dgedge, Martinho; Correia, Maria Ana Chadreque; Rojas, Ana Judith Blanco; Saúte, Francisco; Gimbel-Sherr, Kenneth H; Stubbs, Benjamin A; Mercer, Mary Anne; Gloyd, Stephen
2007-11-01
New WHO strategies for control of malaria in pregnancy (MiP) recommend intermittent preventive treatment (IPTp), bednet use and improved case management. A pilot MiP programme in Mozambique was designed to determine requirements for scale-up. The Ministry of Health worked with a nongovernmental organization and an academic institution to establish and monitor a pilot programme in two impoverished malaria-endemic districts. Implementing the pilot programme required provision of additional sulfadoxine-pyrimethamine (SP), materials for directly observed SP administration, bednets and a modified antenatal card. National-level formulary restrictions on SP needed to be waived. The original protocol required modification because imprecision in estimation of gestational age led to missed SP doses. Multiple incompatibilities with other health initiatives (including programmes for control of syphilis, anaemia and HIV) were discovered and overcome. Key outputs and impacts were measured; 92.5% of 7911 women received at least 1 dose of SP, with the mean number of SP doses received being 2.2. At the second antenatal visit, 13.5% of women used bednets. In subgroups (1167 for laboratory analyses; 2600 births), SP use was significantly associated with higher haemoglobin levels (10.9 g/dL if 3 doses, 10.3 if none), less malaria parasitaemia (prevalence 7.5% if 3 doses, 39.3% if none), and fewer low-birth-weight infants (7.3% if 3 doses, 12.5% if none). National-level scale-up will require attention to staffing, supplies, bednet availability, drug policy, gestational-age estimation and harmonization of vertical initiatives.
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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.
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Oduro, Abraham R.; Fryauff, David J.; Koram, Kwadwo A.; Rogers, William O.; Anto, Francis; Atuguba, Frank; Anyorigiya, Thomas; Adjuik, Martin; Ansah, Patrick; Hodgson, Abraham; Nkrumah, Francis
2010-01-01
Demographics and health practices of 2,232 pregnant women in rural northeastern Ghana and characteristics of their 2,279 newborns were analyzed to determine benefits associated with intermittent preventive treatment (IPTp), antenatal care, and/or bed net use during pregnancy. More than half reported bed net use, 90% reported at least two antenatal care visits, and > 82% took at least one IPTp dose of sulfadoxine-pyrimethamine. Most used a bed net and IPTp (45%) or IPTp alone (38%). Low birth weight (< 2,500 grams) characterized 18.3% of the newborns and was significantly associated with female sex, Nankam ethnicity, first-born status, and multiple births. Among newborns of primigravidae, IPTp was associated with a significantly greater birth weight, significantly fewer low birth weight newborns, improved hemoglobin levels, and less anemia. Babies of multigravidae derived no benefit to birth weight or hemoglobin level from single or multiple doses of sulfadoxine-pyrimethamine during pregnancy. No differences or benefits were seen when a bed net was the only protective factor. PMID:20595482
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Sheehan, Daniel M.
2006-01-15
We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated onmore » a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.« less
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An environmental-level, real-time, pulsed photon dosemeter.
Olsher, R H; Frymire, A; Gregoire, T
2005-01-01
Radiation sources producing short pulses of photon radiation are widespread. Such sources include electron linear accelerators and field emission impulse generators. It is often desirable to measure leakage and skyshine radiation for these sources in real time and at environmental levels as low as 0.02 microSv per pulse. This note provides an overview of the design and performance of a commercial, real-time, pulsed photon dosemeter (PPD) capable of single-pulse dose measurements over the range from 0.02 to 20 microSv. The PPD may also be operated in a multiple-pulse mode that integrates the dose from a train of pulses over a 3 s period. A pulse repetition rate of up to 300 Hz is accommodated.
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Sutiman, Natalia; Zhang, Zhenxian; Tan, Eng Huat; Ang, Mei Kim; Tan, Shao-Weng Daniel; Toh, Chee Keong; Ng, Quan Sing; Chowbay, Balram; Lim, Wan-Teck
2016-01-01
Purpose This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC). Methods This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily. Results The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group. Conclusions Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups. Trial Registration ClinicalTrials.gov NCT00702182 PMID:27135612
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In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy.
Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W
2012-01-01
Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle's geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.
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Chandra, Kumar P; Shiwalkar, Ajay; Kotecha, Jignesh; Thakkar, Purav; Srivastava, Ambrish; Chauthaiwale, Vijay; Sharma, Sanjay K; Cross, Maurice R; Dutt, Chaitanya
2009-01-01
Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic complications through a variety of mechanisms including endothelial dysfunction and structural abnormalities in the vasculature and myocardium. Reducing the AGEs burden and their ensuing pro-inflammatory, pro-oxidative and pro-coagulant effect with associated dysfunctional proteins in various target tissues may retard the progression of and even reverse diabetic macro- and microvascular complications. Pyridinium, 3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]-chloride (TRC4186) has demonstrated AGE-breaking activities in in vitro experiments and improvement in the endothelial and myocardial function in animal models of diabetes mellitus with reduction of AGEs accumulation in tissues over time. The safety of TRC4186 has been established in in vitro and in vivo preclinical studies. Thus, this drug is being developed for the treatment of complications associated with diabetes. This investigation set out to evaluate the safety, tolerability and pharmacokinetics of TRC4186 in healthy human subjects after single and multiple ascending doses, fixed doses in elderly male and female subjects, and with food and different formulations of the compound. Four studies were conducted during phase I clinical development of TRC4186. These were: (i) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in healthy male subjects with doses of TRC4186 ranging from 250 to 2500 mg administered as an oral solution (total six doses); (ii) a randomized, double-blind, placebo-controlled, multiple-dose, dose-ascending study in healthy male subjects with three doses of TRC4186 ranging from 500 to 2000 mg twice daily for 6 days with a final single dose on day 7; (iii) a randomized, open-label, three-way crossover study to assess the effect of food (fasted vs fed) and formulation (solution vs tablet) with TRC4186 500 mg; (iv) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in elderly male and female subjects at a dose of TRC4186 500 mg followed by TRC4186 1000 mg after a 7-day washout period. The safety and tolerability of TRC4186 were assessed by considering adverse events (AEs), ECG findings, vital signs and laboratory investigation results. TRC4186 was rapidly absorbed, with maximum plasma concentrations (C(max)) attained within 1-4 hours. C(max) and area under the plasma concentration-time curve (AUC) were dose proportional over the range 250-2500 mg for a single dose and 500-2000 mg for multiple doses with twice-daily administration. Steady-state conditions were attained within 6 days at different dose levels. C(max) and AUC were not affected by age, sex, race or type of formulation. The tablet formulation of TRC4186 was bioequivalent with the solution form of the drug under fasting conditions and systemic availability of the tablet formulation was reduced by 40% when administered under fed conditions. Terminal elimination and renal clearance in the elderly male (age 69.1 +/- 6.0 years) were not significantly different compared with younger subjects (age 31 +/- 8.6 years). TRC4186 was safe and well tolerated when administered orally with either a single or multiple doses across the different ages, sexes, races and formulations studied. A dose-proportional increase in plasma TRC4186 concentration was seen, with steady state being achieved within 6 days.
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The Modeling Environment for Total Risks studies (MENTOR) system, combined with an extension of the SHEDS (Stochastic Human Exposure and Dose Simulation) methodology, provide a mechanistically consistent framework for conducting source-to-dose exposure assessments of multiple pol...
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Deming, Dustin A; Ninan, Jacob; Bailey, Howard H; Kolesar, Jill M; Eickhoff, Jens; Reid, Joel M; Ames, Matthew M; McGovern, Renee M; Alberti, Dona; Marnocha, Rebecca; Espinoza-Delgado, Igor; Wright, John; Wilding, George; Schelman, William R
2014-04-01
Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.
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Meesat, Ridthee; Belmouaddine, Hakim; Allard, Jean-François; Tanguay-Renaud, Catherine; Lemay, Rosalie; Brastaviceanu, Tiberius; Tremblay, Luc; Paquette, Benoit; Wagner, J Richard; Jay-Gerin, Jean-Paul; Lepage, Martin; Huels, Michael A; Houde, Daniel
2012-09-18
Since the invention of cancer radiotherapy, its primary goal has been to maximize lethal radiation doses to the tumor volume while keeping the dose to surrounding healthy tissues at zero. Sadly, conventional radiation sources (γ or X rays, electrons) used for decades, including multiple or modulated beams, inevitably deposit the majority of their dose in front or behind the tumor, thus damaging healthy tissue and causing secondary cancers years after treatment. Even the most recent pioneering advances in costly proton or carbon ion therapies can not completely avoid dose buildup in front of the tumor volume. Here we show that this ultimate goal of radiotherapy is yet within our reach: Using intense ultra-short infrared laser pulses we can now deposit a very large energy dose at unprecedented microscopic dose rates (up to 10(11) Gy/s) deep inside an adjustable, well-controlled macroscopic volume, without any dose deposit in front or behind the target volume. Our infrared laser pulses produce high density avalanches of low energy electrons via laser filamentation, a phenomenon that results in a spatial energy density and temporal dose rate that both exceed by orders of magnitude any values previously reported even for the most intense clinical radiotherapy systems. Moreover, we show that (i) the type of final damage and its mechanisms in aqueous media, at the molecular and biomolecular level, is comparable to that of conventional ionizing radiation, and (ii) at the tumor tissue level in an animal cancer model, the laser irradiation method shows clear therapeutic benefits.
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Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma
2014-01-01
Background Multiple myeloma is characterized by clonal expansion of B cells producing monoclonal immunoglobulins or fragments thereof, which can be detected in the serum and/or urine and are ideal target antigens for patient-specific immunotherapies. Methods Using phage particles as immunological carriers, we employed a novel chemically linked idiotype vaccine in a clinical phase I/II trial including 15 patients with advanced multiple myeloma. Vaccines composed of purified paraproteins linked to phage were manufactured successfully for each patient. Patients received six intradermal immunizations with phage idiotype vaccines in three different dose groups. Results Phage idiotype was well tolerated by all study participants. A subset of patients (80% in the middle dose group) displayed a clinical response indicated by decrease or stabilization of paraprotein levels. Patients exhibiting a clinical response to phage vaccines also raised idiotype-specific immunoglobulins. Induction of a cellular immune response was demonstrated by a cytotoxicity assay and delayed type hypersensitivity tests. Conclusion We present a simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible patient-specific therapy for patients with advanced multiple myeloma and produced promising anti-tumor activity in a subset of patients. PMID:24885819
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NASA Technical Reports Server (NTRS)
Richmond, Robert; Cruz, Angela; Jansen, Heather; Bors, Karen
2003-01-01
Predicting risk of human cancer following exposure of an individual or a population to ionizing radiation is challenging. To an approximation, this is because uncertainties of uniform absorption of dose and the uniform processing of dose-related damage at the cellular level within a complex set of biological variables degrade the confidence of predicting the delayed expression of cancer as a relatively rare event. Cellular biodosimeters that simultaneously report: 1) the quantity of absorbed dose after exposure to ionizing radiation, 2) the quality of radiation delivering that dose, and 3) the risk of developing cancer by the cells absorbing that dose would therefore be useful. An approach to such a multiparametric biodosimeter will be reported. This is the demonstration of a dose responsive field effect of enhanced expression of keratin 18 (K18) in cultures of human mammary epithelial cells irradiated with cesium-1 37 gamma-rays. Dose response of enhanced K18 expression was experimentally extended over a range of 30 to 90 cGy for cells evaluated at mid-log phase. K18 has been reported to be a marker for tumor staging and for apoptosis, and thereby serves as an example of a potential marker for cancer risk, where the reality of such predictive value would require additional experimental development. Since observed radiogenic increase in expression of K18 is a field effect, ie., chronically present in all cells of the irradiated population, it may be hypothesized that K18 expression in specific cells absorbing particulate irradiation, such as the high-LET-producing atomic nuclei of space radiation, will report on both the single-cell distributions of those particles amongst cells within the exposed population, and that the relatively high dose per cell delivered by densely ionizing tracks of those intersecting particles will lead to cell-specific high-expression levels of K18, thereby providing analytical end points that may be used to resolve both the quantity and the quality of the radiation dose absorbed by individual cells. The principal value of this reported potential multiparametric cellular biodosimeter is suggested to be that it justifies a search for similar but more robust radiogenic assays. That is, K18 is only one radiation dose-sensitive expressed protein, whereas analytical techniques of genomics and proteomics can be used to simultaneously analyze multiple gene and protein expressions resulting from radiation-dose absorption. The potential usefulness of multiparametric cellular biodosimeters will be best realized from quantitatively profiling these multiple markers using these modern techniques.
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Temporal Stability of Multiple Response Systems to 7.5% Carbon Dioxide Challenge
Roberson-Nay, Roxann; Gorlin, Eugenia I.; Beadel, Jessica R.; Cash, Therese; Vrana, Scott; Teachman, Bethany A.
2017-01-01
Self-reported anxiety, and potentially physiological response, to maintained inhalation of carbon dioxide (CO2) enriched air shows promise as a putative marker of panic reactivity and vulnerability. Temporal stability of response systems during low-dose, steady-state CO2 breathing challenge is lacking. Outcomes on multiple levels were measured two times, one week apart, in 93 individuals. Stability was highest during the CO2 breathing phase compared to pre-CO2 and recovery phases, with anxiety ratings, respiratory rate, skin conductance level, and heart rate demonstrating good to excellent temporal stability (ICCs ≥ 0.71). Cognitive symptoms tied to panic were somewhat less stable (ICC = 0.58) than physical symptoms (ICC = 0.74) during CO2 breathing. Escape/avoidance behaviors and DSM-5 panic attacks were not stable. Large effect sizes between task phases also were observed. Overall, results suggest good-excellent levels of temporal stability for multiple outcomes during respiratory stimulation via 7.5% CO2. PMID:28163046
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Wong, Jeffrey Y C; Rosenthal, Joseph; Liu, An; Schultheiss, Timothy; Forman, Stephen; Somlo, George
2009-01-01
Total-body irradiation (TBI) has an important role in patients undergoing hematopoietic cell transplantation (HCT), but is associated with significant toxicities. Targeted TBI using helical tomotherapy results in reduced doses to normal organs, which predicts for reduced toxicities compared with standard TBI. Thirteen patients with multiple myeloma were treated in an autologous tandem transplantation Phase I trial with high-dose melphalan, followed 6 weeks later by total-marrow irradiation (TMI) to skeletal bone. Dose levels were 10, 12, 14, and 16 Gy at 2 Gy daily/twice daily. In a separate allogeneic HCT trial, 8 patients (5 with acute myelogenous leukemia, 1 with acute lymphoblastic leukemia, 1 with non-Hodgkin's lymphoma, and 1 with multiple myeloma) were treated with TMI plus total lymphoid irradiation plus splenic radiotherapy to 12 Gy (1.5 Gy twice daily) combined with fludarabine/melphalan. For the 13 patients in the tandem autologous HCT trial, median age was 54 years (range, 42-66 years). Median organ doses were 15-65% that of the gross target volume dose. Primarily Grades 1-2 acute toxicities were observed. Six patients reported no vomiting; 9 patients, no mucositis; 6 patients, no fatigue; and 8 patients, no diarrhea. For the 8 patients in the allogeneic HCT trial, median age was 52 years (range, 24-61 years). Grades 2-3 nausea, vomiting, mucositis, and diarrhea were observed. In both trials, no Grade 4 nonhematologic toxicity was observed, and all patients underwent successful engraftment. This study shows that TMI using helical tomotherapy is clinically feasible. The reduced acute toxicities observed compare favorably with those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI-containing regimens to patients unable to tolerate standard approaches.
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Grémy, Olivier; Coudert, Sylvie; Renault, Daniel; Miccoli, Laurent
2017-11-01
While the efficacy of a protracted zinc (Zn)- or calcium (Ca)-diethylenetriaminepentaacetic acid (DTPA) treatment in reducing transuranic body burden has already been demonstrated, questions about therapeutic variables remain. In response to this, we designed animal experiments primarily to assess both the effect of fractionation of a given dose and the effect of the frequency of dose fraction, with the same total dose. In our study, rats were contaminated intravenously with plutonium (Pu) then treated several days later with Ca-DTPA given at once or in various split-dose regimens cumulating to the same total dose and spread over several days. Similar efficacies were induced by the injection of the total dose or by splitting the dose in several smaller doses, independent of the number of doses and the dose level per injection. In a second study, rats were pulmonary contaminated, and three weeks later they received a Ca-DTPA dose 11-fold higher than the maximal daily recommended dose, administered either as a single bolus or as numerous multiple injections cumulating to the same dose, based on different injection frequency schedules. Independent of frequency schedule, the various split-dose regimens spread over weeks/months were as efficient as single delivery of the total dose in mobilizing lung plutonium, and had a therapeutic advantage for removal of retained hepatic and bone plutonium burdens. We concluded that cumulative dose level was a therapeutic variable of greater importance than the distribution of split doses for the success of a repeated treatment regimen on retained tissue plutonium. In addition, pulmonary administration of clodronate, which aims at killing alveolar macrophages and subsequently releasing their plutonium content, and which is associated with a continuous Ca-DTPA infusion regimen, suggested that the efficacy of injected Ca-DTPA in decorporating lung deposit is limited, due to its restricted penetration into alveolar macrophages and not because plutonium, as a physicochemical form, is unavailable for chelation.
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Nader, Ahmed; Zahran, Noran; Alshammaa, Aya; Altaweel, Heba; Kassem, Nancy; Wilby, Kyle John
2017-04-01
Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice. A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII ® . A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics. Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c ) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively). Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.
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Botelho, Danielle J; Leo, Bey Fen; Massa, Christopher B; Sarkar, Srijata; Tetley, Terry D; Chung, Kian Fan; Chen, Shu; Ryan, Mary P; Porter, Alexandra E; Zhang, Junfeng; Schwander, Stephan K; Gow, Andrew J
2016-01-01
Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 μg/g body weight) 20 and 110 nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110 nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.
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Barriers to HIV Medication Adherence as a Function of Regimen Simplification.
Chen, Yiyun; Chen, Kun; Kalichman, Seth C
2017-02-01
Barriers to HIV medication adherence may differ by levels of dosing schedules. The current study examined adherence barriers associated with medication regimen complexity and simplification. A total of 755 people living with HIV currently taking anti-retroviral therapy were recruited from community services in Atlanta, Georgia. Participants completed audio-computer-assisted self-interviews that assessed demographic and behavioral characteristics, provided their HIV viral load obtained from their health care provider, and completed unannounced phone-based pill counts to monitor medication adherence over 1 month. Participants taking a single-tablet regimen (STR) were more likely to be adherent than those taking multi-tablets in a single-dose regimen (single-dose MTR) and those taking multi-tablets in a multi-dose regimen (multi-dose MTR), with no difference between the latter two. Regarding barriers to adherence, individuals taking STR were least likely to report scheduling issues and confusion as reasons for missing doses, but they were equally likely to report multiple lifestyle and logistical barriers to adherence. Adherence interventions may need tailoring to address barriers that are specific to dosing regimens.
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Huang, Lianyan; Hayes, Scott; Yang, Guang
2016-01-01
Anesthetic agents are often administered in the neonatal period, a time of rapid brain development and synaptogenesis. Mounting evidence suggests that anesthetics can disrupt neurocognitive development, particularly in cases of multiple or prolonged anesthetic exposure. Previous studies have shown that administering multiple doses of ketamine-xylazine (KX) anesthesia to neonatal mice can induce long-term changes to synaptic plasticity in the cortex, but the effect on neurocognitive function remains unclear. In this study, we exposed neonatal mice to single dose and multiple doses of KX anesthesia in the neonatal period (postnatal days 7, 9, 11), and conducted a series of behavioral tests in young adulthood (1 month of age). Mice receiving multiple doses of KX anesthesia showed deficits in novel object recognition, sociability, preference for social novelty and contextual fear response, but no effect on auditory-cued fear response. Single dose of KX anesthesia had no effect on these behaviors except for contextual fear response. We also observed that multiple exposures to KX anesthesia were associated with decreased CaMKII phosphorylation, which is known to play a role in synapse development and long-term potentiation, likely contributing to learning impairment. PMID:27622724
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Aragonès, Gerard; Suárez, Manuel; Ardid-Ruiz, Andrea; Vinaixa, Maria; Rodríguez, Miguel A; Correig, Xavier; Arola, Lluís; Bladé, Cinta
2016-04-22
Proanthocyanidins (PACs) have been reported to modulate multiple targets by simultaneously controlling many pivotal metabolic pathways in the liver. However, the precise mechanism of PAC action on the regulation of the genes that control hepatic metabolism remains to be clarified. Accordingly, we used a metabolomic approach combining both nuclear magnetic resonance and mass spectrometry analysis to evaluate the changes induced by different doses of grape-seed PACs in the liver of healthy rats. Here, we report that PACs significantly increased the hepatic nicotinamide adenine dinucleotide (NAD(+)) content in a dose-dependent manner by specifically modulating the hepatic concentrations of the major NAD(+) precursors as well as the mRNA levels of the genes that encode the enzymes involved in the cellular metabolism of NAD(+). Notably, Sirtuin 1 (Sirt1) gene expression was also significantly up-regulated in a dose-response pattern. The increase in both the NAD(+) availability and Sirt1 mRNA levels, in turn, resulted in the hepatic activation of SIRT1, which was significantly associated with improved protection against hepatic triglyceride accumulation. Our data clearly indicates that PAC consumption could be a valid tool to enhance hepatic SIRT1 activity through the modulation of NAD(+) levels.
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Aragonès, Gerard; Suárez, Manuel; Ardid-Ruiz, Andrea; Vinaixa, Maria; Rodríguez, Miguel A.; Correig, Xavier; Arola, Lluís; Bladé, Cinta
2016-01-01
Proanthocyanidins (PACs) have been reported to modulate multiple targets by simultaneously controlling many pivotal metabolic pathways in the liver. However, the precise mechanism of PAC action on the regulation of the genes that control hepatic metabolism remains to be clarified. Accordingly, we used a metabolomic approach combining both nuclear magnetic resonance and mass spectrometry analysis to evaluate the changes induced by different doses of grape-seed PACs in the liver of healthy rats. Here, we report that PACs significantly increased the hepatic nicotinamide adenine dinucleotide (NAD+) content in a dose-dependent manner by specifically modulating the hepatic concentrations of the major NAD+ precursors as well as the mRNA levels of the genes that encode the enzymes involved in the cellular metabolism of NAD+. Notably, Sirtuin 1 (Sirt1) gene expression was also significantly up-regulated in a dose-response pattern. The increase in both the NAD+ availability and Sirt1 mRNA levels, in turn, resulted in the hepatic activation of SIRT1, which was significantly associated with improved protection against hepatic triglyceride accumulation. Our data clearly indicates that PAC consumption could be a valid tool to enhance hepatic SIRT1 activity through the modulation of NAD+ levels. PMID:27102823
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Kim, Tae Hwan; Shin, Soyoung; Kim, Sarah; Bulitta, Jürgen B; Weon, Kwon-Yeon; Joo, Sang Hoon; Ma, Eunsook; Yoo, Sun Dong; Park, Gi-Young; Kwon, Dong Rak; Jeong, Seok Won; Lee, Da Young; Shin, Beom Soo
2017-09-10
Gemcitabine and erlotinib are the chemotherapeutic agents used in the treatment of various cancers and their combination is being accepted as a first-line treatment of advanced pancreatic cancer. Hyangsayukgunja-tang (HYT) is a traditional oriental medicine used in various digestive disorders and potentially helpful to treat gastrointestinal adverse effects related to chemotherapy. The present study was aimed to evaluate the effect of HYT on the pharmacokinetics of gemcitabine and erlotinib given simultaneously in rats. Rats were pretreated with HYT at an oral dose of 1200 mg/kg/day once daily for a single day or 14 consecutive days. Immediately after pretreatment with HYT, gemcitabine and erlotinib were administered by intravenous injection (10 mg/kg) and oral administration (20 mg/kg), respectively. The effects of HYT on pharmacokinetics of the two drugs were estimated by non-compartmental analysis and pharmacokinetic modeling. The pharmacokinetics of gemcitabine and erlotinib were not altered by single dose HYT pretreatment. However, the plasma levels of OSI-420 and OSI-413, active metabolites of erlotinib, were significantly decreased in the multiple dose HYT pretreatment group. The pharmacokinetic model estimated increased systemic clearances of OSI-420 and OSI-413 by multiple doses of HYT. These data suggest that HYT may affect the elimination of OSI-420 and OSI-413.
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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.
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Bautista, Christopher A.; Iosif, Ana-Maria; Wilsey, Barth L.; Melnikow, Joy A.; Crichlow, Althea; Henry, Stephen G.
2016-01-01
OBJECTIVE To examine encounter-level factors associated with opioid dose increases during patients’ first year on opioid therapy for chronic pain. DESIGN Case-control study analyzing all opioid prescriptions for patients with chronic pain during their first year after opioid initiation. Cases were patients who experienced an overall dose escalation of ≥30 mg morphine equivalents over the 1-year period; controls did not experience overall dose escalation. Main measures were encounter type; opioid dose change; documented prescribing rationale; documentation of guideline-concordant opioid prescribing practices. Two coders reviewed all encounters associated with opioid prescriptions. Analysis of factors associated with dose increases and provider documentation of prescribing rationale was conducted using multiple logistic regression. RESULTS 674 encounters were coded for 66 patients (22 cases, 44 controls). Fifty-three percent of opioid prescriptions were associated with telephone encounters; 13% were associated with email encounters. No prescribing rationale was documented for 43% of all opioid prescriptions and 25% of dose increases. Likelihood of dose increase and documentation of prescribing rationale did not significantly differ for cases versus controls. Compared to face-to-face encounters, dose increases were significantly less likely for telephone (OR 0.18, 95%CI 0.11 – 0.28) and email (OR 0.23, 95%CI 0.12 – 0.47) encounters; documentation of prescribing rationale was significantly more likely for email (OR 5.06, 95%CI 1.87–13.72) and less likely for telephone (OR 0.30, 95%CI 0.18–0.51) encounters. CONCLUSION Most opioid prescriptions were written without face-to-face encounters. One quarter of dose increases contained no documented prescribing rationale. Documented encounter-level factors were not significantly associated with overall opioid dose escalation. PMID:27477581
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Yang, Feng; Waters, Katrina M; Miller, John H; Gritsenko, Marina A; Zhao, Rui; Du, Xiuxia; Livesay, Eric A; Purvine, Samuel O; Monroe, Matthew E; Wang, Yingchun; Camp, David G; Smith, Richard D; Stenoien, David L
2010-11-30
High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health.
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Yang, Feng; Waters, Katrina M.; Miller, John H.; Gritsenko, Marina A.; Zhao, Rui; Du, Xiuxia; Livesay, Eric A.; Purvine, Samuel O.; Monroe, Matthew E.; Wang, Yingchun; Camp, David G.; Smith, Richard D.; Stenoien, David L.
2010-01-01
Background High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. Principal Findings We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conclusions Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health. PMID:21152398
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Gonçalves, Daniela
Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n = 8 per group) were orally treated with single (30, 60 or 90 mg/kg) or multiple (30 mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24 h post-dosing through amore » cannula introduced in the tail vein of rats. After quantifying opicapone and BIA 9-1079 in plasma, a non-compartmental pharmacokinetic analysis was performed. Opicapone was quickly absorbed (time to reach the maximum plasma concentration ≤ 2 h) in both dosage regimens and the extent of systemic exposure to opicapone increased approximately in a dose-proportional manner after single-dosing within the studied dose range (30–90 mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58–4.50 h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen. - Highlights: • Opicapone is relatively rapid absorbed after oral administration to rats. • Systemic exposure to opicapone increases approximately in a dose-proportional manner. • Opicapone and BIA 9-1079 show a small systemic accumulation after multiple-dosing.« less
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Multiple-, But Not Single-, Dose of Parecoxib Reduces Shoulder Pain after Gynecologic Laparoscopy
Zhang, Hufei; Shu, Haihua; Yang, Lu; Cao, Minghui; Zhang, Jingjun; Liu, Kexuan; Xiao, Liangcan; Zhang, Xuyu
2012-01-01
Background: The aim of this study was to investigate effect of single- and multiple-dose of parecoxib on shoulder pain after gynecologic laparoscopy. Methods: 126 patients requiring elective gynecologic laparoscopy were randomly allocated to three groups. Group M (multiple-dose): receiving parecoxib 40mg at 30min before the end of surgery, at 8 and 20hr after surgery, respectively; Group S (single-dose): receiving parecoxib 40mg at 30min before the end of surgery and normal saline at the corresponding time points; Group C (control): receiving normal saline at the same three time points. The shoulder pain was evaluated, both at rest and with motion, at postoperative 6, 24 and 48hr. The impact of shoulder pain on patients' recovery (activity, mood, walking and sleep) was also evaluated. Meanwhile, rescue analgesics and complications were recorded. Results: The overall incidence of shoulder pain in group M (37.5%) was lower than that in group C (61.9%) (difference=-24.4%; 95% CI: 3.4~45.4%; P=0.023). Whereas, single-dose regimen (61.0%) showed no significant reduction (difference with control=-0.9%; 95% CI: -21.9~20.0%; P=0.931). Moreover, multiple-dose regimen reduced the maximal intensity of shoulder pain and the impact for activity and mood in comparison to the control. Multiple-dose of parecoxib decreased the consumption of rescue analgesics. The complications were similar among all groups and no severe complications were observed. Conclusions: Multiple-, but not single-, dose of parecoxib may attenuate the incidence and intensity of shoulder pain and thereby improve patients' quality of recovery following gynecologic laparoscopy. PMID:23136538
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Fan, Yongjun; Wali, Gautam; Sutharsan, Ratneswary; Bellette, Bernadette; Crane, Denis I.; Sue, Carolyn M.; Mackay-Sim, Alan
2014-01-01
ABSTRACT Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of disorders, diagnosed by progressive gait disturbances with muscle weakness and spasticity, for which there are no treatments targeted at the underlying pathophysiology. Mutations in spastin are a common cause of HSP. Spastin is a microtubule-severing protein whose mutation in mouse causes defective axonal transport. In human patient-derived olfactory neurosphere-derived (ONS) cells, spastin mutations lead to lower levels of acetylated α-tubulin, a marker of stabilised microtubules, and to slower speed of peroxisome trafficking. Here we screened multiple concentrations of four tubulin-binding drugs for their ability to rescue levels of acetylated α-tubulin in patient-derived ONS cells. Drug doses that restored acetylated α-tubulin to levels in control-derived ONS cells were then selected for their ability to rescue peroxisome trafficking deficits. Automated microscopic screening identified very low doses of the four drugs (0.5 nM taxol, 0.5 nM vinblastine, 2 nM epothilone D, 10 µM noscapine) that rescued acetylated α-tubulin in patient-derived ONS cells. These same doses rescued peroxisome trafficking deficits, restoring peroxisome speeds to untreated control cell levels. These results demonstrate a novel approach for drug screening based on high throughput automated microscopy for acetylated α-tubulin followed by functional validation of microtubule-based peroxisome transport. From a clinical perspective, all the drugs tested are used clinically, but at much higher doses. Importantly, epothilone D and noscapine can enter the central nervous system, making them potential candidates for future clinical trials. PMID:24857849
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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.
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Pharmacokinetics interaction between imatinib and genistein in rats.
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.
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Statistical strategies for averaging EC50 from multiple dose-response experiments.
Jiang, Xiaoqi; Kopp-Schneider, Annette
2015-11-01
In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.
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Biology Based Lung Cancer Model for Chronic Low Radon Exposures
NASA Astrophysics Data System (ADS)
TruÅ£ǎ-Popa, Lucia-Adina; Hofmann, Werner; Fakir, Hatim; Cosma, Constantin
2008-08-01
Low dose effects of alpha particles at the tissue level are characterized by the interaction of single alpha particles, affecting only a small fraction of the cells within that tissue. Alpha particle intersections of bronchial target cells during a given exposure period were simulated by an initiation-promotion model, formulated in terms of cellular hits within the cycle time of the cell (dose-rate) and then integrated over the whole exposure period (dose). For a given average number of cellular hits during the lifetime of bronchial cells, the actual number of single and multiple hits was selected from a Poisson distribution. While oncogenic transformation is interpreted as the primary initiation step, stimulated mitosis by killing adjacent cells is assumed to be the primary radiological promotion event. Analytical initiation and promotion functions were derived from experimental in vitro data on oncogenic transformation and cellular survival. To investigate the shape of the lung cancer risk function at chronic, low level exposures in more detail, additional biological factors describing the tissue response and operating specifically at low doses were incorporated into the initiation-promotion model. These mechanisms modifying the initial response at the cellular level were: adaptive response, genomic instability, induction of apoptosis by surrounding cells, and detrimental as well as protective bystander mechanisms. To quantify the effects of these mechanisms as functions of dose, analytical functions were derived from the experimental evidence presently available. Predictions of lung cancer risk, including these mechanisms, exhibit a distinct sublinear dose-response relationship at low exposures, particularly for very low exposure rates.
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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
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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.
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Benton, Michael G; Somasundaram, Swetha; Glasner, Jeremy D; Palecek, Sean P
2006-12-01
One of the most crucial tasks for a cell to ensure its long term survival is preserving the integrity of its genetic heritage via maintenance of DNA structure and sequence. While the DNA damage response in the yeast Saccharomyces cerevisiae, a model eukaryotic organism, has been extensively studied, much remains to be elucidated about how the organism senses and responds to different types and doses of DNA damage. We have measured the global transcriptional response of S. cerevisiae to multiple doses of two representative DNA damaging agents, methyl methanesulfonate (MMS) and gamma radiation. Hierarchical clustering of genes with a statistically significant change in transcription illustrated the differences in the cellular responses to MMS and gamma radiation. Overall, MMS produced a larger transcriptional response than gamma radiation, and many of the genes modulated in response to MMS are involved in protein and translational regulation. Several clusters of coregulated genes whose responses varied with DNA damaging agent dose were identified. Perhaps the most interesting cluster contained four genes exhibiting biphasic induction in response to MMS dose. All of the genes (DUN1, RNR2, RNR4, and HUG1) are involved in the Mec1p kinase pathway known to respond to MMS, presumably due to stalled DNA replication forks. The biphasic responses of these genes suggest that the pathway is induced at lower levels as MMS dose increases. The genes in this cluster with a threefold or greater transcriptional response to gamma radiation all showed an increased induction with increasing gamma radiation dosage. Analyzing genome-wide transcriptional changes to multiple doses of external stresses enabled the identification of cellular responses that are modulated by magnitude of the stress, providing insights into how a cell deals with genotoxicity.
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Neutron Skyshine Considerations For The NIF Shielding Design
DOE Office of Scientific and Technical Information (OSTI.GOV)
Singh, M S; Mecozzi, J M; Tobin, M T
2004-01-28
A series of coupled neutron-photon transport Monte-Carlo calculations was performed to estimate the roof shielding required to limit the skyshine dose to less than 1 mrem/y at the site boundary when conducting DT experiments with annual fusion yields up to 1200 MJ (4.2E20 neutrons/y). The NIF shielding design consists of many different components. The basic components include 10-cm-thick Al chamber with 40-cm-thick target chamber gunite shield having multiple penetrations, 1.83-m-thick concrete Target Bay walls, 1.37-m-thick concrete roof, and multiple concrete floors with numerous penetrations. Under this shielding configuration, the skyshine dose at the nearest site-boundary was calculated to be lessmore » than 0.2 mrem/y for all possible target illumination configurations. The potential dose at the site boundary would be about one-tenth of the cosmic neutron dose that we measured with bubble neutron detectors on board a commercial roundtrip flight from SF to Rochester. This incremental dose increase is well within the normal fluctuations (noise) of the natural background radiation in the Livermore area. The skyshine dose has no impact on the public. The skyshine dose trends at ground and elevated levels are plotted as a function of distance from 20 m to 1000 m from the center of the target bay. The differential neutron and photon energy flux emerging from the NIF roof and at several locations on the ground is plotted to show how it shifts with distance. The results of this study are compared with the neutron skyshine studies done at high-energy accelerators by R. H. Thomas.« less
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Teeguarden, Justin G; Hanson-Drury, Sesha
2013-12-01
Human exposure to the chemical Bisphenol A is almost ubiquitous in surveyed industrialized societies. Structural features similar to estrogen confer the ability of Bisphenol A (BPA) to bind estrogen receptors, giving BPA membership in the group of environmental pollutants called endocrine disruptors. References by scientists, the media, political entities, and non-governmental organizations to many toxicity studies as "low dose" has led to the belief that exposure levels in these studies are similar to humans, implying that BPA is toxic to humans at current exposures. Through systematic, objective comparison of our current, and a previous compilation of the "low-dose" literature to multiple estimates of human external and internal exposure levels, we found that the "low-dose" moniker describes exposures covering 8-12 orders of magnitude, the majority (91-99% of exposures) being greater than the upper bound of human exposure in the general infant, child and adult U.S. Population. "low dose" is therefore a descriptor without specific meaning regarding human exposure. Where human exposure data are available, for BPA and other environmental chemicals, reference to toxicity study exposures by direct comparison to human exposure would be more informative, more objective, and less susceptible to misunderstanding. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Terrestrial Gamma Radiation Dose Rate of West Sarawak
NASA Astrophysics Data System (ADS)
Izham, A.; Ramli, A. T.; Saridan Wan Hassan, W. M.; Idris, H. N.; Basri, N. A.
2017-10-01
A study of terrestrial gamma radiation (TGR) dose rate was conducted in west of Sarawak, covering Kuching, Samarahan, Serian, Sri Aman, and Betong divisions to construct a baseline TGR dose rate level data of the areas. The total area covered was 20,259.2 km2, where in-situ measurements of TGR dose rate were taken using NaI(Tl) scintillation detector Ludlum 19 micro R meter NaI(Tl) approximately 1 meter above ground level. Twenty-nine soil samples were taken across the 5 divisions covering 26 pairings of 9 geological formations and 7 soil types. A hyperpure Germanium detector was then used to find the samples' 238U, 232Th, and 40K radionuclides concentrations producing a correction factor Cf = 0.544. A total of239 measured data were corrected with Cf resulting in a mean Dm of 47 ± 1 nGy h-1, with a range between 5 nGy h-1 - 103 nGy h-1. A multiple regression analysis was conducted between geological means and soil types means against the corrected TGR dose rate Dm, generating Dg,s= 0.847Dg+ 0.637Ds- 22.313 prediction model with a normalized Beta equation of Dg,s= 0.605Dg+ 0.395Ds. The model has an 84.6% acceptance of Whitney- Mann test null hypothesis when tested against the corrected TGR dose rates.
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Pharmacokinetics and safety of eszopiclone in healthy Chinese volunteers.
Wu, F; Zhao, X L; Wei, M J; Wang, S M; Zhou, H; Guo, S J; Zhang, P
2012-12-01
The main objective of this study was to investigate the pharmacokinetic characters of eszopiclone (CAS: 138729-47-2) after single and multiple-dose oral administration in healthy adult Chinese volunteers.In single-dose study, 12 subjects were given oral administrations of 1.5, 3 and 6 mg eszopiclone in an open-label, randomized, crossover fashion. In multiple-dose study, 8 subjects were given 3 mg eszopiclone once daily consecutively for 7 days. Blood samples were collected over 24 h and plasma eszopiclone were determined using a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay. The safety and tolerability of eszopiclone was evaluated by adverse events recording, physical examination, laboratory testing, vital signs, and 12-lead ECG findings.The main pharmacokinetic parameters of eszopiclone after single-dose administration were as follows: doses of 1.5, 3 and 6 mg; Cmax of 18.08±4.65, 38.29±15.41 and 76.38±23.34 ng/ml; Tmax of 0.94±0.39, 1.04±0.63 and 1.08±0.51 h; AUC0-24 of 110.90±23.06, 227.36±62.41 and 504.10±140.13 ng*h/ml; elimination half-lives of 5.84±1.03, 5.53±1.91 and 6.17±1.23 h. After multiple-dose administration, the steady-state levels of eszopiclone were achieved by the 4th day, and the main pharmacokinetic parameters were Css_max at 33.43±5.63 ng/ml and AUCss (0-24) at 263.30±51.21 ng*h/ml. The most common adverse event was bitter or abnormal taste. All the adverse events were judged as mild to moderate and resolved without any medication.The pharmacokinetic character of eszopiclone is linear and dose-proportional over the range of 1.5-6 mg. The systemic exposure does not accumulate with once-daily administrations. Eszopiclone appears to have good safety and is well tolerated. © Georg Thieme Verlag KG Stuttgart · New York.
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Radiation Dose Testing on Juno High Voltage Cables
NASA Technical Reports Server (NTRS)
Green, Nelson W.; Kirkham, Harold; Kim, Wousik; McAlpine, Bill
2008-01-01
The Juno mission to Jupiter will have a highly elliptical orbit taking the spacecraft through the radiation belts surrounding the planet. During these passes through the radiation belts, the spacecraft will be subject to high doses of radiation from energetic electrons and protons with energies ranging from 10 keV to 1 GeV. While shielding within the spacecraft main body will reduce the total absorbed dose to much of the spacecraft electronics, instruments and cables on the outside of the spacecraft will receive much higher levels of absorbed dose. In order to estimate the amount of degradation to two such cables, testing has been performed on two coaxial cables intended to provide high voltages to three of the instruments on Juno. Both cables were placed in a vacuum of 5x10(exp -6) torr and cooled to -50(deg)C prior to exposure to the radiation sources. Measurements of the coaxial capacitance per unit length and partial discharge noise floor indicate that increasing levels of radiation make measurable but acceptably small changes to the F EP Teflon utilized in the construction of these cables. In addition to the radiation dose testing, observations were made on the internal electrostatic charging characteristics of these cables and multiple discharges were recorded.
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Radiation Dose Testing on Juno High Voltage Cables
NASA Technical Reports Server (NTRS)
Green, Nelson W.; Kirkham, Harold; Kim, Wousik; McAlpine, Bill
2008-01-01
The Juno mission to Jupiter will have a highly elliptical orbit taking the spacecraft through the radiation belts surrounding the planet. During these passes through the radiation belts, the spacecraft will be subject to high doses of radiation from energetic electrons and protons with energies ranging from 10 keV to 1 GeV. While shielding within the spacecraft main body will reduce the total absorbed dose to much of the spacecraft electronics, instruments and cables on the outside of the spacecraft will receive much higher levels of absorbed dose. In order to estimate the amount of degradation to two such cables, testing has been performed on two coaxial cables intended to provide high voltages to three of the instruments on Juno. Both cables were placed in a vacuum of 5x10-6 torr and cooled to -50 C prior to exposure to the radiation sources. Measurements of the coaxial capacitance per unit length and partial discharge noise floor indicate that increasing levels of radiation make measurable but acceptably small changes to the F EP Teflon utilized in the construction of these cables. In addition to the radiation dose testing, observations were made on the internal electrostatic charging characteristics of these cables and multiple discharges were recorded.
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Fundamental Flaws of Hormesis for Public Health Decisions
Thayer, Kristina A.; Melnick, Ronald; Burns, Kathy; Davis, Devra; Huff, James
2005-01-01
Hormesis (defined operationally as low-dose stimulation, high-dose inhibition) is often used to promote the notion that while high-level exposures to toxic chemicals could be detrimental to human health, low-level exposures would be beneficial. Some proponents claim hormesis is an adaptive, generalizable phenomenon and argue that the default assumption for risk assessments should be that toxic chemicals induce stimulatory (i.e., “beneficial”) effects at low exposures. In many cases, nonmonotonic dose–response curves are called hormetic responses even in the absence of any mechanistic characterization of that response. Use of the term “hormesis,” with its associated descriptors, distracts from the broader and more important questions regarding the frequency and interpretation of nonmonotonic dose responses in biological systems. A better understanding of the biological basis and consequences of nonmonotonic dose–response curves is warranted for evaluating human health risks. The assumption that hormesis is generally adaptive is an oversimplification of complex biological processes. Even if certain low-dose effects were sometimes considered beneficial, this should not influence regulatory decisions to allow increased environmental exposures to toxic and carcinogenic agents, given factors such as interindividual differences in susceptibility and multiplicity in exposures. In this commentary we evaluate the hormesis hypothesis and potential adverse consequences of incorporating low-dose beneficial effects into public health decisions. PMID:16203233
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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.
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Samuels, Mary H; Kolobova, Irina; Niederhausen, Meike; Janowsky, Jeri S; Schuff, Kathryn G
2018-05-01
The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition. A total of 138 subjects with levothyroxine (L-T4)-treated hypothyroidism and normal thyrotropin (TSH) levels underwent measures of quality of life (36-Item Short Form Health Survey, Underactive Thyroid-Dependent Quality of Life Questionnaire), mood (Profile of Mood States, Affective Lability Scale), and cognition (executive function, memory). They were then randomly assigned to receive an unchanged, higher, or lower L-T4 dose in double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). Doses were adjusted every 6 weeks based on TSH levels. Baseline measures were reassessed at 6 months. At the end of the study, by intention to treat, mean L-T4 doses were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 μg/kg (P < 0.001), and mean TSH levels were 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. There were minor differences in a few outcomes between the three arms, which were no longer significant after correction for multiple comparisons. Subjects could not ascertain how their L-T4 doses had been adjusted (P = 0.55) but preferred L-T4 doses they perceived to be higher (P < 0.001). Altering L-T4 doses in hypothyroid subjects to vary TSH levels in and near the reference range does not affect quality of life, mood, or cognition. L-T4-treated subjects prefer perceived higher L-T4 doses despite a lack of objective benefit. Adjusting L-T4 doses in hypothyroid patients based on symptoms in these areas may not result in significant clinical improvement.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Ma, C; Yu, L; Vrieze, T
Purpose: Added filtration such as tin filter has the potential to improve dose efficiency of x-ray beam in lung-cancer screening CT. However, dose efficiency with added beam filtration is highly dependent on patient attenuation level. In this phantom study, we evaluated the image quality at different tube voltages with and without added tin filter when attenuation level varies. Methods: A 30 x 20 cm anthropomorphic thorax phantom with three added extension rings were used to simulate small (S), medium (M), large (L), and extra-large (XL) adult patients. These phantoms were scanned on a 192-slice CT scanner (Force, Siemens) at 100more » and 120kV without tin filtration, and 100 and 150 kV with tin filtration (100Sn and 150Sn), at multiple dose levels at each kV. Images were reconstructed using iterative reconstruction (ADMIRE, Siemens). Radiation dose was measured with a 0.6 cc ion chamber in the middle and peripheral areas of the phantom. Image quality was assessed using mean image noise at uniform areas in the central region and lung. Radiation dose that is required for each kV to match the noise in a routine lung-cancer CT screening technique (120kV, 25 quality reference mAs) was calculated. Results: At each of the four phantom sizes, 100Sn had the lowest noise in both soft tissue and lung. Compared with 120 kV, 100Sn saved 39%–60% dose for the same noise, depending on phantom size. For the XL phantom (50 by 40 cm), 150Sn provided images with the least beam-hardening artifact in peripheral region. Conclusion: For thoracic CT, added tin filtration can provide considerable dose reduction compared with 120 kV. 100Sn provides better dose efficiencies for all phantom sizes, while 150Sn provides better image quality in peripheral region for extra-large patients. Drs.Joel G. Fletcher and Cynthia H. McCollough receive research support from Siemens Healthcare.« less
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Muindi, Josephia R; Roth, Michael D; Wise, Robert A; Connett, John E; O'Connor, George T; Ramsdell, Joe W; Schluger, Neil W; Romkes, Marjorie; Branch, Robert A; Sciurba, Frank C
2008-01-01
Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers-all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cRA)-in subjects with emphysema, evaluated strategies to overcome self-induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low-dose ATRA (1 mg/kg/day, n = 21), or high-dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13-cRA (1 mg/kg/day, n = 40). High-dose ATRA produced the highest peak plasma ATRA Cmax. However, at follow-up, plasma ATRA C(max) was significantly decreased from baseline in subjects whose day 1 levels exceeded 100 ng/mL (P < .0001). In contrast, administration of 13-cRA produced lower plasma ATRA C(max) (<100 ng/mL), but the levels were significantly higher at follow-up than those on day 1 (P < .001). Plasma ATRA levels as determined on day 1 correlated with changes in pulmonary diffusing capacity at 6 months, consistent with concentration-dependent biologic effects (r2 = -0.25). The authors conclude that intermittent therapy with high-dose ATRA produced the greatest ATRA exposure, but alternative approaches for limiting self-induced ATRA catabolism should be sought.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
W. C. Griffith
In this project we provide an example of how to develop multi-tiered models to go across levels of biological organization to provide a framework for relating results of studies of low doses of ionizing radiation. This framework allows us to better understand how to extrapolate laboratory results to policy decisions, and to identify future studies that will increase confidence in policy decisions. In our application of the conceptual Model we were able to move across multiple levels of biological assessment for rodents going from molecular to organism level for in vitro and in vivo endpoints and to relate these tomore » human in vivo organism level effects. We used the rich literature on the effects of ionizing radiation on the developing brain in our models. The focus of this report is on disrupted neuronal migration due to radiation exposure and the structural and functional implications of these early biological effects. The cellular mechanisms resulting in pathogenesis are most likely due to a combination of the three mechanisms mentioned. For the purposes of a computational model, quantitative studies of low dose radiation effects on migration of neuronal progenitor cells in the cerebral mantle of experimental animals were used. In this project we were able to show now results from studies of low doses of radiation can be used in a multidimensional framework to construct linked models of neurodevelopment using molecular, cellular, tissue, and organ level studies conducted both in vitro and in vivo in rodents. These models could also be linked to behavioral endpoints in rodents which can be compared to available results in humans. The available data supported modeling to 10 cGy with limited data available at 5 cGy. We observed gradual but non-linear changes as the doses decreased. For neurodevelopment it appears that the slope of the dose response decreases from 25 cGy to 10 cGy. Future studies of neurodevelopment should be able to better define the dose response in this range.« less
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Effects of amoxicillin/clavulanic acid on the pharmacokinetics of valproic acid
Lee, Soo-Yun; Huh, Wooseong; Jung, Jin Ah; Yoo, Hye Min; Ko, Jae-Wook; Kim, Jung-Ryul
2015-01-01
Valproic acid (VPA) is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC) administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500 mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125 mg were administered three times daily for 7 days and then a single dose of VPA was administered. Blood samples were collected up to 48 hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0 h·mg/L vs 889.6 h·mg/L; Cmax, 52.1 mg/L vs 53.0 mg/L). There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI]) of AUClast and Cmax (95.7 [85.9–106.5] and 98.3 [91.6–105.6], respectively). Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary. PMID:26309401
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A 2D ion chamber array audit of wedged and asymmetric fields in an inhomogeneous lung phantom.
Lye, Jessica; Kenny, John; Lehmann, Joerg; Dunn, Leon; Kron, Tomas; Alves, Andrew; Cole, Andrew; Williams, Ivan
2014-10-01
The Australian Clinical Dosimetry Service (ACDS) has implemented a new method of a nonreference condition Level II type dosimetric audit of radiotherapy services to increase measurement accuracy and patient safety within Australia. The aim of this work is to describe the methodology, tolerances, and outcomes from the new audit. The ACDS Level II audit measures the dose delivered in 2D planes using an ionization chamber based array positioned at multiple depths. Measurements are made in rectilinear homogeneous and inhomogeneous phantoms composed of slabs of solid water and lung. Computer generated computed tomography data sets of the rectilinear phantoms are supplied to the facility prior to audit for planning of a range of cases including reference fields, asymmetric fields, and wedged fields. The audit assesses 3D planning with 6 MV photons with a static (zero degree) gantry. Scoring is performed using local dose differences between the planned and measured dose within 80% of the field width. The overall audit result is determined by the maximum dose difference over all scoring points, cases, and planes. Pass (Optimal Level) is defined as maximum dose difference ≤3.3%, Pass (Action Level) is ≤5.0%, and Fail (Out of Tolerance) is >5.0%. At close of 2013, the ACDS had performed 24 Level II audits. 63% of the audits passed, 33% failed, and the remaining audit was not assessable. Of the 15 audits that passed, 3 were at Pass (Action Level). The high fail rate is largely due to a systemic issue with modeling asymmetric 60° wedges which caused a delivered overdose of 5%-8%. The ACDS has implemented a nonreference condition Level II type audit, based on ion chamber 2D array measurements in an inhomogeneous slab phantom. The powerful diagnostic ability of this audit has allowed the ACDS to rigorously test the treatment planning systems implemented in Australian radiotherapy facilities. Recommendations from audits have led to facilities modifying clinical practice and changing planning protocols.
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Pomalidomide for Multiple Myeloma
A summary of results from a phase III trial that compared the combination of pomalidomide (Pomalyst®) and low-dose dexamethasone versus high-dose dexamethasone alone in patients with multiple myeloma that has progressed despite other treatments.
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Zablotska, Lydia B.; Lane, Rachel S.D.; Frost, Stanley E.; Thompson, Patsy A.
2014-01-01
Uranium workers are chronically exposed to low levels of radon decay products (RDP) and gamma (γ) radiation. Risks of leukemia from acute and high doses of γ-radiation are well-characterized, but risks from lower doses and dose-rates and from RDP exposures are controversial. Few studies have evaluated risks of other hematologic cancers in uranium workers. The purpose of this study was to analyze radiation-related risks of hematologic cancers in the cohort of Eldorado uranium miners and processors first employed in 1932–1980 in relation to cumulative RDP exposures and γ-ray doses. The average cumulative RDP exposure was 100.2 working level months and the average cumulative whole-body γ-radiation dose was 52.2 millisievert. We identified 101 deaths and 160 cases of hematologic cancers in the cohort. Overall, male workers had lower mortality and cancer incidence rates for all outcomes compared with the general Canadian male population, a likely healthy worker effect. No statistically significant association between RDP exposure or γ-ray doses, or a combination of both, and mortality or incidence of any hematologic cancer was found. We observed consistent but non-statistically significant increases in risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma (HL) incidence and non-Hodgkin lymphoma (NHL) mortality with increasing γ-ray doses. These findings are consistent with recent studies of increased risks of CLL and NHL incidence after γ-radiation exposure. Further research is necessary to understand risks of other hematologic cancers from low-dose exposures to γ-radiation. PMID:24583244
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New approach to CT pixel-based photon dose calculations in heterogeneous media
DOE Office of Scientific and Technical Information (OSTI.GOV)
Wong, J.W.; Henkelman, R.M.
The effects of small cavities on dose in water and the dose in a homogeneous nonunit density medium illustrate that inhomogeneities do not act independently in photon dose perturbation, and serve as two constraints which should be satisfied by approximate methods of computed tomography (CT) pixel-based dose calculations. Current methods at best satisfy only one of the two constraints and show inadequacies in some intermediate geometries. We have developed an approximate method that satisfies both these constraints and treats much of the synergistic effect of multiple inhomogeneities correctly. The method calculates primary and first-scatter doses by first-order ray tracing withmore » the first-scatter contribution augmented by a component of second scatter that behaves like first scatter. Multiple-scatter dose perturbation values extracted from small cavity experiments are used in a function which approximates the small residual multiple-scatter dose. For a wide range of geometries tested, our method agrees very well with measurements. The average deviation is less than 2% with a maximum of 3%. In comparison, calculations based on existing methods can have errors larger than 10%.« less
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Proteomic analysis of mouse islets after multiple low-dose streptozotocin injection.
Xie, Xiaolei; Li, Shuai; Liu, Siyu; Lu, Yan; Shen, Pingping; Ji, Jianguo
2008-02-01
The islets of Langerhans are scattered throughout the pancreas and play a major role in the control of metabolic fuel homeostasis. To get a better understanding of the mechanisms underlying type 1 diabetes mellitus, we have generated a mouse model by injections of multiple low-dose streptozotocin. The islets in the mouse pancreas were handpicked and proteins from the islets were then isolated and separated by two-dimensional gel electrophoresis. Seven proteins were found to be altered significantly at expression level. Among the seven proteins, four were up-regulated and three were down-regulated in diabetic mice as compared with controls. These proteins were successfully identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and the changes of selected protein expression were further validated by quantitative real time PCR and Western blotting. Voltage-dependent anion-selective channel protein 1 and peroxiredoxin-4 were found for the first time to be associated with type 1 diabetes mellitus in mouse islets in the current study. These results suggest that glucose transport, beta cell proliferation/death, and oxidative stress play important roles in maintaining the balance of glucose level. Our study also provides novel insight into the mechanism of type 1 diabetes mellitus.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Zhao, Bo; Yang, Yong, E-mail: yangy2@upmc.edu; Li, Xiang
In linac-based stereotactic radiosurgery (SRS) and radiotherapy (SRT), circular cone(s) or conformal arc(s) are conventionally used to treat intracranial lesions. However, when the target is in close proximity to critical structures, it is frequently quite challenging to generate a quality plan using these techniques. In this study, we investigated the dosimetric characteristics of using high–dose rate RapidArc (RA) technique for radiosurgical treatment of intracranial lesions. A total of 10 intracranial SRS/SRT cases previously planned using dynamic conformal arc (DCA) or cone-based techniques have been included in this study. For each case, 3 treatment plans were generated: (1) a DCA planmore » with multiple noncoplanar arcs, (2) a high–dose rate RA plan with arcs oriented the same as DCA (multiple-arc RA), and 3) a high–dose rate RA plan with a single coplanar arc (single-arc RA). All treatment plans were generated under the same prescription and similar critical structure dose limits. Plan quality for different plans was evaluated by comparing various dosimetric parameters such as target coverage, conformity index (CI), homogeneity index (HI), critical structures, and normal brain tissue doses as well as beam delivery time. With similar critical structure sparing, high–dose rate RA plans can achieve much better target coverage, dose conformity, and dose homogeneity than the DCA plans can. Plan quality indices CI and HI, for the DCA, multiple-arc RA, and single-arc RA techniques, were measured as 1.67 ± 0.39, 1.32 ± 0.28, and 1.38 ± 0.30 and 1.24 ± 0.11, 1.10 ± 0.04, and 1.12 ± 0.07, respectively. Normal brain tissue dose (V{sub 12} {sub Gy}) was found to be similar for DCA and multiple-arc RA plans but much larger for the single-arc RA plans. Beam delivery was similar for DCA and multiple-arc RA plans but shorter with single-arc RA plans. Multiple-arc RA SRS/SRT can provide better treatment plans than conventional DCA plans, especially for complex cases.« less
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Gonçalves, Daniela; Alves, Gilberto; Fortuna, Ana; Soares-da-Silva, Patrício; Falcão, Amílcar
2017-05-15
Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n=8 per group) were orally treated with single (30, 60 or 90mg/kg) or multiple (30mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24h post-dosing through a cannula introduced in the tail vein of rats. After quantifying opicapone and BIA 9-1079 in plasma, a non-compartmental pharmacokinetic analysis was performed. Opicapone was quickly absorbed (time to reach the maximum plasma concentration≤2h) in both dosage regimens and the extent of systemic exposure to opicapone increased approximately in a dose-proportional manner after single-dosing within the studied dose range (30-90mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58-4.50h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen. Copyright © 2017 Elsevier Inc. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Barcellos-Hoff, Mary Helen
We plan to study tissue-level mechanisms important to human breast radiation carcinogenesis. We propose that the cell biology of irradiated tissues reveals a coordinated multicellular damage response program in which individual cell contributions are primarily directed towards suppression of carcinogenesis and reestablishment of homeostasis. We identified transforming growth factor β1 (TGFβ) as a pivotal signal. Notably, we have discovered that TGFβ suppresses genomic instability by controlling the intrinsic DNA damage response and centrosome integrity. However, TGFβ also mediates disruption of microenvironment interactions, which drive epithelial to mesenchymal transition in irradiated human mammary epithelial cells. This apparent paradox of positive andmore » negative controls by TGFβ is the topic of the present proposal. First, we postulate that these phenotypes manifest differentially following fractionated or chronic exposures; second, that the interactions of multiple cell types in tissues modify the responses evident in this single cell type culture models. The goals are to: 1) study the effect of low dose rate and fractionated radiation exposure in combination with TGFβ on the irradiated phenotype and genomic instability of non-malignant human epithelial cells; and 2) determine whether stromal-epithelial interactions suppress the irradiated phenotype in cell culture and the humanized mammary mouse model. These data will be used to 3) develop a systems biology model that integrates radiation effects across multiple levels of tissue organization and time. Modeling multicellular radiation responses coordinated via extracellular signaling could have a significant impact on the extrapolation of human health risks from high dose to low dose/rate radiation exposure.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Sahbaee, P; Zhang, Y; Solomon, J
Purpose: To substantiate the interdependency of contrast dose, radiation dose, and image quality in CT towards the patient- specific optimization of the imaging protocols Methods: The study deployed two phantom platforms. A variable sized (12, 18, 23, 30, 37 cm) phantom (Mercury-3.0) containing an iodinated insert (8.5 mgI/ml) was imaged on a representative CT scanner at multiple CTDI values (0.7–22.6 mGy). The contrast and noise were measured from the reconstructed images for each phantom diameter. Linearly related to iodine-concentration, contrast-to-noise ratio (CNR), were calculated for 16 iodine-concentration levels (0–8.5 mgI/ml). The analysis was extended to a recently developed suit ofmore » 58 virtual human models (5D XCAT) with added contrast dynamics. Emulating a contrast-enhanced abdominal image procedure and targeting a peak-enhancement in aorta, each XCAT phantom was “imaged” using a simulation platform (CatSim, GE). 3D surfaces for each patient/size established the relationship between iodine-concentration, dose, and CNR. The ratios of change in iodine-concentration versus dose (IDR) to yield a constant change in CNR were calculated for each patient size. Results: Mercury phantom results show the image-quality size- dependence on CTDI and IC levels. For desired image-quality values, the iso-contour-lines reflect the trade off between contrast-material and radiation doses. For a fixed iodine-concentration (4 mgI/mL), the IDR values for low (1.4 mGy) and high (11.5 mGy) dose levels were 1.02, 1.07, 1.19, 1.65, 1.54, and 3.14, 3.12, 3.52, 3.76, 4.06, respectively across five sizes. The simulation data from XCAT models confirmed the empirical results from Mercury phantom. Conclusion: The iodine-concentration, image quality, and radiation dose are interdependent. The understanding of the relationships between iodine-concentration, image quality, and radiation dose will allow for a more comprehensive optimization of CT imaging devices and techniques, providing the methodology to balance iodine-concentration and dose based on patient’s attributes.« less
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Aw-Zoretic, J; Seth, D; Katzman, G; Sammet, S
2014-10-01
The purpose of this review is to determine the averaged effective dose and lifetime attributable risk factor from multiple head computed tomography (CT) dose data on children with ventriculoperitoneal shunts (VPS). A total of 422 paediatric head CT exams were found between October 2008 and January 2011 and retrospectively reviewed. The CT dose data was weighted with the latest IRCP 103 conversion factor to obtain the effective dose per study and the averaged effective dose was calculated. Estimates of the lifetime attributable risk were also calculated from the averaged effective dose using a conversion factor from the latest BEIR VII report. Our study found the highest effective doses in neonates and the lowest effective doses were observed in the 10-18 years age group. We estimated a 0.007% potential increase risk in neonates and 0.001% potential increased risk in teenagers over the base risk. Multiple head CTs in children equates to a slight potential increase risk in lifetime attributable risk over the baseline risk for cancer, slightly higher in neonates relative to teenagers. The potential risks versus clinical benefit must be assessed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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Heery, Christopher R; O'Sullivan-Coyne, Geraldine; Madan, Ravi A; Cordes, Lisa; Rajan, Arun; Rauckhorst, Myrna; Lamping, Elizabeth; Oyelakin, Israel; Marté, Jennifer L; Lepone, Lauren M; Donahue, Renee N; Grenga, Italia; Cuillerot, Jean-Marie; Neuteboom, Berend; Heydebreck, Anja von; Chin, Kevin; Schlom, Jeffrey; Gulley, James L
2017-05-01
Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development. This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3 + 3 cohort design and assigned patients sequentially at trial entry according to the 3 + 3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0-1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT01772004. Patient recruitment to the dose-escalation part reported here is closed. Between Jan 31, 2013, and Oct 8, 2014, 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). 18 patients were analysed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. In all 53 enrolled patients (the safety analysis set), common treatment-related adverse events (occurring in >10% of patients) included fatigue (21 patients [40%]), influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]). Grade 3-4 treatment-related adverse events occurred in nine (17%) of 53 patients, with autoimmune disorder (n=3), increased blood creatine phosphokinase (n=2), and increased aspartate aminotransferase (n=2) each occurring in more than one patient (autoimmune disorder in two patients at 10 mg/kg and one patient at 20 mg/kg, increased blood creatine phosphokinase in two patients at 20 mg/kg, and increased aspartate aminotransferase in one patient at 1 mg/kg, and one patient at 10 mg/kg). Six (11%) of 53 patients had a serious treatment-related adverse event: autoimmune disorder (two [13%]), lower abdominal pain (one [7%]), fatigue (one [7%]), and influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level, and autoimmune disorder (one [5%]), increased amylase (one [5%]), myositis (one [5%]), and dysphonia (one [5%]) in three patients who received the 20 mg/kg dose. We recorded some evidence of clinical activity in various solid tumours, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95-99 h (3·9-4·1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study. Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. National Cancer Institute and Merck KGaA. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Hu, Chuanpu; Randazzo, Bruce; Sharma, Amarnath; Zhou, Honghui
2017-10-01
Exposure-response modeling plays an important role in optimizing dose and dosing regimens during clinical drug development. The modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate the level of improvement achievable by jointly modeling two such endpoints in the latent variable IDR modeling framework through the sharing of model parameters. This is illustrated with an application to the exposure-response of guselkumab, a human IgG1 monoclonal antibody in clinical development that blocks IL-23. A Phase 2b study was conducted in 238 patients with psoriasis for which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores. A latent variable Type I IDR model was developed to evaluate the therapeutic effect of guselkumab dosing on 75, 90 and 100% improvement of PASI scores from baseline and PGA scores, with placebo effect empirically modeled. The results showed that the joint model is able to describe the observed data better with fewer parameters compared with the common approach of separately modeling the endpoints.
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Kunka, R L; Hussey, E K; Shaw, S; Warner, P; Aubert, B; Richard, I; Fowler, P A; Pakes, G E
1997-06-01
A suppository formulation of the 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single doses (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3-14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not dose-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to dose from 25 to 100 mg; area under the plasma concentration-time curve (AUC infinity) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5 h, and the t1/2 was approximately 2 h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t 1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite concentrations were two to three-fold higher than corresponding sumatriptan concentrations. No clinically significant accumulation of sumatriptan or its metabolite occurred. Overall, these studies show that sumatriptan administration via a suppository formulation is well tolerated, allows rapid absorption of sumatriptan, results in sumatriptan Cmax values that are proportional to dose from 25 to 100 mg, and is not associated with accumulation of sumatriptan or its metabolite.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Albert, R.E.; Burns, F.J.
1976-02-01
Results are reported from experiments that involved either single or multiple doses of benzo(a)pyrene in mouse skin followed by prolonged observation. Preliminary results indicate linearity in dose and time and no evidence of recovery or enhancement for multiple doses of initiator given for extended periods of time. (auth)
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Triple dose of gadolinium-DTPA and delayed MRI in patients with benign multiple sclerosis.
Filippi, M; Capra, R; Campi, A; Colombo, B; Prandini, F; Marcianò, N; Gasparotti, R; Comi, G
1996-01-01
OBJECTIVES--To evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) or delayed MRI increase the number, size, and conspicuousness of enhancing lesions in patients with benign multiple sclerosis. METHODS--T1 weighted brain MRI was carried out on 20 patients with benign multiple sclerosis (expanded disability status scale < 3 with a disease duration > 10 years) in two sessions. In the first session, one scan was obtained before and two scans five to seven minutes and 20-30 minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, the same procedure was repeated with 0.3 mmol/kg Gd-DTPA (triple dose). RESULTS--Nine enhancing lesions were found in seven patients (35%) using the standard dose of Gd-DTPA. The numbers of enhancing lesions increased to 13 (P = 0.03) and the number of patients with such lesions to eight (40%) on the delayed standard dose scans. On the early triple dose scans, we found 19 enhancing lesions in 10 patients (50%). The number of enhancing lesions was significantly higher (P = 0.01) than that obtained with the early standard dose. The number of enhancing lesions was 18 and the number of "active" patients 11 (55%) on the delayed triple dose scans. The enhancing areas increased progressively from the early standard dose scans to the delayed triple dose scans. The contrast ratios of the lesions detected in early standard dose scans was lower than those of lesions present in the early (P = 0.01) and delayed (P = 0.04) triple dose scans. CONCLUSIONS--More enhancing lesions were detected in patients with benign multiple sclerosis with both delay of MRI and the use of triple dose of Gd-DTPA suggesting that the amount of inflammation in the lesions of such patients is mild and heterogeneous. Images PMID:8778257
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Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu
2005-07-01
We compared the results of the multiple-dose guinea pig maximization test (GPMT) and the non-radioactive murine local lymph-node assay (LLNA) for various biocides. Thirteen out of 17 positive biocides in the GPMT gave positive results in the LLNA. In the GPMT, the minimum first induction doses ranged over four orders (0.00005-0.5%), while elicitation-threshold doses, which were evaluated using an optimally sensitized group of animals in the multiple-dose studies, ranged over five orders (0.00006-2.8%). In the LLNA, minimum induction doses ranged over more than three orders (0.01-30%). With respect to 13 biocides that were positive in both the GPMT and the LLNA, results were quantitatively compared. When compared after conversion to corresponding area doses (microg/cm), the minimum doses required to elicit skin reaction in guinea pigs were always lower than that for induction in mice with all biocides. Correlation between minimum induction doses from the GPMT and the LLNA seemed poor (r=0.57), while that between minimum induction doses in the LLNA and elicitation-threshold doses in the GPMT was relatively good (r=0.73). The results suggest the possibility to estimate human elicitation-threshold doses, which are definitely lacking in the process of risk assessment for skin-sensitizers, from the data of the LLNA.
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Thalakada, Rosanne; Legal, Michael; Lau, Tim T Y; Luey, Tiffany; Batterink, Josh; Ensom, Mary H H
2012-01-01
Background: Recent guidelines recommend a vancomycin trough (predose) level between 15 and 20 mg/L in the treatment of invasive gram-positive infections, but most initial dosing nomograms are designed to achieve lower targets (5–15 mg/L). Clinicians need guidance about appropriate initial dosing to achieve the higher target. Objective: To develop and validate a high-target vancomycin dosing nomogram to achieve trough levels of 15–20 mg/L. Methods: A retrospective study was conducted at 2 teaching hospitals, St Paul’s Hospital and Vancouver General Hospital in Vancouver, British Columbia. Patients who were treated with vancomycin between January 2008 and June 2010 and who had achieved a trough level of 14.5–20.5 mg/L were identified. Demographic and clinical data were collected. Multiple linear regression was used to develop a vancomycin dosing nomogram for each hospital site. An integrated nomogram was constructed by merging the data from the 2 hospitals. A unique set of patients at each institution was used for validating their respective nomograms and a pooled group of patients for validating the integrated nomogram. Predictive success was evaluated, and a nomogram was deemed significantly different from another nomogram if p < 0.05 via “χ2 testing. Results: Data from 78 patients at one hospital and 91 patients at the other were used in developing the respective institutional nomograms. For each hospital’s data set, both age and initial serum creatinine were significantly associated with the predicted dosing interval (p < 0.001). Validation in a total of 105 test patients showed that the integrated nomogram had a predictive success rate of 56%. Conclusions: A novel vancomycin dosing nomogram was developed and validated at 2 Canadian teaching hospitals. This integrated nomogram is a tool that clinicians can use in selecting appropriate initial vancomycin regimens on the basis of age and serum creatinine, to achieve high-target levels of 15–20 mg/L. The nomogram should not replace clinical judgment for patients with unstable and/or reduced renal function. PMID:22783028
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Previous Dosage of Allopurinol Is a Strong Determinant of Febuxostat Efficacy.
Koide, Hiroyoshi; Hira, Daiki; Tsujimoto, Masayuki; Katsube, Yurie; Minegaki, Tetsuya; Uzu, Takashi; Ikeda, Yoshito; Morita, Shin-Ya; Nishiguchi, Kohshi; Terada, Tomohiro
2017-01-01
Febuxostat has currently played pivotal role in the treatment of hyperuricemia, but there is little comprehensive information for the determinants of individual difference in efficacy of febuxostat. Therefore, the present study, a retrospective investigation, was carried out to analyze the effects of patient characteristics on the efficacy of febuxostat. A total of 225 patients who were continuously prescribed the same dose of febuxostat for 8-12 weeks from the initial therapy were enrolled in the present study. The data, including patient information and laboratory data, were collected from electronic medical records. Serum urate lowering effects of febuxostat were evaluated by calculating the change in serum urate level at baseline and at 8-12 weeks after starting febuxostat. The multiple regression analysis showed the change in serum urate level was significantly lower in male patients and in those with a lower baseline serum urate level, higher previous dose of allopurinol, lower dose of febuxostat and lower body surface area-unadjusted estimated glomerular filtration rate. Concomitantly administered drugs did not show a significantly influence on the efficacy of febuxostat. In conclusion, it should be noted that the serum urate lowering efficacy of febuxostat may decrease in patients with a higher previous dose of allopurinol, renal impairment or male patients. The basic findings of the present study are believed to contribute to the proper use of febuxostat.
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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.
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Chen, Feng; Li, Li; Xu, Fang; Sun, Yan; Du, Feifei; Ma, Xutao; Zhong, Chenchun; Li, Xiuxue; Wang, Fengqing; Zhang, Nating; Li, Chuan
2013-09-01
Flavonols and terpene lactones are putatively responsible for the properties of Ginkgo biloba leaf extracts that relate to prevention and treatment of cardiovascular disease and cerebral insufficiency. Here, we characterized rat systemic and cerebral exposure to these ginkgo compounds after dosing, as well as the compounds' pharmacokinetics. Rats received single or multiple doses of ShuXueNing injection (prepared from GBE50 for intravenous administration) or GBE50 (a standardized extract of G. biloba leaves for oral administration). Brain delivery of the ginkgo compounds was assessed with microdialysis. Various rat samples were analysed using liquid chromatography/mass spectrometry. Slow terminal elimination features of the flavonols counterbalanced the influence of poor oral bioavailability on their systemic exposure levels, which also resulted in significant accumulation of the compounds in plasma during the subchronic treatment with ShuXueNing injection and GBE50. Unlike the flavonols, the terpene lactones had poor enterohepatic circulation due to their rapid renal excretion and unknown metabolism. The flavonol glycosides occurred as major forms in plasma after dosing with ShuXueNing injection, while the flavonol aglycone conjugates were predominant in plasma after dosing with GBE50. Cerebral exposure was negligible for the flavonols and low for the terpene lactones. Unlike the significant systemic exposure levels, the levels of cerebral exposure to the flavonols and terpene lactones are low. The elimination kinetic differences between the two classes of ginkgo compounds influence their relative systemic exposure levels. The information gained is relevant to linking ginkgo administration to the medicinal effects. © 2013 The Authors. British Journal of Pharmacology published by John Wiley &. Sons Ltd on behalf of The British Pharmacological Society.
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Chen, Feng; Li, Li; Xu, Fang; Sun, Yan; Du, Feifei; Ma, Xutao; Zhong, Chenchun; Li, Xiuxue; Wang, Fengqing; Zhang, Nating; Li, Chuan
2013-01-01
BACKGROUND AND PURPOSE Flavonols and terpene lactones are putatively responsible for the properties of Ginkgo biloba leaf extracts that relate to prevention and treatment of cardiovascular disease and cerebral insufficiency. Here, we characterized rat systemic and cerebral exposure to these ginkgo compounds after dosing, as well as the compounds’ pharmacokinetics. EXPERIMENTAL APPROACH Rats received single or multiple doses of ShuXueNing injection (prepared from GBE50 for intravenous administration) or GBE50 (a standardized extract of G. biloba leaves for oral administration). Brain delivery of the ginkgo compounds was assessed with microdialysis. Various rat samples were analysed using liquid chromatography/mass spectrometry. KEY RESULTS Slow terminal elimination features of the flavonols counterbalanced the influence of poor oral bioavailability on their systemic exposure levels, which also resulted in significant accumulation of the compounds in plasma during the subchronic treatment with ShuXueNing injection and GBE50. Unlike the flavonols, the terpene lactones had poor enterohepatic circulation due to their rapid renal excretion and unknown metabolism. The flavonol glycosides occurred as major forms in plasma after dosing with ShuXueNing injection, while the flavonol aglycone conjugates were predominant in plasma after dosing with GBE50. Cerebral exposure was negligible for the flavonols and low for the terpene lactones. CONCLUSION AND IMPLICATIONS Unlike the significant systemic exposure levels, the levels of cerebral exposure to the flavonols and terpene lactones are low. The elimination kinetic differences between the two classes of ginkgo compounds influence their relative systemic exposure levels. The information gained is relevant to linking ginkgo administration to the medicinal effects. PMID:23808355
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Aluminum exacerbates cyclosporin induced nephrotoxicity in rats.
Tariq, M; Morais, C; Sujata, B; Sobki, S; al Sulaiman, M; al Khader, A
1999-01-01
Cyclosporin (CSA) has been universally used as an immunosuppressant for the management of allotransplantation and autoimmune diseases. However, nephrotoxicity of CSA limits its use to optimum level. Aluminum (Al) is an extensively distributed element in the environment and human exposure to this metal is unavoidable. Recent studies suggest that even a slight impairment of renal function may increase the Al body burden significantly, which may lead to neurotoxicity, nephrotoxicity, osteodystrophy or hypochromic anemia. In the present study, an attempt was made to study the effect of concomitant use of Al and CSA on structure and function of kidney in rats. This study was undertaken in two steps. In the first set of experiments, the effect of single dose of Al (1% Al2(SO4)3 18H2O) on the nephrotoxicity of multiple doses of CSA (12.5 mg/kg, 25 mg/kg and 50 mg/kg) was studied, where as in the second set of experiments the effect of multiple doses of Al (0.25%, 0.5% and 1%) on single dose of CSA (50 mg/kg) was undertaken. Male Sprague-Dawley rats (weighing 230 +/- 20 g) were used in this study. CSA was given once a day by gavage for seven days, where as Al was given in drinking water for the same period. Twenty four hours after the last dose of CSA, animals were sacrificed and blood and kidney were collected for biochemical and histopathological studies. The bio-chemical parameters included blood urea nitrogen (BUN), serum creatinine (SCr), CSA and Al levels. The kidney homogenates were assayed for malondialdehyde (MDA) and lipid hydroperoxides (LPH). Treatment of rats with CSA alone produced dose-dependent structural and functional changes in kidney. Although Al alone failed to produce any deleterious effect on renal function, it significantly increased the bioavailability and nephrotoxicity of CSA. Al also exacerbated CSA induced increase in oxidative stress (as evident by increased MDA and LPH). Thus, the exacerbation of CSA nephrotoxicity by Al may be attributed to increased bioavailability of CSA and excessive generation of free radicals following concomitant use of these drugs.
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Zhou, Qing-he; Zhu, Bo; Wei, Chang-na; Yan, Min
2016-03-24
Studies have shown that abdominal girth and vertebral column length have high predictive value for spinal spread after administering a dose of plain bupivacaine. we designed a study to identify the specific correlations between abdominal girth, vertebral column length and a 0.5% dosage of plain bupivacaine, which should provide a minimum upper block level (T12) and a suitable upper block level (T10) for lower limb surgeries. A suitable dose of 0.5% plain bupivacaine was administered intrathecally between the L3 and L4 vertebrae for lower limb surgeries. If the upper cephalad spread of the patient by loss of pinprick discrimination was T12 or T10, the patient was enrolled in this study. Five patient variables and intrathecal plain bupivacaine dose were recorded. Linear regression and multiple regression analyses were performed. Totals of 111 patients and 121 patients who lost pinprick discrimination at T12 and T10, respectively, were analyzed in this study. Linear regression analysis showed that only abdominal girth and plain bupivacaine dose were strongly correlated (r =-0.827 for T12, r = -0.806 for T10; both p < 0.0001). Multiple linear regression analysis showed that both abdominal girth and vertebral column length were the key determinants of plain bupivacaine dose (both p < 0.0001). R(2) was 0.874 and 0.860 for the loss of pinprick discrimination at T12 and T10, respectively. Our data indicated that vertebral column length and abdominal girth were strongly correlated with the dosage of intrathecal plain bupivacaine for the loss of pinprick discrimination at T12 and T10. The two regression equations were YT12 = 3.547 + 0.045X1-0.044X2 and YT10 = 3.848 + 0.047X1- 0.046X2 (Y, 0.5% plain bupivacaine volume; X1, vertebral column length;and X 2, abdominal girth), which can accurately predict the minimum and suitable intrathecal bupivacaine dose for lower limb surgery to a great extent, separately.
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López-López, C; Arranz-Esteban, A; Martinez-Ureta, M V; Sánchez-Rascón, M C; Morales-Sánchez, C; Chico-Fernández, M
To analyse the influence of psychotropic substance use on the level of pain in patients with severe trauma. Longitudinal analytical study. Intensive Care Unit (ICU) of Trauma and Emergencies. severe trauma, non-communicative and mechanical ventilation >48hours. Two groups of patients were created: users and non-users of psychotropic substances according to medical records. Measurement of pain level at baseline and during mobilization, using the Pain Indicator Behaviour Scale. demographic characteristics, pain score, sedation level and type and dose of analgesia and sedation. Sample of 84 patients, 42 in each group. The pain level in both groups, during mobilisation, showed significant differences p=0.011, with a mean of 3.11(2.40) for the user group and 1.83(2.14) for the non-user group. A relative risk of 2.5 CI (1,014-6,163) was found to have moderate / severe pain in the user group compared to the non-user group. The mean dose of analgesia and continuous sedation was significantly higher in the user group: P=.032 and P=.004 respectively. There was no difference in bolus dose of analgesia and sedation with P=.624 and P=.690 respectively. Patients with a history of consumption of psychoactive substances show higher levels of pain and experience a higher risk of this being moderate/severe compared to non-users despite receiving higher doses of analgesia and sedation infusion. Key words: pain, multiple trauma, drug users. Copyright © 2017 Sociedad Española de Enfermería Intensiva y Unidades Coronarias (SEEIUC). Publicado por Elsevier España, S.L.U. All rights reserved.
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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).
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Faggioni, Lorenzo; Paolicchi, Fabio; Bastiani, Luca; Guido, Davide; Caramella, Davide
2017-01-01
To evaluate the awareness of radiation protection issues and the knowledge of dose levels of imaging procedures among medical students, radiology residents, and radiography students at an academic hospital. A total of 159 young doctors and students (including 60 radiology residents, 56 medical students, and 43 radiography students) were issued a questionnaire consisting of 16 multiple choice questions divided into three separated sections (i.e., demographic data, awareness about radiation protection issues, and knowledge about radiation dose levels of common radiological examinations). Medical students claimed to have at least a good knowledge of radiation protection issues more frequently than radiology residents and radiography students (94.4% vs 55% and 35.7%, respectively; P<0.05), with no cases of perceived excellent knowledge among radiography students. However, the actual knowledge of essential radiation protection topics such as regulations, patient and tissue susceptibility to radiation damage, professional radiation risk and dose optimisation, as well as of radiation doses delivered by common radiological procedures was significantly worse among medical students than radiology residents and radiography students (P<0.05). Those latter significantly outperformed radiology residents as to knowledge of radiation protection issues (P<0.01). Overall, less than 50% of survey respondents correctly answered all questions of the survey. Radiology residents, radiography students and medical students have a limited awareness about radiation protection, with a specific gap of knowledge concerning real radiation doses of daily radiological examinations. Both undergraduate and postgraduate teaching needs to be effectively implemented with radiation safety courses. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Roberts, S.A.; Price, V.F.; Jollow, D.J.
1990-09-01
High doses of 3-hydroxyacetanilide (3HAA), a structural isomer of acetaminophen, do not produce hepatocellular necrosis in normal male hamsters or in those sensitized to acetaminophen-induced liver damage by pretreatment with a combination of 3-methylcholanthrene, borneol, and diethyl maleate. Although 3HAA was not hepatotoxic, the administration of acetyl-labeled (3H or 14C)3HAA (400 mg/kg, ip) produced levels of covalently bound radiolabel that were similar to those observed after an equimolar, hepatotoxic dose of (G-3H)acetaminophen. The covalent nature of 3HAA binding was demonstrated by retention of the binding after repetitive organic solvent extraction following protease digestion. Hepatic and renal covalent binding after 3HAAmore » was approximately linear with both dose and time. In addition, 3HAA produced only a modest depletion of hepatic glutathione, suggesting the lack of a glutathione threshold. 3-Methylcholanthrene pretreatment increased and pretreatment with cobalt chloride and piperonyl butoxide decreased the hepatic covalent binding of 3HAA, indicating the involvement of cytochrome P450 in the formation of the 3HAA reactive metabolite. The administration of multiple doses or a single dose of (ring-3H)3HAA to hamsters pretreated with a combination of 3-methylcholanthrene, borneol, and diethyl maleate produced hepatic levels of 3HAA covalent binding that were in excess of those observed after a single, hepatotoxic acetaminophen dose. These data suggest that the nature and/or the intracellular processing of the reactive metabolites of acetaminophen and 3HAA are different. These data also demonstrate that absolute levels of covalently bound xenobiotic metabolites cannot be utilized as absolute predictors of cytotoxic potential.« less
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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.
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Modeling Environment for Total Risk-4M
MENTOR-4M uses an integrated, mechanistically consistent, source-to-dose modeling framework to quantify simultaneous exposures and doses of individuals and populations to multiple contaminants. It is an implementation of the MENTOR system for exposures to Multiple contaminants fr...
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NASA Astrophysics Data System (ADS)
Lavoie, Lindsey K.
The technology of computed tomography (CT) imaging has soared over the last decade with the use of multi-detector CT (MDCT) scanners that are capable of performing studies in a matter of seconds. While the diagnostic information obtained from MDCT imaging is extremely valuable, it is important to ensure that the radiation doses resulting from these studies are at acceptably safe levels. This research project focused on the measurement of organ doses resulting from modern MDCT scanners. A commercially-available dosimetry system was used to measure organ doses. Small dosimeters made of optically-stimulated luminescent (OSL) material were analyzed with a portable OSL reader. Detailed verification of this system was performed. Characteristics studied include energy, scatter, and angular responses; dose linearity, ability to erase the exposed dose and ability to reuse dosimeters multiple times. The results of this verification process were positive. While small correction factors needed to be applied to the dose reported by the OSL reader, these factors were small and expected. Physical, tomographic pediatric and adult phantoms were used to measure organ doses. These phantoms were developed from CT images and are composed of tissue-equivalent materials. Because the adult phantom is comprised of numerous segments, dosimeters were placed in the phantom at several organ locations, and doses to select organs were measured using three clinical protocols: pediatric craniosynostosis, adult brain perfusion and adult cardiac CT angiography (CTA). A wide-beam, 320-slice, volumetric CT scanner and a 64-slice, MDCT scanner were used for organ dose measurements. Doses ranged from 1 to 26 mGy for the pediatric protocol, 1 to 1241 mGy for the brain perfusion protocol, and 2-100 mGy for the cardiac protocol. In most cases, the doses measured on the 64-slice scanner were higher than those on the 320-slice scanner. A methodology to measure organ doses with OSL dosimeters received from CT imaging has been presented. These measurements are especially important in keeping with the ALARA (as low as reasonably achievable) principle. While diagnostic information from CT imaging is valuable and necessary, the dose to patients is always a consideration. This methodology aids in this important task. (Full text of this dissertation may be available via the University of Florida Libraries web site. Please check http://www.uflib.ufl.edu/etd.html)
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Simulated space radiation-induced mutants in the mouse kidney display widespread genomic change
Grygoryev, Dmytro; Lasarev, Michael; Ohlrich, Anna; Rwatambuga, Furaha A.; Johnson, Sorrel; Dan, Cristian; Eckelmann, Bradley; Hryciw, Gwen; Mao, Jian-Hua; Snijders, Antoine M.; Gauny, Stacey; Kronenberg, Amy
2017-01-01
Exposure to a small number of high-energy heavy charged particles (HZE ions), as found in the deep space environment, could significantly affect astronaut health following prolonged periods of space travel if these ions induce mutations and related cancers. In this study, we used an in vivo mutagenesis assay to define the mutagenic effects of accelerated 56Fe ions (1 GeV/amu, 151 keV/μm) in the mouse kidney epithelium exposed to doses ranging from 0.25 to 2.0 Gy. These doses represent fluences ranging from 1 to 8 particle traversals per cell nucleus. The Aprt locus, located on chromosome 8, was used to select induced and spontaneous mutants. To fully define the mutagenic effects, we used multiple endpoints including mutant frequencies, mutation spectrum for chromosome 8, translocations involving chromosome 8, and mutations affecting non-selected chromosomes. The results demonstrate mutagenic effects that often affect multiple chromosomes for all Fe ion doses tested. For comparison with the most abundant sparsely ionizing particle found in space, we also examined the mutagenic effects of high-energy protons (1 GeV, 0.24 keV/μm) at 0.5 and 1.0 Gy. Similar doses of protons were not as mutagenic as Fe ions for many assays, though genomic effects were detected in Aprt mutants at these doses. Considered as a whole, the data demonstrate that Fe ions are highly mutagenic at the low doses and fluences of relevance to human spaceflight, and that cells with considerable genomic mutations are readily induced by these exposures and persist in the kidney epithelium. The level of genomic change produced by low fluence exposure to heavy ions is reminiscent of the extensive rearrangements seen in tumor genomes suggesting a potential initiation step in radiation carcinogenesis. PMID:28683078
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Simulated space radiation-induced mutants in the mouse kidney display widespread genomic change.
Turker, Mitchell S; Grygoryev, Dmytro; Lasarev, Michael; Ohlrich, Anna; Rwatambuga, Furaha A; Johnson, Sorrel; Dan, Cristian; Eckelmann, Bradley; Hryciw, Gwen; Mao, Jian-Hua; Snijders, Antoine M; Gauny, Stacey; Kronenberg, Amy
2017-01-01
Exposure to a small number of high-energy heavy charged particles (HZE ions), as found in the deep space environment, could significantly affect astronaut health following prolonged periods of space travel if these ions induce mutations and related cancers. In this study, we used an in vivo mutagenesis assay to define the mutagenic effects of accelerated 56Fe ions (1 GeV/amu, 151 keV/μm) in the mouse kidney epithelium exposed to doses ranging from 0.25 to 2.0 Gy. These doses represent fluences ranging from 1 to 8 particle traversals per cell nucleus. The Aprt locus, located on chromosome 8, was used to select induced and spontaneous mutants. To fully define the mutagenic effects, we used multiple endpoints including mutant frequencies, mutation spectrum for chromosome 8, translocations involving chromosome 8, and mutations affecting non-selected chromosomes. The results demonstrate mutagenic effects that often affect multiple chromosomes for all Fe ion doses tested. For comparison with the most abundant sparsely ionizing particle found in space, we also examined the mutagenic effects of high-energy protons (1 GeV, 0.24 keV/μm) at 0.5 and 1.0 Gy. Similar doses of protons were not as mutagenic as Fe ions for many assays, though genomic effects were detected in Aprt mutants at these doses. Considered as a whole, the data demonstrate that Fe ions are highly mutagenic at the low doses and fluences of relevance to human spaceflight, and that cells with considerable genomic mutations are readily induced by these exposures and persist in the kidney epithelium. The level of genomic change produced by low fluence exposure to heavy ions is reminiscent of the extensive rearrangements seen in tumor genomes suggesting a potential initiation step in radiation carcinogenesis.
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2014-01-01
Background Fluralaner is a novel systemic insecticide and acaricide that provides long acting efficacy in dogs after a single oral treatment. This study investigated the safety of oral administration of fluralaner in chewable tablets to dogs at the highest recommended treatment dose and at multiples of this dose. Methods Thirty-two (16 male and 16 female) healthy 8-week old Beagle dogs weighing 2.0 - 3.6 kg at first administration were included in the study. Fluralaner was administered on three occasions at 8-week intervals at doses of up to 56, 168, and 280 mg fluralaner/kg body weight, equivalent to 1, 3, and 5 times the highest recommended treatment dose of fluralaner; sham dosed dogs served as controls. During the study, all dogs were clinically observed, and their health was carefully monitored including body weight development, food consumption and measurement of hematology, coagulation, clinical chemistry (including measurement of levels of ACTH and C-reactive protein) and urinalysis. Following euthanasia of the dogs, complete gross post mortem examination, including organ weight determination, and histopathological examination of multiple tissues were conducted. Results There were no clinical findings related to fluralaner treatment. Statistically significant differences between the treated groups and the control group were observed for some clinical pathology parameters and organ weights; none of these findings were considered to be of clinical relevance. Conclusions Oral administration of fluralaner at the highest recommended treatment dose (56 mg/kg) at 8-week intervals is well tolerated and has a safety margin of more than five in healthy dogs eight weeks of age or older and weighing at least 2 kg. PMID:24606886
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Pharmacokinetics of isotretinoin during repetitive dosing to patients.
Brazzell, R K; Vane, F M; Ehmann, C W; Colburn, W A
1983-01-01
The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Okamoto, Masahiko, E-mail: masaoka@showa.gunma-u.ac.jp; Ishikawa, Hitoshi; Ebara, Takeshi
2012-02-01
Purpose: To determine the predictive risk factors for Grade 2 or worse rectal bleeding after high-dose-rate brachytherapy (HDR-BT) combined with hypofractionated external-beam radiotherapy (EBRT) for prostate cancer using dose-volume histogram analysis. Methods and Materials: The records of 216 patients treated with HDR-BT combined with EBRT were analyzed. The treatment protocols for HDR-BT were 5 Gy Multiplication-Sign five times in 3 days or 7 Gy Multiplication-Sign three, 10.5 Gy Multiplication-Sign two, or 9 Gy Multiplication-Sign two in 2 days. The EBRT doses ranged from 45 to 51 Gy with a fractional dose of 3 Gy. Results: In 20 patients Grade 2more » or worse rectal bleeding developed, and the cumulative incidence rate was 9% at 5 years. By converting the HDR-BT and EBRT radiation doses into biologic effective doses (BED), the BED{sub 3} at rectal volumes of 5% and 10% in the patients who experienced bleeding were significantly higher than those in the remaining 196 patients. Univariate analysis showed that a higher rectal BED{sub 3-5%} and the use of fewer needles in brachytherapy were correlated with the incidence of bleeding, but BED{sub 3-5%} was found to be the only significant factor on multivariate analysis. Conclusions: The radiation dose delivered to small rectal lesions as 5% is important for predicting Grade 2 or worse rectal bleeding after HDR-BT combined with EBRT for prostate cancer.« less
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Yoshii, Yukie; Matsumoto, Hiroki; Yoshimoto, Mitsuyoshi; Zhang, Ming-Rong; Oe, Yoko; Kurihara, Hiroaki; Narita, Yoshitaka; Jin, Zhao-Hui; Tsuji, Atsushi B; Yoshinaga, Keiichiro; Fujibayashi, Yasuhisa; Higashi, Tatsuya
2018-02-01
Glioblastoma is the most aggressive malignant brain tumor in humans and is difficult to cure using current treatment options. Hypoxic regions are frequently found in glioblastoma, and increased levels of hypoxia are associated with poor clinical outcomes of glioblastoma patients. Hypoxia plays important roles in the progression and recurrence of glioblastoma because of drug delivery deficiencies and induction of hypoxia-inducible factor-1α in tumor cells, which lead to poor prognosis. We focused on a promising hypoxia-targeted internal radiotherapy agent, 64 Cu-diacetyl-bis (N 4 -methylthiosemicarbazone) ( 64 Cu-ATSM), to address the need for additional treatment for glioblastoma. This compound can target the overreduced state under hypoxic conditions within tumors. Clinical positron emission tomography studies using radiolabeled Cu-ATSM have shown that Cu-ATSM accumulates in glioblastoma and its uptake is associated with high hypoxia-inducible factor-1α expression. To evaluate the therapeutic potential of this agent for glioblastoma, we examined the efficacy of 64 Cu-ATSM in mice bearing U87MG glioblastoma tumors. Administration of single dosage (18.5, 37, 74, 111, and 148 MBq) and multiple dosages (37 MBq × 4) of 64 Cu-ATSM was investigated. Single administration of 64 Cu-ATSM in high-dose groups dose-dependently inhibited tumor growth and prolonged survival, with slight and reverse signs of adverse events. Multiple dosages of 64 Cu-ATSM remarkably inhibited tumor growth and prolonged survival. By splitting the dose of 64 Cu-ATSM, no adverse effects were observed. Our findings indicate that multiple administrations of 64 Cu-ATSM have effective antitumor effects in glioblastoma without side effects, indicating its potential for treating this fatal disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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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
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Barilla, Denise; Prasad, Pratapa; Hubert, Martine; Gumbhir-Shah, Kavita
2004-03-01
This was an open-label, randomized, three-period, three-treatment, multiple dose, crossover study in 12 healthy male and female subjects. This study evaluated single dose and steady-state pharmacokinetics of fluvastatin following single and multiple dose administrations of a new extended release fluvastatin 8 h matrix tablet, Lescol XL 80 mg and 160 mg doses once a day. The study also included a twice a day administration of an immediate release (IR) form of fluvastatin capsule, Lescol, for comparative purposes. All doses were administered for 7 days. The safety and tolerability were also assessed. The pharmacokinetics of fluvastatin were evaluated on days 1 and 7 following each treatment. Fluvastatin systemic exposure was 50% less when administered as Lescol XL 80 mg qd compared with Lescol IR 40 mg bid. Conversely, fluvastatin systemic exposure was 22% higher when administered as Lescol XL 160 mg qd compared with Lescol IR 40 mg bid. Single doses of Lescol XL 80 mg and 160 mg were dose proportional but, deviation (30%) from dose proportionality was observed for the Lescol XL 160 mg at steady-state. There appeared to be moderate (20%-40%) accumulation of serum fluvastatin maximal concentrations and exposure after multiple doses of Lescol XL tablets. Both Lescol XL 80 mg and 160 mg showed delayed absorption and longer apparent elimination half-life compared with fluvastatin IR capsule. Single and multiple doses of fluvastatin were generally well tolerated in this healthy volunteer population. Adverse event profiles were consistent with the published safety profile of the marketed formulations. Aside from one incidence of creatine phosphokinase (CPK) elevation (following Lescol XL 160 mg qd treatment), there were no safety concerns with any of the treatments when administered acutely (7 days). Copyright 2004 John Wiley & Sons, Ltd.
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Frost, Charles; Nepal, Sunil; Wang, Jessie; Schuster, Alan; Byon, Wonkyung; Boyd, Rebecca A; Yu, Zhigang; Shenker, Andrew; Barrett, Yu Chen; Mosqueda-Garcia, Rogelio; LaCreta, Frank
2013-01-01
Aim Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. Method This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily– with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). Results Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3–1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile. Conclusion Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures. PMID:23451769
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Kaasalainen, Touko; Palmu, Kirsi; Lampinen, Anniina; Reijonen, Vappu; Leikola, Junnu; Kivisaari, Riku; Kortesniemi, Mika
2015-09-01
Medical professionals need to exercise particular caution when developing CT scanning protocols for children who require multiple CT studies, such as those with craniosynostosis. To evaluate the utility of ultra-low-dose CT protocols with model-based iterative reconstruction techniques for craniosynostosis imaging. We scanned two pediatric anthropomorphic phantoms with a 64-slice CT scanner using different low-dose protocols for craniosynostosis. We measured organ doses in the head region with metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters. Numerical simulations served to estimate organ and effective doses. We objectively and subjectively evaluated the quality of images produced by adaptive statistical iterative reconstruction (ASiR) 30%, ASiR 50% and Veo (all by GE Healthcare, Waukesha, WI). Image noise and contrast were determined for different tissues. Mean organ dose with the newborn phantom was decreased up to 83% compared to the routine protocol when using ultra-low-dose scanning settings. Similarly, for the 5-year phantom the greatest radiation dose reduction was 88%. The numerical simulations supported the findings with MOSFET measurements. The image quality remained adequate with Veo reconstruction, even at the lowest dose level. Craniosynostosis CT with model-based iterative reconstruction could be performed with a 20-μSv effective dose, corresponding to the radiation exposure of plain skull radiography, without compromising required image quality.
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A Path Model for Evaluating Dosing Parameters for Children With Cerebral Palsy
Christy, Jennifer B.; Heathcock, Jill C.; Kolobe, Thubi H.A.
2014-01-01
Dosing of pediatric rehabilitation services for children with cerebral palsy (CP) has been identified as a national priority. Establishing dosing parameters for pediatric physical therapy interventions is critical for informing clinical decision making, health policy, and guidelines for reimbursement. The purpose of this perspective article is to describe a path model for evaluating dosing parameters of interventions for children with CP. The model is intended for dose-related and effectiveness studies of pediatric physical therapy interventions. The premise of the model is: Intervention type (focus on body structures, activity, or the environment) acts on a child first through the family, then through the dose (frequency, intensity, time), to yield structural and behavioral changes. As a result, these changes are linked to improvements in functional independence. Community factors affect dose as well as functional independence (performance and capacity), influencing the relationships between type of intervention and intervention responses. The constructs of family characteristics; child characteristics (eg, age, level of severity, comorbidities, readiness to change, preferences); plastic changes in bone, muscle, and brain; motor skill acquisition; and community access warrant consideration from researchers who are designing intervention studies. Multiple knowledge gaps are identified, and a framework is provided for conceptualizing dosing parameters for children with CP. PMID:24231231
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In vitro analysis of low-level laser irradiation on human osteoblast-like cells proliferation
NASA Astrophysics Data System (ADS)
Bloise, Nora; Saino, Enrica; Bragheri, Francesca; Minzioni, Paolo; Cristiani, Ilaria; Imbriani, Marcello; Visai, Livia
2011-07-01
The objective of this study was to examine the in vitro effect of a single or a multiple doses of low-level laser irradiation (LLLI) on proliferation of the human osteosarcoma cell line, SAOS-2. SAOS-2 cells were divided in five groups and exposed to LLLI (659 nm diode laser; 11 mW power output): group I as a control (dark), group II exposed to a single laser dose of 1 J/cm2, group III irradiated with a single dose of 3 J/cm2, and group IV and V exposed for three consecutive days to 1 or 3 J/cm², respectively. Cellular proliferation was assessed daily up to 7 days of culturing. The obtained results showed an increase in proliferative capacity of SAOS-2 cells during the first 96 h of culturing time in once-irradiated cells, as compared to control cells. Furthermore, a significantly higher proliferation in the group IV and V was detected if compared to a single dose or to control group after 96 h and 7 days. In conclusion, the effect of the single dose on cell proliferation was transitory and repeated irradiations were necessary to observe a strong enhancement of SAOS-2 growth. As a future perspective, we would like to determine the potential of LLLI as a new approach for promoting bone regeneration onto biomaterials.
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miR-26b enhances radiosensitivity of hepatocellular carcinoma cells by targeting EphA2.
Jin, Qiao; Li, Xiang Jun; Cao, Pei Guo
2016-08-01
Although low-dose radiotherapy (RT) that involves low collateral damage is more suitable for hepatocellular carcinoma (HCC) than traditional high-dose RT, but to achieve satisfactory therapeutic effect with low-dose RT, it is necessary to sensitize HCC cells to irradiation. This study was aimed to determine whether radiosensitivity of HCC cells can be enhanced using miR-26b by targeting erythropoietin producing human hepatocelluar A2 (EphA2). The levels of miR-26b and EphA2 expression in multiple HCC cell lines were assessed by qPCR and western blotting, respectively, and compared with those in a hepatic cell line. HCC 97H cells were transfected with miR-26b mimics, EphA2-ShRNA or EphA2 over-expression vector before exposure to low-dose irradiation. Different degrees of miR-26b down-regulation and EphA2 up-regulation were observed in all HCC cell lines, among which the HCC 97H cell line expressed the lowest level of miR-26b and highest level of EphA2. EphA2 was verified as the target of miR-26b by dual luciferase reporter assay. HCC 97H cells transfected with miR-26b mimics or EphA2-ShRNA reduced the expression of EphA2 protein, with significantly lower cell proliferation rate and cell invasion ability and higher apoptosis rate in response to low-dose irradiation than those in the non-transfected cells. These results were reversed after EphA2 was overexpressed by transfection with the EphA2 overexpression vector. Co-transfection with miR-26b mimics and EphA2 overexpression vector barely altered EphA2 expression level and cell response to low-dose irradiation. These data suggest that miR-26b enhances radiosensitivity of HCC 97H cells by targeting EphA2 protein.
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Lu, P; Fleischmann, R; Curtis, C; Ignatenko, S; Clarke, S H; Desai, M; Wong, S L; Grebe, K M; Black, K; Zeng, J; Stolzenbach, J; Medema, J K
2018-02-01
Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.
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Zaouchi, Yousr; Bahri, Nada Ben; Rezgui, S; Bettaieb, Taoufik
2013-10-01
The effects of fertilization and the nature of the inoculum as well as the variation of the dose intake of the latter on the level of Jacaranda mimosifolia D.Don mycorhization were tested. Young plants were treated with two inoculums presenting different origins, compositions and modes of application: one is a commercial product containing Glomus irregulare, and the other is a composite indigenous inoculum resulting from trapping five species of genus Glomus and also from multiplication on mycotrophic plants: leek (Allium porrum L.) and vetch (Vicia sativa L.). For each inoculum, two doses were tested and for each dose of inoculum, four levels of fertilization based on a complete commercial fertilizer (Osmocote) were tested: 0 g/plant, 2 g/plant, 4 g/plant, and 6g/plant. Three repetitions were performed for each combination treatment of inoculum/fertilizer. One-year-old young Jacaranda plants, being about 40 cm high, were cultured under greenhouse in 10/12 cm caliber pots. After six months, all the inoculated plants were mycorrhized. According to endomycorrhizal structures found on their roots, plants receiving doses of composite indigenous inoculum reached a more advanced stage of mycorrhization than those treated with the commercial inoculum. The existence of an interaction effect between the inoculum dose and the level of fertilization on Jacaranda mycorhization rate was excluded. These two parameters of variation were studied as simple effects. The increase in commercial inoculum dose had a significant positive influence on the level of Jacaranda plants mycorrhization (P=0.05). The rate of mycorrhization jumped from 12.69% to 21.92%. Nonetheless, for plants receiving increasing doses of composite indigenous inoculum, the level of mycorrhization has varied randomly. In both instances of inoculum treatments, increasing the dose of fertilizer significantly inhibited endomycorrhizal colonization of Jacaranda roots (P=0.01). Thus, the rate of root colonization decreased from 47.43% to 2.41% for plants receiving the composite indigenous inoculums. It decreased from 32.35% to 3.95% for those treated with the commercial inoculum. Mycorrhization had a positive effect on root dry biomass of Jacaranda, as in the case of unfertilize ave the highest rates of colonization. Copyright © 2013. Published by Elsevier SAS.
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Harrison, Lester I; Skinner, Shari L; Marbury, Thomas C; Owens, Mary L; Kurup, Sarala; McKane, Scott; Greene, Robert J
2004-06-01
The safety and efficacy of imiquimod 5% cream is being evaluated for the treatment of dysplastic lesions of the epidermis (actinic keratoses, AK). The objective of this clinical study was to describe the pharmacokinetics and safety of topical imiquimod during multiple dosing of AK subjects. A total of 58 adult subjects with 5 to 20 AK lesions at the treatment site applied imiquimod cream three times per week for up to 16 weeks as follows: 12 males and 11 females applied 12.5 mg imiquimod to the face; 11 males applied 25 mg to the entire balding area of the scalp; and 12 males and 12 females applied 75 mg to both hands and forearms. Pharmacokinetics and safety were assessed after the first and last doses, as well as biweekly. Imiquimod and its metabolites were measured in the serum and urine using sensitive liquid chromatography/mass spectrometry methods. Less than 0.6% of the applied doses was recovered in the urine of all subjects. Serum imiquimod levels were low, reflecting minimal dermal absorption, and increased with dose, although not proportionally. Peak levels at the end of dosing were 0.1, 0.2, and 1.6 ng/ml for the face, scalp, and hands/arms groups, respectively. A two- to fourfold accumulation was seen at the end of dosing. Local application site reactions were the most common adverse event, reported by approximately 50% of the subjects in each treatment group. The small number of systemic adverse events, including 'flu-like symptoms, were mostly mild and did not show a dose response. Thus, minimal systemic absorption and good safety margins for topical imiquimod were seen in AK subjects with doses as high as 75 mg three times per week for 16 weeks.
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Zablotska, Lydia B; Lane, Rachel S D; Frost, Stanley E; Thompson, Patsy A
2014-04-01
Uranium workers are chronically exposed to low levels of radon decay products (RDP) and gamma (γ) radiation. Risks of leukemia from acute and high doses of γ-radiation are well-characterized, but risks from lower doses and dose-rates and from RDP exposures are controversial. Few studies have evaluated risks of other hematologic cancers in uranium workers. The purpose of this study was to analyze radiation-related risks of hematologic cancers in the cohort of Eldorado uranium miners and processors first employed in 1932-1980 in relation to cumulative RDP exposures and γ-ray doses. The average cumulative RDP exposure was 100.2 working level months and the average cumulative whole-body γ-radiation dose was 52.2 millisievert. We identified 101 deaths and 160 cases of hematologic cancers in the cohort. Overall, male workers had lower mortality and cancer incidence rates for all outcomes compared with the general Canadian male population, a likely healthy worker effect. No statistically significant association between RDP exposure or γ-ray doses, or a combination of both, and mortality or incidence of any hematologic cancer was found. We observed consistent but non-statistically significant increases in risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma (HL) incidence and non-Hodgkin lymphoma (NHL) mortality with increasing γ-ray doses. These findings are consistent with recent studies of increased risks of CLL and NHL incidence after γ-radiation exposure. Further research is necessary to understand risks of other hematologic cancers from low-dose exposures to γ-radiation. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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Li, Su; Zhang, Dongsheng; Sun, Jian; Li, Zhinming; Deng, Liting; Zou, Benyan; Zhan, Jing; Jiang, Wenqi
2012-01-01
The safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m (2) SM03. Mean clearance was similar at doses ≤ 360 mg/m (2) and decreased significantly at dose 480 mg/m (2), supporting saturation of B-cell binding at 360 mg/m (2). Across all dose levels and histologies, one patient achieved partial response at 480 mg/m (2) dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60-480 mg/m (2) and had potential efficacy in Chinese patients with follicular lymphoma.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Yang, Feng; Waters, Katrina M.; Miller, John H.
2010-11-30
Background: High doses of ionizing radiation result in biological damage, however the precise relationships between long term health effects, including cancer, and low dose exposures remain poorly understood and are currently extrapolated using high dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose dependent responses to radiation. Principle Findings: We have identified 6845 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts one hour post-exposure. Dual statistical analyses based on spectral counts and peakmore » intensities identified 287 phosphopeptides (from 231 proteins) and 244 phosphopeptides (from 182 proteins) that varied significantly following exposure to 2 and 50 cGy respectively. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatics analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role of MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conlcusions: Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provides a basis for the systems level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low dose radiation exposure on human health.« less
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Classical Michaelis-Menten and system theory approach to modeling metabolite formation kinetics.
Popović, Jovan
2004-01-01
When single doses of drug are administered and kinetics are linear, techniques, which are based on the compartment approach and the linear system theory approach, in modeling the formation of the metabolite from the parent drug are proposed. Unlike the purpose-specific compartment approach, the methodical, conceptual and computational uniformity in modeling various linear biomedical systems is the dominant characteristic of the linear system approach technology. Saturation of the metabolic reaction results in nonlinear kinetics according to the Michaelis-Menten equation. The two compartment open model with Michaelis-Menten elimination kinetics is theorethicaly basic when single doses of drug are administered. To simulate data or to fit real data using this model, one must resort to numerical integration. A biomathematical model for multiple dosage regimen calculations of nonlinear metabolic systems in steady-state and a working example with phenytoin are presented. High correlation between phenytoin steady-state serum levels calculated from individual Km and Vmax values in the 15 adult epileptic outpatients and the observed levels at the third adjustment of phenytoin daily dose (r=0.961, p<0.01) were found.
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Bunaciu, Rodica P.
2015-01-01
Carcinogenesis is a multifactorial process, frequently encompassing 3 stages: initiation, promotion and progression. It is characterized by multiple deviations from normal both at the cell and organism levels. Although most people have a small number of cells that present deviations from normal, most of those cells will not cause cancer. However, some will. What tips the balance between normal and abnormal is the subject of intense scientific research as well as unfounded speculations. Chronic inflammation is one of the risk factors for cancer. Resveratrol is consumed by the population as a dietary supplement in the hope of decreasing the risk of inflammation and cancer and other chronic diseases such as diabetes and vascular diseases. There is a discrepancy between the doses used in the animal studies showing that resveratrol decreases all three stages of carcinogenesis, and the doses ingested by the population either as supplements or in the diet. While there is health benefit from using high resveratrol doses, it might be also of practical and scientific benefit to focus future effort in understanding the effects of normal dietary resveratrol levels. PMID:26478855
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Khalili, Mohammad; Eghtesadi, Shahryar; Mirshafiey, Abbas; Eskandari, Ghazaleh; Sanoobar, Meisam; Sahraian, Mohamad Ali; Motevalian, Abbas; Norouzi, Abbas; Moftakhar, Shirin; Azimi, Amirreza
2014-01-01
Multiple sclerosis is a neurodegenerative and demyelinating disease of central nervous system. High levels of oxidative stress are associated with inflammation and play an important role in pathogenesis of multiple sclerosis. This double-blind, randomized controlled clinical study was carried out to determine the effect of daily consumption of lipoic acid on oxidative stress among multiple sclerosis patients. A total of 52 relapsing-remitting multiple sclerosis patients, aged 18-50 years with Expanded Disability Status Scale ≤5.5 were assigned to consume either lipoic acid (1200 mg/day) or placebo capsules for 12 weeks. Fasting blood samples were collected before the first dose taken and 12 hours after the last. Dietary intakes were obtained by using 3-day dietary records. Consumption of lipoic acid resulted in a significant improvement of total antioxidant capacity (TAC) in comparison to the placebo group (P = 0.004). Although a significant change of TAC (-1511 mmol/L, P = 0.001) was found within lipoic acid group, other markers of oxidative stress including superoxide dismutase activity, glutathione peroxidase activity, and malondialdehyde levels were not affected by lipoic acid consumption. These results suggest that 1200 mg of lipoic acid improves serum TAC among multiple sclerosis patients but does not affect other markers of oxidative stress.
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Protein binding of isofluorophate in vivo after coexposure to multiple chemicals.
Vogel, John S; Keating, Garrett A; Buchholz, Bruce A
2002-01-01
Full toxicologic profiles of chemical mixtures, including dose-response extrapolations to realistic exposures, is a prohibitive analytical problem, even for a restricted class of chemicals. We present an approach to probing in vivo interactions of pesticide mixtures at relevant low doses using a monitor compound to report the response of biochemical pathways shared by mixture components. We use accelerator mass spectrometry (AMS) to quantify [14C]-diisopropylfluorophosphate as a tracer at attomole levels with 1-5% precision after coexposures to parathion (PTN), permethrin (PER), and pyridostigmine bromide separately and in conjunction. Pyridostigmine shows an overall protective effect against tracer binding in plasma, red blood cells, muscle, and brain that is not explained as competitive protein binding. PTN and PER induce a significant 25-30% increase in the amount of tracer reaching the brain with or without pyridostigmine. The sensitivity of AMS for isotope-labeled tracer compounds can be used to probe the physiologic responses of specific biochemical pathways to multiple compound exposures. PMID:12634135
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Sun, Huizhen; Hou, Jian; Zhou, Yun; Yang, Yuqing; Cheng, Juan; Xu, Tian; Xiao, Lili; Chen, Weihong; Yuan, Jing
2017-05-01
Association of exposure to polycyclic aromatic hydrocarbons (PAHs) with increased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation has been reported in occupational population and children. However, studies on the association between them in general population are limited. A total of 1864 eligible subjects from the baseline Wuhan participants of the Wuhan-Zhuhai Cohort Study (n = 3053) were included in this study, after excluding individuals with certain disease and missing data on urinary monohydroxy PAHs (OH-PAHs) and 8-OHdG levels. Urinary monohydroxy PAHs and 8-OHdG levels were measured by gas chromatography-mass spectrometry and high performance liquid chromatography-electrochemical detection, respectively. Association of urinary OH-PAHs with urinary 8-OHdG was analyzed by multiple linear regression analysis. We found a dose-dependent relationship between urinary PAHs metabolites and urinary 8-OHdG (p < 0.05 for all). Furthermore, more evidence for the association of total concentrations of urinary OH-PAHs with 8-OHdG levels were observed in individuals with normal body mass index or central obesity (p < 0.01 for all). There was a dose-dependent relationship between urinary OH-PAHs levels and urinary 8-OHdG levels among a general Chinese population. Exposure to background PAHs may have a greater influence on urinary 8-OHdG levels in individuals with central obesity. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid.
Flanagan, Shawn; Fang, Edward; Muñoz, Kelly A; Minassian, Sonia L; Prokocimer, Philippe G
2014-09-01
Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate. Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. Ninety healthy volunteers. Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100-400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days. A dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1 μg/ml) and the area under the concentration-time curve (17.4-58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100-400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores. These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes. © 2014 Cubist Pharmaceuticals. Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.
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Gut Microbiota and Tacrolimus Dosing in Kidney Transplantation
Lee, John R.; Muthukumar, Thangamani; Dadhania, Darshana; Taur, Ying; Jenq, Robert R.; Toussaint, Nora C.; Ling, Lilan; Pamer, Eric; Suthanthiran, Manikkam
2015-01-01
Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels. PMID:25815766
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Dewaraja, Yuni K.; Frey, Eric C.; Sgouros, George; Brill, A. Bertrand; Roberson, Peter; Zanzonico, Pat B.; Ljungberg, Michael
2012-01-01
In internal radionuclide therapy, a growing interest in voxel-level estimates of tissue-absorbed dose has been driven by the desire to report radiobiologic quantities that account for the biologic consequences of both spatial and temporal nonuniformities in these dose estimates. This report presents an overview of 3-dimensional SPECT methods and requirements for internal dosimetry at both regional and voxel levels. Combined SPECT/CT image-based methods are emphasized, because the CT-derived anatomic information allows one to address multiple technical factors that affect SPECT quantification while facilitating the patient-specific voxel-level dosimetry calculation itself. SPECT imaging and reconstruction techniques for quantification in radionuclide therapy are not necessarily the same as those designed to optimize diagnostic imaging quality. The current overview is intended as an introduction to an upcoming series of MIRD pamphlets with detailed radionuclide-specific recommendations intended to provide best-practice SPECT quantification–based guidance for radionuclide dosimetry. PMID:22743252
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NASA Astrophysics Data System (ADS)
Anderle, Kristjan; Stroom, Joep; Vieira, Sandra; Pimentel, Nuno; Greco, Carlo; Durante, Marco; Graeff, Christian
2018-01-01
Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.
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Lee, Soo-Han; Kim, Seung-Hyun; Noh, Yook-Hwan; Choi, Byung-Moon; Noh, Gyu-Jeong; Park, Woo-Dae; Kim, Eun-Jung; Cho, Ik-Hyun; Bae, Chun-Sik
2016-02-01
Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
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Paediatric x-ray radiation dose reduction and image quality analysis.
Martin, L; Ruddlesden, R; Makepeace, C; Robinson, L; Mistry, T; Starritt, H
2013-09-01
Collaboration of multiple staff groups has resulted in significant reduction in the risk of radiation-induced cancer from radiographic x-ray exposure during childhood. In this study at an acute NHS hospital trust, a preliminary audit identified initial exposure factors. These were compared with European and UK guidance, leading to the introduction of new factors that were in compliance with European guidance on x-ray tube potentials. Image quality was assessed using standard anatomical criteria scoring, and visual grading characteristics analysis assessed the impact on image quality of changes in exposure factors. This analysis determined the acceptability of gradual radiation dose reduction below the European and UK guidance levels. Chest and pelvis exposures were optimised, achieving dose reduction for each age group, with 7%-55% decrease in critical organ dose. Clinicians confirmed diagnostic image quality throughout the iterative process. Analysis of images acquired with preliminary and final exposure factors indicated an average visual grading analysis result of 0.5, demonstrating equivalent image quality. The optimisation process and final radiation doses are reported for Carestream computed radiography to aid other hospitals in minimising radiation risks to children.
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Dantoft, Thomas Meinertz; Skovbjerg, Sine; Andersson, Linus; Claeson, Anna-Sara; Lind, Nina; Nordin, Steven; Brix, Susanne
2015-01-01
Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by reports of recurrent symptoms in response to low level exposure to various chemical substances. Recent findings suggests that dysregulation of the immune system may play a role in MCS pathophysiology. The aim of this study was to examine baseline and low dose n-butanol-induced upper airway inflammatory response profiles in MCS subjects versus healthy controls. Eighteen participants with MCS and 18 age- and sex-matched healthy controls were enrolled in the study. Epithelial lining fluid was collected from the nasal cavity at three time points: baseline, within 15 minutes after being exposed to 3.7 ppm n-butanol in an exposure chamber and four hours after exposure termination. A total of 19 cytokines and chemokines were quantified. Furthermore, at baseline and during the exposure session, participants rated the perceived intensity, valence and levels of symptoms and autonomic recordings were obtained. The physiological and psychophysical measurements during the n-butanol exposure session verified a specific response in MCS individuals only. However, MCS subjects and healthy controls displayed similar upper airway inflammatory mediator profiles (P>0.05) at baseline. Likewise, direct comparison of mediator levels in the MCS group and controls after n-butanol exposure revealed no significant group differences. We demonstrate no abnormal upper airway inflammatory mediator levels in MCS subjects before or after a symptom-eliciting exposure to low dose n-butanol, implying that upper airways of MCS subjects are functionally intact at the level of cytokine and chemokine production and secretory capacity. This suggests that previous findings of increased cytokine plasma levels in MCS are unlikely to be caused by systemic priming via excessive upper airway inflammatory processes.
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1978-11-01
middle, or high levels of 2,4-DNT in the feed averaged 34, 93, or 266 mg/kg/day, respectively. The female rats consumed an average of 38, 108, or 145 mg...intake of males fed the low, middle or high levels of 2,4-DNT in the feed averaged 47, 137, or 413 mg/kg/day, respectively. The female mice consumed an...Experimental Procedures All dogs were observed daily for behavioral changes and toxic signs. Body weights of all dogs were recorded weekly. Blood
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False-positive buprenorphine EIA urine toxicology results due to high dose morphine: a case report.
Tenore, Peter L
2012-01-01
In monitoring a patient with chronic pain who was taking high-dose morphine and oxycodone with weekly urine enzymatic immunoassay (EIA) toxicology testing, the authors noted consistent positives for buprenorphine. The patient was not taking buprenorphine, and gas chromatography/mass spectroscopy (GCMS) testing on multiple samples revealed no buprenorphine, indicating a case of false-positive buprenorphine EIAs in a high-dose opiate case. The authors discontinued oxycodone for a period of time and then discontinued morphine. Urine monitoring with EIAs and GCMS revealed false-positive buprenorphine EIAs, which remained only when the patient was taking morphine. When taking only oxycodone and no morphine, urine samples became buprenorphine negative. When morphine was reintroduced, false-positive buprenorphine results resumed. Medical practitioners should be aware that high-dose morphine (with morphine urine levels turning positive within the 15,000 to 28,000 mg/mL range) may produce false-positive buprenorphine EIAs with standard urine EIA toxicology testing.
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Zhou, Huili; Wu, Guolan; Hu, Xingjiang; Zhu, Meixiang; Zhai, You; Liu, Jian; Shentu, Jianzhong; Wu, Lihua
2015-06-01
A new generic formulation of cycloserine has been developed in China but the pharmacokinetic properties of cycloserine in the Chinese population have not been reported. The aim of our study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of cycloserine capsules in healthy Chinese volunteers. This open-label, single- and multiple-dose 3-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of cycloserine (250, 500, or 1000 mg) in separate trial periods, with a 1-week washout between periods. Those allocated to the 250-mg dose continued into the multiple-dose phase, in which they received 250 mg BID for 5 consecutive days. During the single-dose phase, blood samples were collected at regular intervals from 0 to 72 hours after drug administration and the concentrations of cycloserine were determined using LC-MS/MS. During the multiple-dose phase, blood samples were obtained before drug administration on Days 4, 5, and 6 to determine the Cmin at steady state. On Day 6, blood samples were also collected from 0 to 72 hours after drug administration. Pharmacokinetic parameters were estimated using noncompartmental methods. Tolerability was determined using clinical evaluation and monitoring of adverse events. The study enrolled 12 healthy Chinese volunteers (6 men: mean [SD] age = 23.0 [2.6] years, weight = 60.2 [6.2] kg, height = 170.0 [3.0] cm, and body mass index = 20.7 [1.7]; 6 women: mean [SD] age = 25.3 [1.4] years, weight = 51.5 [3.3] kg, height = 160.0 [4.0] cm, and body mass index = 20.1 [0.9]). After administration of a single dose, cycloserine was rapidly absorbed, reaching peak plasma concentrations approximately 0.84 hours after oral administration, and t½ in plasma was about 13.0 hours. The geometric mean (SD) Cmax value increased in proportion to cycloserine dose, from 19.42 (5.89) to 84.76 (21.74) mg/L, and the geometric mean (SD) AUC0-72h value increased from 264.16 (133.37) to 1153.87 (522.16) mg·h/L in the range of a 250- to 1000-mg dose. After administration of multiple doses of cycloserine 250 mg BID, the mean (SD) t½ was 13.56 (4.38) hours, the apparent total clearance of the drug from plasma after oral administration was 1.02 (0.42) L/h, and the apparent volume of distribution was 18.22 (5.25) L, which were comparable with those after single dosing. The accumulation index was 2.19 (0.51), and the fluctuation was 1.05 (0.35). Results of the t tests of Cmax and AUC found no significant differences between the male and female groups. No serious adverse events were reported, and there were no discontinuations due to adverse events. The pharmacokinetic properties of cycloserine were linear at doses from 250 mg to 1000 mg. After multiple doses, the pharmacokinetic properties of cycloserine were consistent with those after single doses. At the doses studied, cycloserine appears to be well tolerated in these healthy volunteers. Chinese Clinical Trials registration: ChiCTR-TTRCC-13003982. Copyright © 2015. Published by Elsevier Inc.
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Goldman, S A
1996-10-01
Neurotoxicity in relation to concomitant administration of lithium and neuroleptic drugs, particularly haloperidol, has been an ongoing issue. This study examined whether use of lithium with neuroleptic drugs enhances neurotoxicity leading to permanent sequelae. The Spontaneous Reporting System database of the United States Food and Drug Administration and extant literature were reviewed for spectrum cases of lithium/neuroleptic neurotoxicity. Groups taking lithium alone (Li), lithium/haloperidol (LiHal) and lithium/ nonhaloperidol neuroleptics (LiNeuro), each paired for recovery and sequelae, were established for 237 cases. Statistical analyses included pairwise comparisons of lithium levels using the Wilcoxon Rank Sum procedure and logistic regression to analyze the relationship between independent variables and development of sequelae. The Li and Li-Neuro groups showed significant statistical differences in median lithium levels between recovery and sequelae pairs, whereas the LiHal pair did not differ significantly. Lithium level was associated with sequelae development overall and within the Li and LiNeuro groups; no such association was evident in the LiHal group. On multivariable logistic regression analysis, lithium level and taking lithium/haloperidol were significant factors in the development of sequelae, with multiple possibly confounding factors (e.g., age, sex) not statistically significant. Multivariable logistic regression analyses with neuroleptic dose as five discrete dose ranges or actual dose did not show an association between development of sequelae and dose. Database limitations notwithstanding, the lack of apparent impact of serum lithium level on the development of sequelae in patients treated with haloperidol contrasts notably with results in the Li and LiNeuro groups. These findings may suggest a possible effect of pharmacodynamic factors in lithium/neuroleptic combination therapy.
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Retrieving atmospheric transmissivity for biologically active daily dose, in various european sites
NASA Astrophysics Data System (ADS)
de La Casinière, A.; Touré, M. L.; Lenoble, J.; Cabot, T.
2003-04-01
In the frame of the European Project EDUCE, global UV irradiance spectra recorded all along the year in several European sites are stored in a common database located in Finland. From the spectra set of some of these stations, are calculated atmospheric transmissivities for daily doses of four biologically active UV radiation, namely: UV-B, erythema, DNA damage, and plant damage. A transmissivity is defined as the ratio of the ground level value of the daily dose of interest to its corresponding extra-atmospheric value. Multiple linear correlation of the various transmissivities with three predictors (daily sunshine fraction, cosine of the daily minimum SZA, and daily total ozone column) assumed to be independent variables, are done for year 2000. The coefficients obtained from year 2000 correlation in a given site are expected to retrieve, from the local predictors, the daily dose for year 2001 in the same site, the average error being lesser than 10% for monthly mean values, and lesser than 5% for three-monthly mean values, depending on the daily dose type. Comparison of yearly mean daily doses retrieved in a given site from coefficients obtained in other sites is also presented.
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Kim, Steven B; Kodell, Ralph L; Moon, Hojin
2014-03-01
In chemical and microbial risk assessments, risk assessors fit dose-response models to high-dose data and extrapolate downward to risk levels in the range of 1-10%. Although multiple dose-response models may be able to fit the data adequately in the experimental range, the estimated effective dose (ED) corresponding to an extremely small risk can be substantially different from model to model. In this respect, model averaging (MA) provides more robustness than a single dose-response model in the point and interval estimation of an ED. In MA, accounting for both data uncertainty and model uncertainty is crucial, but addressing model uncertainty is not achieved simply by increasing the number of models in a model space. A plausible set of models for MA can be characterized by goodness of fit and diversity surrounding the truth. We propose a diversity index (DI) to balance between these two characteristics in model space selection. It addresses a collective property of a model space rather than individual performance of each model. Tuning parameters in the DI control the size of the model space for MA. © 2013 Society for Risk Analysis.
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Kundu, Amartya; Fitzgibbons, Timothy P
2015-09-24
Sinus bradycardia has been reported after administration of pulse dose steroids, although most cases have occurred in children and are asymptomatic. We report a case of acute symptomatic sinus bradycardia due to pulse dose steroids in a woman with multiple sclerosis. Interestingly, this patient also suffered from inappropriate sinus tachycardia due to autonomic involvement of multiple sclerosis. A 48-year-old Caucasian woman with multiple sclerosis and chronic palpitations due to inappropriate sinus tachycardia was prescribed a 5-day course of intravenous methylprednisolone for treatment of an acute flare. Immediately following the fourth dose of intravenous methylprednisolone, she developed dyspnea, chest heaviness, and lightheadedness. She was referred to the emergency department where an electrocardiogram showed marked sinus bradycardia (40 beats per minute). Initial laboratory test results, including a complete blood count, basic metabolic profile and cardiac biomarkers, were normal. She was admitted for observation on telemetry monitoring. Her heart rate gradually increased and her symptoms resolved. Her outpatient dose of atenolol, taken for symptomatic inappropriate sinus tachycardia, was resumed. Our patient's acute symptoms were attributed to symptomatic sinus bradycardia due to pulse dose steroid treatment. Although several theories have been suggested to explain this phenomenon, the exact mechanism still remains unknown. It does not warrant any specific treatment, as it is a self-limiting side effect that resolves after discontinuing steroid infusion. Young patients who are free of any active cardiac conditions can safely be administered pulse dose steroids without monitoring. However, older patients with active cardiac conditions should have heart rate and blood pressure monitoring during infusion. Our patient also suffered from inappropriate sinus tachycardia, a manifestation of autonomic involvement of multiple sclerosis that has not been previously described. This case has implications for the pathogenesis and treatment of dysautonomia in patients with multiple sclerosis.
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Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Schachtel, Emily
2014-07-03
The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Adults (n=198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n=101) or matching placebo lozenges (n=97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P<0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P<0.01). There were no serious adverse events. Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010.
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Learning from agriculture: understanding low-dose antimicrobials as drivers of resistome expansion
You, Yaqi; Silbergeld, Ellen K.
2014-01-01
Antimicrobial resistance is a growing public health challenge worldwide, with agricultural use of antimicrobials being one major contributor to the emergence and dissemination of antimicrobial resistance (AMR). Globally, most antimicrobials are used in industrial food animal production, a major context for microbiomes encountering low-doses or subtherapeutic-levels of antimicrobial agents from all mechanistic classes. This modern practice exerts broad eco-evolutionary effects on the gut microbiome of food animals, which is subsequently transferred to animal waste. This waste contains complex constituents that are challenging to treat, including AMR determinants and low-dose antimicrobials. Unconfined storage or land deposition of a large volume of animal waste causes its wide contact with the environment and drives the expansion of the environmental resistome through mobilome facilitated horizontal genet transfer. The expanded environmental resistome, which encompasses both natural constituents and anthropogenic inputs, can persist under multiple stressors from agriculture and may re-enter humans, thus posing a public health risk to humans. For these reasons, this review focuses on agricultural antimicrobial use as a laboratory for understanding low-dose antimicrobials as drivers of resistome expansion, briefly summarizes current knowledge on this topic, highlights the importance of research specifically on environmental microbial ecosystems considering AMR as environmental pollution, and calls attention to the needs for longitudinal studies at the systems level. PMID:24959164
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Schwendler, Teresa; Shipley, Cara; Budd, Nadine; Trude, Angela; Surkan, Pamela J.; Steeves, Elizabeth Anderson; de Morais Sato, Priscila; Eckmann, Thomas; Loh, Hong; Gittelsohn, Joel
2017-01-01
Higher rates of obesity and obesity-related chronic disease are prevalent in communities where there is limited access to affordable, healthy food. The B’More Healthy Communities for Kids (BHCK) trial worked at multiple levels of the food environment including food wholesalers and corner stores to improve the surrounding community’s access to healthy food. The objective of this article is to describe the development and implementation of BHCK’s corner store and wholesaler interventions through formal process evaluation. Researchers evaluated each level of the intervention to assess reach, dose delivered, and fidelity. Corner store and wholesaler reach, dose delivered, and fidelity were measured by number of interactions, promotional materials distributed, and maintenance of study materials, respectively. Overall, the corner store implementation showed moderate reach, dose delivered, and high fidelity. The wholesaler intervention was implemented with high reach, dose, and fidelity. The program held 355 corner store interactive sessions and had 9,347 community member interactions, 21% of which were with children between the ages of 10 and 14 years. There was a 15% increase in corner store promoted food stocking during Wave 1 and a 17% increase during Wave 2. These findings demonstrate a successfully implemented food retailer intervention in a low-income urban setting. PMID:28343413
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Learning from agriculture: understanding low-dose antimicrobials as drivers of resistome expansion.
You, Yaqi; Silbergeld, Ellen K
2014-01-01
Antimicrobial resistance is a growing public health challenge worldwide, with agricultural use of antimicrobials being one major contributor to the emergence and dissemination of antimicrobial resistance (AMR). Globally, most antimicrobials are used in industrial food animal production, a major context for microbiomes encountering low-doses or subtherapeutic-levels of antimicrobial agents from all mechanistic classes. This modern practice exerts broad eco-evolutionary effects on the gut microbiome of food animals, which is subsequently transferred to animal waste. This waste contains complex constituents that are challenging to treat, including AMR determinants and low-dose antimicrobials. Unconfined storage or land deposition of a large volume of animal waste causes its wide contact with the environment and drives the expansion of the environmental resistome through mobilome facilitated horizontal genet transfer. The expanded environmental resistome, which encompasses both natural constituents and anthropogenic inputs, can persist under multiple stressors from agriculture and may re-enter humans, thus posing a public health risk to humans. For these reasons, this review focuses on agricultural antimicrobial use as a laboratory for understanding low-dose antimicrobials as drivers of resistome expansion, briefly summarizes current knowledge on this topic, highlights the importance of research specifically on environmental microbial ecosystems considering AMR as environmental pollution, and calls attention to the needs for longitudinal studies at the systems level.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Lin, X; Sun, T; Yin, Y
Purpose: To study the dosimetric impact of intensity-modulated radiotherapy (IMRT), hybrid intensity-modulated radiotherapy (h-IMRT) and volumetric modulated arc therapy(VMAT) for whole-brain radiotherapy (WBRT) with simultaneous integrated boost in patients with multiple brain metastases. Methods: Ten patients with multiple brain metastases were included in this analysis. The prescribed dose was 45 Gy to the whole brain (PTVWBRT) and 55 Gy to individual brain metastases (PTVboost) delivered simultaneously in 25 fractions. Three treatment techniques were designed: the 7 equal spaced fields IMRT plan, hybrid IMRT plan and VMAT with two 358°arcs. In hybrid IMRT plan, two fields(90°and 270°) were planned to themore » whole brain. This was used as a base dose plan. Then 5 fields IMRT plan was optimized based on the two fields plan. The dose distribution in the target, the dose to the organs at risk and total MU in three techniques were compared. Results: For the target dose, conformity and homogeneity in PTV, no statistically differences were observed in the three techniques. For the maximum dose in bilateral lens and the mean dose in bilateral eyes, IMRT and h-IMRT plans showed the highest and lowest value respectively. No statistically significant differences were observed in the dose of optic nerve and brainstem. For the monitor units, IMRT and VMAT plans showed the highest and lowest value respectively. Conclusion: For WBRT with simultaneous integrated boost in patients with multiple brain metastases, hybrid IMRT could reduce the doses to lens and eyes. It is feasible for patients with brain metastases.« less
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Environmental Radiation Effects: A Need to Question Old Paradigms
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hinton, T.G.; Bedford, J.; Ulsh, B.
2003-03-27
A historical perspective is given of the current paradigm that does not explicitly protect the environment from radiation, but instead, relies on the concept that if dose limits are set to protect humans then the environment is automatically protected as well. We summarize recent international questioning of this paradigm and briefly present three different frameworks for protecting biota that are being considered by the U.S. DOE, the Canadian government and the International Commission on Radiological Protection. We emphasize that an enhanced collaboration is required between what has traditionally been separated disciplines of radiation biology and radiation ecology if we aremore » going to properly address the current environmental radiation problems. We then summarize results generated from an EMSP grant that allowed us to develop a Low Dose Irradiation Facility that specifically addresses effects of low-level, chronic irradiation on multiple levels of biological organization.« less
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Dynamically accumulated dose and 4D accumulated dose for moving tumors
DOE Office of Scientific and Technical Information (OSTI.GOV)
Li Heng; Li Yupeng; Zhang Xiaodong
2012-12-15
Purpose: The purpose of this work was to investigate the relationship between dynamically accumulated dose (dynamic dose) and 4D accumulated dose (4D dose) for irradiation of moving tumors, and to quantify the dose uncertainty induced by tumor motion. Methods: The authors established that regardless of treatment modality and delivery properties, the dynamic dose will converge to the 4D dose, instead of the 3D static dose, after multiple deliveries. The bounds of dynamic dose, or the maximum estimation error using 4D or static dose, were established for the 4D and static doses, respectively. Numerical simulations were performed (1) to prove themore » principle that for each phase, after multiple deliveries, the average number of deliveries for any given time converges to the total number of fractions (K) over the number of phases (N); (2) to investigate the dose difference between the 4D and dynamic doses as a function of the number of deliveries for deliveries of a 'pulsed beam'; and (3) to investigate the dose difference between 4D dose and dynamic doses as a function of delivery time for deliveries of a 'continuous beam.' A Poisson model was developed to estimate the mean dose error as a function of number of deliveries or delivered time for both pulsed beam and continuous beam. Results: The numerical simulations confirmed that the number of deliveries for each phase converges to K/N, assuming a random starting phase. Simulations for the pulsed beam and continuous beam also suggested that the dose error is a strong function of the number of deliveries and/or total deliver time and could be a function of the breathing cycle, depending on the mode of delivery. The Poisson model agrees well with the simulation. Conclusions: Dynamically accumulated dose will converge to the 4D accumulated dose after multiple deliveries, regardless of treatment modality. Bounds of the dynamic dose could be determined using quantities derived from 4D doses, and the mean dose difference between the dynamic dose and 4D dose as a function of number of deliveries and/or total deliver time was also established.« less
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Ceruletide intravenous dose-response study by a simplified scintigraphic technique
DOE Office of Scientific and Technical Information (OSTI.GOV)
Krishnamurthy, G.T.; Turner, F.E.; Mangham, D.
1985-04-01
The intravenous dose response of a ceruletide diethylamine (ceruletide) was established by a simplified scintigraphic technique where multiple graded doses were given sequentially on a single occasion. The gallbladder volume was presented nongeometrically by /sup 99m/Tc-IDA counts. The mean latent period, ejection period, and ejection rate were similar for all four groups of subjects given 1-20 ng/kg of ceruletide. The ejection fractions were similar to the values when the identical dose of ceruletide was administered sequentially either before or after another dose. A dose of 5 ng/kg produced the most physiologic type of emptying. Intravenous doses of 10 ng/kg andmore » larger caused adverse reactions in 42% of the total doses in the form of abdominal pain, nausea, systolic and diastolic hypotension, or bradycardia. It is concluded that the dose response of a cholecystokininlike agent (ceruletide) can be established reliably by a scintigraphic technique where multiple graded doses are given on a single occasion.« less
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Messerli, Michael; Ottilinger, Thorsten; Warschkow, René; Leschka, Sebastian; Alkadhi, Hatem; Wildermuth, Simon; Bauer, Ralf W
2017-06-01
To determine whether ultralow dose chest CT with tin filtration can be used for emphysema quantification and lung volumetry and to assess differences in emphysema measurements and lung volume between standard dose and ultralow dose CT scans using advanced modeled iterative reconstruction (ADMIRE). 84 consecutive patients from a prospective, IRB-approved single-center study were included and underwent clinically indicated standard dose chest CT (1.7±0.6mSv) and additional single-energy ultralow dose CT (0.14±0.01mSv) at 100kV and fixed tube current at 70mAs with tin filtration in the same session. Forty of the 84 patients (48%) had no emphysema, 44 (52%) had emphysema. One radiologist performed fully automated software-based pulmonary emphysema quantification and lung volumetry of standard and ultralow dose CT with different levels of ADMIRE. Friedman test and Wilcoxon rank sum test were used for multiple comparison of emphysema and lung volume. Lung volumes were compared using the concordance correlation coefficient. The median low-attenuation areas (LAA) using filtered back projection (FBP) in standard dose was 4.4% and decreased to 2.6%, 2.1% and 1.8% using ADMIRE 3, 4, and 5, respectively. The median values of LAA in ultralow dose CT were 5.7%, 4.1% and 2.4% for ADMIRE 3, 4, and 5, respectively. There was no statistically significant difference between LAA in standard dose CT using FBP and ultralow dose using ADMIRE 4 (p=0.358) as well as in standard dose CT using ADMIRE 3 and ultralow dose using ADMIRE 5 (p=0.966). In comparison with standard dose FBP the concordance correlation coefficients of lung volumetry were 1.000, 0.999, and 0.999 for ADMIRE 3, 4, and 5 in standard dose, and 0.972 for ADMIRE 3, 4 and 5 in ultralow dose CT. Ultralow dose CT at chest X-ray equivalent dose levels allows for lung volumetry as well as detection and quantification of emphysema. However, longitudinal emphysema analyses should be performed with the same scan protocol and reconstruction algorithms for reproducibility. Copyright © 2017 Elsevier B.V. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Gu, X; Hrycushko, B; Lee, H
2014-06-01
Purpose: Traditional extended SSD total body irradiation (TBI) techniques can be problematic in terms of patient comfort and/or dose uniformity. This work aims to develop a comfortable TBI technique that achieves a uniform dose distribution to the total body while reducing the dose to organs at risk for complications. Methods: To maximize patient comfort, a lazy Susan-like couch top immobilization system which rotates about a pivot point was developed. During CT simulation, a patient is immobilized by a Vac-Lok bag within the body frame. The patient is scanned head-first and then feet-first following 180° rotation of the frame. The twomore » scans are imported into the Pinnacle treatment planning system and concatenated to give a full-body CT dataset. Treatment planning matches multiple isocenter volumetric modulated arc (VMAT) fields of the upper body and multiple isocenter parallel-opposed fields of the lower body. VMAT fields of the torso are optimized to satisfy lung dose constraints while achieving a therapeutic dose to the torso. The multiple isocenter VMAT fields are delivered with an indexed couch, followed by body frame rotation about the pivot point to treat the lower body isocenters. The treatment workflow was simulated with a Rando phantom, and the plan was mapped to a solid water slab phantom for point- and film-dose measurements at multiple locations. Results: The treatment plan of 12Gy over 8 fractions achieved 80.2% coverage of the total body volume within ±10% of the prescription dose. The mean lung dose was 8.1 Gy. All ion chamber measurements were within ±1.7% compared to the calculated point doses. All relative film dosimetry showed at least a 98.0% gamma passing rate using a 3mm/3% passing criteria. Conclusion: The proposed patient comfort-oriented TBI technique provides for a uniform dose distribution within the total body while reducing the dose to the lungs.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Wu, R; Liu, A; Poenisch, F
Purpose: Treatment planning for Intensity Modulated Proton Therapy (IMPT) for head and neck cancer is time-consuming due to the large number of organs-at-risk (OAR) to be considered. As there are many competing objectives and also wide range of acceptable OAR constraints, the final approved plan may not be most optimal for the given structures. We evaluated the dose reduction to the contralateral parotid by implementing standardized constraints during optimization for scanning beam proton therapy planning. Methods: Twenty-four (24) consecutive patients previously treated for base of tongue carcinoma were retrospectively selected. The doses were 70Gy, 63Gy and 57Gy (SIB in 33more » fractions) for high-, intermediate-, and standard-risk clinical target volumes (CTV), respectively; the treatment included bilateral neck. Scanning beams using MFO with standardized bilateral anterior oblique and PA fields were applied. New plans where then developed and optimized by employing additional contralateral parotid constraints at multiple defined dose levels. Using a step-wise iterative process, the volume-based constraints at each level were then further reduced until known target coverages were compromised. The newly developed plans were then compared to the original clinically approved plans using paired student t-testing. Results: All 24 newly optimized treatment plans maintained initial plan quality as compared to the approved plans, and the 98% prescription dose coverage to the CTV’s were not compromised. Representative DVH comparison is shown in FIGURE 1. The contralateral parotid doses were reduced at all levels of interest when systematic constraints were applied to V10, V20, V30 and V40Gy (All P<0.0001; TABLE 1). Overall, the mean contralateral parotid doses were reduced by 2.26 Gy on average, a ∼13% relative improvement. Conclusion: Applying systematic and volume-based contralateral parotid constraints for IMPT planning significantly reduced the dose at all dosimetric levels for patients with base of tongue cancer.« less
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Monte Carlo simulations of the dose from imaging with GE eXplore 120 micro-CT using GATE
DOE Office of Scientific and Technical Information (OSTI.GOV)
Bretin, Florian; Bahri, Mohamed Ali; Luxen, André
Purpose: Small animals are increasingly used as translational models in preclinical imaging studies involving microCT, during which the subjects can be exposed to large amounts of radiation. While the radiation levels are generally sublethal, studies have shown that low-level radiation can change physiological parameters in mice. In order to rule out any influence of radiation on the outcome of such experiments, or resulting deterministic effects in the subjects, the levels of radiation involved need to be addressed. The aim of this study was to investigate the radiation dose delivered by the GE eXplore 120 microCT non-invasively using Monte Carlo simulationsmore » in GATE and to compare results to previously obtained experimental values. Methods: Tungsten X-ray spectra were simulated at 70, 80, and 97 kVp using an analytical tool and their half-value layers were simulated for spectra validation against experimentally measured values of the physical X-ray tube. A Monte Carlo model of the microCT system was set up and four protocols that are regularly applied to live animal scanning were implemented. The computed tomography dose index (CTDI) inside a PMMA phantom was derived and multiple field of view acquisitions were simulated using the PMMA phantom, a representative mouse and rat. Results: Simulated half-value layers agreed with experimentally obtained results within a 7% error window. The CTDI ranged from 20 to 56 mGy and closely matched experimental values. Derived organ doses in mice reached 459 mGy in bones and up to 200 mGy in soft tissue organs using the highest energy protocol. Dose levels in rats were lower due to the increased mass of the animal compared to mice. The uncertainty of all dose simulations was below 14%. Conclusions: Monte Carlo simulations proved a valuable tool to investigate the 3D dose distribution in animals from microCT. Small animals, especially mice (due to their small volume), receive large amounts of radiation from the GE eXplore 120 microCT, which might alter physiological parameters in a longitudinal study setup.« less
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Z-Index Parameterization for Volumetric CT Image Reconstruction via 3-D Dictionary Learning.
Bai, Ti; Yan, Hao; Jia, Xun; Jiang, Steve; Wang, Ge; Mou, Xuanqin
2017-12-01
Despite the rapid developments of X-ray cone-beam CT (CBCT), image noise still remains a major issue for the low dose CBCT. To suppress the noise effectively while retain the structures well for low dose CBCT image, in this paper, a sparse constraint based on the 3-D dictionary is incorporated into a regularized iterative reconstruction framework, defining the 3-D dictionary learning (3-DDL) method. In addition, by analyzing the sparsity level curve associated with different regularization parameters, a new adaptive parameter selection strategy is proposed to facilitate our 3-DDL method. To justify the proposed method, we first analyze the distributions of the representation coefficients associated with the 3-D dictionary and the conventional 2-D dictionary to compare their efficiencies in representing volumetric images. Then, multiple real data experiments are conducted for performance validation. Based on these results, we found: 1) the 3-D dictionary-based sparse coefficients have three orders narrower Laplacian distribution compared with the 2-D dictionary, suggesting the higher representation efficiencies of the 3-D dictionary; 2) the sparsity level curve demonstrates a clear Z-shape, and hence referred to as Z-curve, in this paper; 3) the parameter associated with the maximum curvature point of the Z-curve suggests a nice parameter choice, which could be adaptively located with the proposed Z-index parameterization (ZIP) method; 4) the proposed 3-DDL algorithm equipped with the ZIP method could deliver reconstructions with the lowest root mean squared errors and the highest structural similarity index compared with the competing methods; 5) similar noise performance as the regular dose FDK reconstruction regarding the standard deviation metric could be achieved with the proposed method using (1/2)/(1/4)/(1/8) dose level projections. The contrast-noise ratio is improved by ~2.5/3.5 times with respect to two different cases under the (1/8) dose level compared with the low dose FDK reconstruction. The proposed method is expected to reduce the radiation dose by a factor of 8 for CBCT, considering the voted strongly discriminated low contrast tissues.
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Effect of Cytotoxic Therapy on Sexuality and Gonadal Function
1981-01-01
have produced toxicities involving multiple organ and testosterone levels fall. systems. Drug induced azoospermia and amenor- In women FSH stimulates ...Additionally, several men complained that Summary although their libido was satisfactory, orgasm The dose of a cytotoxic agent that produces was not...some of the men enced irritability and some became physically PATIENTS LIBIDO RATING: MALES 10 9 8 SEXUAL ACTIVITY 5 Fig. 1. Correlation of WEEKLY 4
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1965-01-01
Rainbow trout were fed a pelleted diet containing killed cells of the etiologic agent of a bacterial disease, redmouth. These fish in addition to appropriate controls were subsequently challenged with virulent homologous organisms. Ninety per cent of the redmouth immunized fish survived the basic challenge using virulent organisms in contrast to 20% survival for the controls. Multiple challenge doses at increased levels also are discussed.
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SU-E-T-197: Helical Cranial-Spinal Treatments with a Linear Accelerator
DOE Office of Scientific and Technical Information (OSTI.GOV)
Anderson, J; Bernard, D; Liao, Y
2014-06-01
Purpose: Craniospinal irradiation (CSI) of systemic disease requires a high level of beam intensity modulation to reduce dose to bone marrow and other critical structures. Current helical delivery machines can take 30 minutes or more of beam-on time to complete these treatments. This pilot study aims to test the feasibility of performing helical treatments with a conventional linear accelerator using longitudinal couch travel during multiple gantry revolutions. Methods: The VMAT optimization package of the Eclipse 10.0 treatment planning system was used to optimize pseudo-helical CSI plans of 5 clinical patient scans. Each gantry revolution was divided into three 120° arcsmore » with each isocenter shifted longitudinally. Treatments requiring more than the maximum 10 arcs used multiple plans with each plan after the first being optimized including the dose of the others (Figure 1). The beam pitch was varied between 0.2 and 0.9 (couch speed 5- 20cm/revolution and field width of 22cm) and dose-volume histograms of critical organs were compared to tomotherapy plans. Results: Viable pseudo-helical plans were achieved using Eclipse. Decreasing the pitch from 0.9 to 0.2 lowered the maximum lens dose by 40%, the mean bone marrow dose by 2.1% and the maximum esophagus dose by 17.5%. (Figure 2). Linac-based helical plans showed dose results comparable to tomotherapy delivery for both target coverage and critical organ sparing, with the D50 of bone marrow and esophagus respectively 12% and 31% lower in the helical linear accelerator plan (Figure 3). Total mean beam-on time for the linear accelerator plan was 8.3 minutes, 54% faster than the tomotherapy average for the same plans. Conclusions: This pilot study has demonstrated the feasibility of planning pseudo-helical treatments for CSI targets using a conventional linac and dynamic couch movement, and supports the ongoing development of true helical optimization and delivery.« less
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Huang, Hsin-Chan; Singh, Bismark; Morton, David P; Johnson, Gregory P; Clements, Bruce; Meyers, Lauren Ancel
2017-01-01
Vaccines are arguably the most important means of pandemic influenza mitigation. However, as during the 2009 H1N1 pandemic, mass immunization with an effective vaccine may not begin until a pandemic is well underway. In the U.S., state-level public health agencies are responsible for quickly and fairly allocating vaccines as they become available to populations prioritized to receive vaccines. Allocation decisions can be ethically and logistically complex, given several vaccine types in limited and uncertain supply and given competing priority groups with distinct risk profiles and vaccine acceptabilities. We introduce a model for optimizing statewide allocation of multiple vaccine types to multiple priority groups, maximizing equal access. We assume a large fraction of available vaccines are distributed to healthcare providers based on their requests, and then optimize county-level allocation of the remaining doses to achieve equity. We have applied the model to the state of Texas, and incorporated it in a Web-based decision-support tool for the Texas Department of State Health Services (DSHS). Based on vaccine quantities delivered to registered healthcare providers in response to their requests during the 2009 H1N1 pandemic, we find that a relatively small cache of discretionary doses (DSHS reserved 6.8% in 2009) suffices to achieve equity across all counties in Texas.
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Ward, Robert M.; Kearns, Gregory L.; Tammara, Brinda; Bishop, Phyllis; O’Gorman, Molly A.; James, Laura P.; Katz, Mitchell H.; Maguire, Mary K.; Rath, Natalie; Meng, Xu; Comer, Gail M.
2011-01-01
SUMMARY Children with GERD may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drug’s kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed-release tablets in pediatric patients with GERD aged ≥6 through 11 years (study 1) and 12 through 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose, and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar toPK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug-associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults. PMID:20852004
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A 2D ion chamber array audit of wedged and asymmetric fields in an inhomogeneous lung phantom
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lye, Jessica; Dunn, Leon, E-mail: leon.dunn@arpansa.gov.au; Alves, Andrew
Purpose: The Australian Clinical Dosimetry Service (ACDS) has implemented a new method of a nonreference condition Level II type dosimetric audit of radiotherapy services to increase measurement accuracy and patient safety within Australia. The aim of this work is to describe the methodology, tolerances, and outcomes from the new audit. Methods: The ACDS Level II audit measures the dose delivered in 2D planes using an ionization chamber based array positioned at multiple depths. Measurements are made in rectilinear homogeneous and inhomogeneous phantoms composed of slabs of solid water and lung. Computer generated computed tomography data sets of the rectilinear phantomsmore » are supplied to the facility prior to audit for planning of a range of cases including reference fields, asymmetric fields, and wedged fields. The audit assesses 3D planning with 6 MV photons with a static (zero degree) gantry. Scoring is performed using local dose differences between the planned and measured dose within 80% of the field width. The overall audit result is determined by the maximum dose difference over all scoring points, cases, and planes. Pass (Optimal Level) is defined as maximum dose difference ≤3.3%, Pass (Action Level) is ≤5.0%, and Fail (Out of Tolerance) is >5.0%. Results: At close of 2013, the ACDS had performed 24 Level II audits. 63% of the audits passed, 33% failed, and the remaining audit was not assessable. Of the 15 audits that passed, 3 were at Pass (Action Level). The high fail rate is largely due to a systemic issue with modeling asymmetric 60° wedges which caused a delivered overdose of 5%–8%. Conclusions: The ACDS has implemented a nonreference condition Level II type audit, based on ion chamber 2D array measurements in an inhomogeneous slab phantom. The powerful diagnostic ability of this audit has allowed the ACDS to rigorously test the treatment planning systems implemented in Australian radiotherapy facilities. Recommendations from audits have led to facilities modifying clinical practice and changing planning protocols.« less
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Shared Dosimetry Error in Epidemiological Dose-Response Analyses
DOE Office of Scientific and Technical Information (OSTI.GOV)
Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail
2015-03-23
Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takesmore » up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. Use of these methods for several studies, including the Mayak Worker Cohort and the U.S. Atomic Veterans Study, is discussed.« less
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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
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Prospective iterative trial of proteasome inhibitor-based desensitization.
Woodle, E S; Shields, A R; Ejaz, N S; Sadaka, B; Girnita, A; Walsh, R C; Alloway, R R; Brailey, P; Cardi, M A; Abu Jawdeh, B G; Roy-Chaudhury, P; Govil, A; Mogilishetty, G
2015-01-01
A prospective iterative trial of proteasome inhibitor (PI)-based therapy for reducing HLA antibody (Ab) levels was conducted in five phases differing in bortezomib dosing density and plasmapheresis timing. Phases included 1 or 2 bortezomib cycles (1.3 mg/m(2) × 6-8 doses), one rituximab dose and plasmapheresis. HLA Abs were measured by solid phase and flow cytometry (FCM) assays. Immunodominant Ab (iAb) was defined as highest HLA Ab level. Forty-four patients received 52 desensitization courses (7 patients enrolled in multiple phases): Phase 1 (n = 20), Phase 2 (n = 12), Phase 3 (n = 10), Phase 4 (n = 5), Phase 5 (n = 5). iAb reductions were observed in 38 of 44 (86%) patients and persisted up to 10 months. In Phase 1, a 51.5% iAb reduction was observed at 28 days with bortezomib alone. iAb reductions increased with higher bortezomib dosing densities and included class I, II, and public antigens (HLA DRβ3, HLA DRβ4 and HLA DRβ5). FCM median channel shifts decreased in 11/11 (100%) patients by a mean of 103 ± 54 mean channel shifts (log scale). Nineteen out of 44 patients (43.2%) were transplanted with low acute rejection rates (18.8%) and de novo DSA formation (12.5%). In conclusion, PI-based desensitization consistently and durably reduces HLA Ab levels providing an alternative to intravenous immune globulin-based desensitization. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.
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Diao, Lei; Hang, Yaming; Othman, Ahmed A; Mehta, Devangi; Amaravadi, Lakshmi; Nestorov, Ivan; Tran, Jonathan Q
2016-11-01
Daclizumab high yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit of the interleukin-2 receptor and is being developed for treatment of multiple sclerosis (MS). This manuscript characterized the pharmacokinetic-pharmacodynamic (PK-PD) relationships of daclizumab HYP in subjects with MS. Approximately 1400 subjects and 7000 PD measurements for each of three biomarkers [CD25 occupancy, CD56 bright natural killer (NK) cell count, regulatory T cell (Treg) count] from four clinical trials were analyzed using non-linear mixed effects modelling. Evaluated regimens included 150 or 300 mg subcutaneous (s.c.) every 4 weeks. CD25 occupancy was characterized using a sigmoidal maximum response (E max ) model. Upon daclizumab HYP treatment, CD25 saturation was rapid with complete saturation occurring after approximately 7 h and maintained when daclizumab HYP serum concentration was ≥5 mg l -1 . After the last 150 mg s.c. dose, unoccupied CD25 returned to baseline levels in approximately 24 weeks, with daclizumab HYP serum concentration approximately ≤1 mgl -1 1L. CD56 bright NK cell expansion was characterized using an indirect response model. Following daclizumab HYP 150 mg s.c. every 4 weeks, expansion plateaus approximately at week 36, at which the average maximum expansion ratio is 5.2. After the last dose, CD56 bright NK cells gradually declined to baseline levels within 24 weeks. Treg reduction was characterized by a sigmoidal E max model. Average maximum reduction of 60% occurred approximately 4 days post 150 mg s.c. dose. After the last dose, Tregs were projected to return to baseline levels in approximately 20 weeks. Robust PK-PD models of CD25 occupancy, CD56 bright NK cell expansion and Treg reduction by daclizumab HYP were developed to characterize its key pharmacodynamic effects in the target patient population. © 2016 The British Pharmacological Society.
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Conformal image-guided microbeam radiation therapy at the ESRF biomedical beamline ID17
DOE Office of Scientific and Technical Information (OSTI.GOV)
Donzelli, Mattia, E-mail: donzelli@esrf.fr; Bräuer-Krisch, Elke; Nemoz, Christian
Purpose: Upcoming veterinary trials in microbeam radiation therapy (MRT) demand for more advanced irradiation techniques than in preclinical research with small animals. The treatment of deep-seated tumors in cats and dogs with MRT requires sophisticated irradiation geometries from multiple ports, which impose further efforts to spare the normal tissue surrounding the target. Methods: This work presents the development and benchmarking of a precise patient alignment protocol for MRT at the biomedical beamline ID17 of the European Synchrotron Radiation Facility (ESRF). The positioning of the patient prior to irradiation is verified by taking x-ray projection images from different angles. Results: Usingmore » four external fiducial markers of 1.7 mm diameter and computed tomography-based treatment planning, a target alignment error of less than 2 mm can be achieved with an angular deviation of less than 2{sup ∘}. Minor improvements on the protocol and the use of smaller markers indicate that even a precision better than 1 mm is technically feasible. Detailed investigations concerning the imaging dose lead to the conclusion that doses for skull radiographs lie in the same range as dose reference levels for human head radiographs. A currently used online dose monitor for MRT has been proven to give reliable results for the imaging beam. Conclusions: The ESRF biomedical beamline ID17 is technically ready to apply conformal image-guided MRT from multiple ports to large animals during future veterinary trials.« less
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Weisel, Katja C.; Dimopoulos, Meletios A.; Moreau, Philippe; Lacy, Martha Q.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Banos, Anne; Oriol, Albert; Alegre, Adrian; Chen, Christine; Cavo, Michele; Garderet, Laurent; Ivanova, Valentina; Martinez-Lopez, Joaquin; Knop, Stefan; Yu, Xin; Hong, Kevin; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Miguel, Jesus San
2016-01-01
Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 − < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 − < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30. PMID:27081177
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Paraquat detoxication with multiple emulsions.
Frasca, S; Couvreur, P; Seiller, M; Pareau, D; Lacour, B; Stambouli, M; Grossiord, J L
2009-10-01
In this study, we show that detoxifying W/O/W multiple emulsions, prepared with an appropriate extractant/trapping couple, represent a promising technology for quick and safe poisoning treatments, with application to the highly toxic herbicide Paraquat, responsible of poisonings from low-dose exposure leading to several deaths every year. In vitro tests led to the choice of an appropriate extractant/trapping couple system with significant detoxication performance. In vivo tests showed (i) that rats receiving high doses of Paraquat, then a detoxifying emulsion, presented an increase from 50% to 100% of the MST (median survival time) and (ii) that no mortality was observed during 30 days with rats dosed with emulsions initially loaded with Paraquat at a concentration much higher than the lethal dose, proving the stability and the inocuity of the detoxifying multiple emulsion in the gastrointestinal tract.
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Sharapova, T; Devanarayan, V; LeRoy, B; Liguori, M J; Blomme, E; Buck, W; Maher, J
2016-01-01
MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases. © The Author(s) 2015.
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He, Yixin; Du, Min; Gao, Yan; Liu, Hongshuai; Wang, Hongwei; Wu, Xiaojun; Wang, Zhengtao
2013-01-01
Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory disease found mostly in young adults in the western world. Oxidative stress induced neuronal apoptosis plays an important role in the pathogenesis of MS. In current study, astragaloside IV (ASI), a natural saponin molecule isolated from Astragalus membranceus, given at 20 mg/kg daily attenuated the severity of experimental autoimmune encephalomyelitis (EAE) in mice significantly. Further studies disclosed that ASI treatment inhibited the increase of ROS and pro-inflammatory cytokine levels, down-regulation of SOD and GSH-Px activities, and elevation of iNOS, p53 and phosphorylated tau in central nervous system (CNS) as well as the leakage of BBB of EAE mice. Meanwhile, the decreased ratio of Bcl-2/Bax was reversed by ASI. Moreover, ASI regulated T-cell differentiation and infiltration into CNS. In neuroblast SH-SY5Y cells, ASI dose-dependently reduced cellular ROS level and phosphorylation of tau in response to hydrogen peroxide challenge by modulation of Bcl-2/Bax ratio. ASI also inhibited activation of microglia both in vivo and in vitro. iNOS up-regulation induced by IFNγ stimulation was abolished by ASI dose-dependently in BV-2 cells. In summary, ASI prevented the severity of EAE progression possibly by counterbalancing oxidative stress and its effects via reduction of cellular ROS level, enhancement of antioxidant defense system, increase of anti-apoptotic and anti-inflammatory pathways, as well as modulation of T-cell differentiation and infiltration into CNS. The study suggested ASI may be effective for clinical therapy/prevention of MS.
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Preclinical Mammalian Safety Studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA).
Wagner, Michael J; Mitra, Rahul; McArthur, Mark J; Baze, Wallace; Barnhart, Kirstin; Wu, Sherry Y; Rodriguez-Aguayo, Cristian; Zhang, Xinna; Coleman, Robert L; Lopez-Berestein, Gabriel; Sood, Anil K
2017-06-01
To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice ( N = 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed. Following single-dose EPHARNA administration to mice, no gross pathologic or dose-related microscopic findings were observed in either the acute (24 hours) or recovery (14 and 28 days) phases. The no-observed-adverse-effect level (NOAEL) for EPHARNA is considered >225 μg/kg when administered as a single injection intravenously in CD-1 mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. There appeared to be a mild hemolytic reaction in the female mice. In Rhesus macaques, minimal to moderate infiltration of mononuclear cells was found in some organs including the gastrointestinal tract, heart, and kidney. No differences attributed to EPHARNA were observed. These results demonstrate that EPHARNA is well tolerated at all doses tested. These data, combined with previously published in vivo validation studies, have led to an ongoing first-in-human phase I clinical trial (NCT01591356). Mol Cancer Ther; 16(6); 1114-23. ©2017 AACR . ©2017 American Association for Cancer Research.
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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 7th, 8th, and 9th administration to determine the Cmin at steady state; on the 9th 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) Cmax value increased from 35.77 (6.98) to 117.12 (19.78) µg/mL, and the mean (SD) AUC0-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) Cmax was 66.49 (8.49) µg/mL, the AUC0-t was 135.65 (26.91) µg×h/mL, the t1/2 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 Cmax 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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NASA Astrophysics Data System (ADS)
Sahbaee, Pooyan; Abadi, Ehsan; Sanders, Jeremiah; Becchetti, Marc; Zhang, Yakun; Agasthya, Greeshma; Segars, Paul; Samei, Ehsan
2016-03-01
The purpose of this study was to substantiate the interdependency of image quality, radiation dose, and contrast material dose in CT towards the patient-specific optimization of the imaging protocols. The study deployed two phantom platforms. First, a variable sized phantom containing an iodinated insert was imaged on a representative CT scanner at multiple CTDI values. The contrast and noise were measured from the reconstructed images for each phantom diameter. Linearly related to iodine-concentration, contrast to noise ratio (CNR), was calculated for different iodine-concentration levels. Second, the analysis was extended to a recently developed suit of 58 virtual human models (5D-XCAT) with added contrast dynamics. Emulating a contrast-enhanced abdominal image procedure and targeting a peak-enhancement in aorta, each XCAT phantom was "imaged" using a CT simulation platform. 3D surfaces for each patient/size established the relationship between iodine-concentration, dose, and CNR. The Sensitivity of Ratio (SR), defined as ratio of change in iodine-concentration versus dose to yield a constant change in CNR was calculated and compared at high and low radiation dose for both phantom platforms. The results show that sensitivity of CNR to iodine concentration is larger at high radiation dose (up to 73%). The SR results were highly affected by radiation dose metric; CTDI or organ dose. Furthermore, results showed that the presence of contrast material could have a profound impact on optimization results (up to 45%).
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Escribano, Begona M; Aguilar-Luque, Macarena; Bahamonde, Carmen; Conde, Cristina; Lillo, Rafael; Sanchez-Lopez, Fernando; Giraldo, Ana I; Cruz, Antonio H; Luque, Evelio; Gascon, Felix; Aguera, Eduardo; Tunez, Isaac
2016-01-01
The main aim of this study was to verify the effect of natalizumab on the levels of circulating catecholamines and indolamine and their possible relation with MS. For this purpose, 12 healthy individuals (control group) and 12 relapsing-remitting multiple sclerosis patients (RR-MS) were selected. The patients were treated with 300 mg of natalizumab during 56 weeks (1 dose/4 weeks) (MS-56). This selection was based on the McDonalds revision criterion and scheduled to star treatment with natalizumab. Blood samples were taken before treatment (basal level) and after 56 weeks of using natalizumab. Melatonin was measured in serum and in plasma, catecholamines (dopamine, epinephrine, and norepinephrine), carbonylated proteins, 8-hydroxy-2'deoxyguanosine (8OH-dG) and the ratio reduced glutathione/oxidised glutathione (GSH/GSSG). The epinephrine and dopamine levels diminished in the basal group with respect to the control and did not recover normal levels with the treatment. The melatonin was decreased in RR-MS patients and went back to its normal levels with natalizumab. Norepinephrine was increased in RR-MS and decreased in MS-56 until it equalled the control group. Natalizumab normalizes altered melatonin and norepinephrine levels in MS.
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Abraham, Sara A; Kearfott, Kimberlee J
2018-06-15
Optically stimulated luminescent dosimeters are devices that, when stimulated with light, emit light in proportion to the integrated ionizing radiation dose. The stimulation of optically stimulated luminescent material results in the loss of a small fraction of signal stored within the dosimetric traps. Previous studies have investigated the signal loss due to readout stimulation and the optical annealing of optically stimulated luminescent dosimeters. This study builds on former research by examining the behavior of optically stimulated luminescent signals after annealing, exploring the functionality of a previously developed signal loss model, and comparing uncertainties for dosimeters reused with or without annealing. For a completely annealed dosimeter, the minimum signal level was 56 ± 8 counts, and readings followed a Gaussian distribution. For dosimeters above this signal level, the fractional signal loss due to the reading process has a linear relationship with the calculated signal. At low signal levels (below 20,000 counts) in this optically stimulated luminescent dosimeter system, calculated signal percent errors increase significantly but otherwise are on average 0.72 ± 0.27%, 0.40 ± 0.19%, 0.33 ± 0.12%, and 0.24 ± 0.07% for 30, 75, 150, and 300 readings, respectively. Theoretical calculations of uncertainties showed that annealing before reusing dosimeters allows for dose errors below 1% with as few as 30 readings. Reusing dosimeters multiple times increases the dose errors especially with low numbers of readouts, so theoretically around 300 readings would be necessary to achieve errors around 1% or below in most scenarios. Note that these dose errors do not include the error associated with the signal-to-dose conversion factor.
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Roberts, D R; Chatterjee, A R; Yazdani, M; Marebwa, B; Brown, T; Collins, H; Bolles, G; Jenrette, J M; Nietert, P J; Zhu, X
2016-12-01
While there have been recent reports of brain retention of gadolinium following gadolinium-based contrast agent administration in adults, a retrospective series of pediatric patients has not previously been reported, to our knowledge. We investigated the relationship between the number of prior gadolinium-based contrast agent doses and increasing T1 signal in the dentate nucleus on unenhanced T1-weighted MR imaging. We hypothesized that despite differences in pediatric physiology and the smaller gadolinium-based contrast agent doses that pediatric patients are typically administered based on weighted-adjusted dosing, the pediatric brain would also demonstrate dose-dependent increasing T1 signal in the dentate nucleus. We included children with multiple gadolinium-based contrast agent administrations at our institution. A blinded reader placed ROIs within the dentate nucleus and adjacent cerebellar white matter. To eliminate reader bias, we also performed automated ROI delineation of the dentate nucleus, cerebellar white matter, and pons. Dentate-to-cerebellar white matter and dentate-to pons ratios were compared with the number of gadolinium-based contrast agent administrations. During 20 years at our institution, 280 patients received at least 5 gadolinium-based contrast agent doses, with 1 patient receiving 38 doses. Sixteen patients met the inclusion/exclusion criteria for ROI analysis. Blinded reader dentate-to-cerebellar white matter ratios were significantly associated with gadolinium-based contrast agent doses (r s = 0.77, P = .001). The dentate-to-pons ratio and dentate-to-cerebellar white matter ratios based on automated ROI placement were also significantly correlated with gadolinium-based contrast agent doses (t = 4.98, P < .0001 and t = 2.73, P < .02, respectively). In pediatric patients, the number of prior gadolinium-based contrast agent doses is significantly correlated with progressive T1-weighted dentate hyperintensity. Definitive confirmation of gadolinium deposition requires tissue analysis. Any potential clinical sequelae of gadolinium retention in the developing brain are unknown. Given this uncertainty, we suggest taking a cautious stance, including the use, in pediatric patients, of higher stability, macrocyclic agents, which in both human and animal studies have been shown to be associated with lower levels of gadolinium deposition, and detailed documentation of dosing. Most important, a patient should not be deprived of a well-indicated contrasted MR examination. © 2016 by American Journal of Neuroradiology.
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Van Sanden, Suzy; Ito, Tetsuro; Diels, Joris; Vogel, Martin; Belch, Andrew; Oriol, Albert
2018-03-01
Daratumumab (a human CD38-directed monoclonal antibody) and pomalidomide (an immunomodulatory drug) plus dexamethasone are both relatively new treatment options for patients with heavily pretreated multiple myeloma. A matching adjusted indirect comparison (MAIC) was used to compare absolute treatment effects of daratumumab versus pomalidomide + low-dose dexamethasone (LoDex; 40 mg) on overall survival (OS), while adjusting for differences between the trial populations. The MAIC method reduces the risk of bias associated with naïve indirect comparisons. Data from 148 patients receiving daratumumab (16 mg/kg), pooled from the GEN501 and SIRIUS studies, were compared separately with data from patients receiving pomalidomide + LoDex in the MM-003 and STRATUS studies. The MAIC-adjusted hazard ratio (HR) for OS of daratumumab versus pomalidomide + LoDex was 0.56 (95% confidence interval [CI], 0.38-0.83; p = .0041) for MM-003 and 0.51 (95% CI, 0.37-0.69; p < .0001) for STRATUS. The treatment benefit was even more pronounced when the daratumumab population was restricted to pomalidomide-naïve patients (MM-003: HR, 0.33; 95% CI, 0.17-0.66; p = .0017; STRATUS: HR, 0.41; 95% CI, 0.21-0.79; p = .0082). An additional analysis indicated a consistent trend of the OS benefit across subgroups based on M-protein level reduction (≥50%, ≥25%, and <25%). The MAIC results suggest that daratumumab improves OS compared with pomalidomide + LoDex in patients with heavily pretreated multiple myeloma. This matching adjusted indirect comparison of clinical trial data from four studies analyzes the survival outcomes of patients with heavily pretreated, relapsed/refractory multiple myeloma who received either daratumumab monotherapy or pomalidomide plus low-dose dexamethasone. Using this method, daratumumab conferred a significant overall survival benefit compared with pomalidomide plus low-dose dexamethasone. In the absence of head-to-head trials, these indirect comparisons provide useful insights to clinicians and reimbursement authorities around the relative efficacy of treatments. © AlphaMed Press 2017.
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Deviations from Haber’s Law for Multiple Measures of Acute Lung Injury in Chlorine-Exposed Mice
Hoyle, Gary W.; Chang, Weiyuan; Chen, Jing; Schlueter, Connie F.; Rando, Roy J.
2010-01-01
Chlorine gas is considered a chemical threat agent that can cause acute lung injury. Studies in the early 20th century on war gases led Haber to postulate that the dose of an inhaled chemical expressed as the product of gas concentration and exposure time leads to a constant toxicological effect (Haber’s Law). In the present work, mice were exposed to a constant dose of chlorine (100 ppm-h) delivered using different combinations of concentration and time (800 ppm/7.5 min, 400 ppm/15 min, 200 ppm/30 min, and 100 ppm/60 min). Significant effects of exposure protocol on survival evaluated 6 h after exposure were observed, ranging from 0% for the 7.5-min exposure to 100% for the 30- and 60-min exposures. Multiple parameters indicative of lung injury were examined to determine if any aspects of lung injury were differentially affected by the exposure protocols. Most parameters (pulmonary edema, neutrophil influx, and levels of protein, immunoglobulin M, and the chemokine KC [Cxcl1] in lavage fluid) indicated that lung injury was most pronounced for the 15-min exposure and least for the 60-min exposure. In contrast, changes in pulmonary function at baseline and in response to inhaled methacholine were similar following the three exposure regimens. The results indicate that the extent of lung injury following chlorine inhalation depends not only on total dose but also on the specifics of exposure concentration and time, and they suggest that evaluation of countermeasures against chlorine-induced lung injury should be performed using multiple types of exposure scenarios. PMID:20819911
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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.
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TH-AB-207A-03: Skin Dose to Patients Receiving Multiple CTA and CT Exams of the Head
DOE Office of Scientific and Technical Information (OSTI.GOV)
Nawfel, RD; Young, G
Purpose: To measure patient skin dose from CT angiography (CTA) and CT exams of the head, and determine if patients having multiple exams could receive cumulative doses that approach or exceed deterministic thresholds. Methods: This study was HIPAA compliant and conducted with IRB approval. Patient skin doses were measured over a 4 month period using nanoDot OSL dosimeters placed on the head of 52 patients for two CT scanners. On each scanner, 26 patients received CT exams (scanner 1: 10 females, 16 males, mean age 64.2 years; scanner 2: 18 females, 8 males, mean age 61.2 years). CT exam dosemore » metrics, CTDIvol and dose-length product (DLP) were recorded for each exam. Additionally, skin dose was measured on an acrylic skull phantom in each scanner and on a neuro-interventional imaging system using clinical protocols. Measured dose data was used to estimate peak skin dose (PSD) for 4 patients receiving multiple exams including CTA, head CT, and cerebral angiography. Results: For scanner 1, the mean PSD for CTA exams (98.9 ± 5.3 mGy) and for routine head CT exams (39.2 ± 3.7 mGy) agreed reasonably well with the PSD measured on the phantom, 105.4 mGy and 40.0 mGy, respectively. Similarly for scanner 2, the mean PSD for CTA exams (98.8 ± 7.4 mGy) and for routine head CT exams (42.9 ± 9.4 mGy) compared well with phantom measurements, 95.2 mGy and 37.6 mGy, respectively. In addition, the mean PSD was comparable between scanners for corresponding patient exams, CTA and routine head CT respectively. PSD estimates ranged from 1.9 – 4.5 Gy among 4 patients receiving multiple exams. Conclusion: Patients having several exams including both CTA and routine head CT may receive cumulative doses approaching or exceeding the threshold for single dose deterministic effects.« less
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Down-regulation of multiple low dose streptozotocin-induced diabetes by mycophenolate mofetil
MAKSIMOVIC-IVANIC, D; TRAJKOVIC, V; MILJKOVIC, DJ; STOJKOVIC, M MOSTARICA; STOSIC-GRUJICIC, S
2002-01-01
The new immunosuppressive agent mycophenolate mofetil (MMF) has been shown recently to exert a protective effects in certain animal models of autoimmunity, including diabetes in diabetes-prone bio-breeding (BB) rats. In the present study, the immunomodulatory potential of MMF was investigated in autoimmune diabetes induced by multiple low doses of streptozotocin (MLD-STZ) in genetically susceptible DA rats 20 mg STZ/kg body weight (b.w.) for 5 days] and CBA/H mice (40 mg STZ/kg b.w. for 5 days). In both species, short time treatment of animals with MMF (25 mg/kg) during the early development of the disease, as well as continuous MMF treatment, prevented the appearance of hyperglycaemia and inflammatory infiltrates in the pancreatic tissue. Moreover, clinical manifestations of diabetes were suppressed by application of the drug after the onset of clinical symptoms. Treatment with guanosine (1 mg/kg) in parallel with MMF completely reversed MMF activity in vivo, indicating that inhibition of inosine monophosphate dehydrogenase (IMPDH) was responsible for the observed suppressive effects. MMF-mediated protection from diabetes correlated with reduced ex vivo spontaneous spleen mononuclear cell (MNC) proliferation and defective adhesive cell interactions. MMF-treated animals also had lower local production of IFN-γ, as well as IL-12 and nitric oxide (NO) production by peripheral tissues (spleen and peritoneal cells), compared to that in control diabetic groups, while IL-10 level was elevated. Together, these data demonstrate that MMF interferes with autoimmune process in streptozotocin-induced diabetes at multiple levels, including lymphocyte proliferation and adhesion, as well as pro/anti-inflammatory cytokine balance. PMID:12165076
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Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian E; Simon, Steven L
2016-02-10
Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure. Copyright © 2015 John Wiley & Sons, Ltd.
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Zhou, Huili; Zheng, Yunliang; Wu, Guolan; Hu, Xingjiang; Zhai, You; Iv, Duo; Liu, Jian; Wu, Lihua; Shentu, Jianzhong
2016-02-01
Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase indicated for the chronic management of hyperuricemia in patients with gout. The aim of the present study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of febuxostat capsules in healthy Chinese volunteers. This openlabel, single- and multiple-dose three-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of febuxostat 40, 80, or 120 mg in separate trial periods, with a 1-week washout between periods. Those allocated to the 40 mg and 80 mg dose continued into the multiple-dose phase, in which they received 40 mg or 80 mg once daily for 6 consecutive days. During the course of the study, blood samples were collected and the concentrations of febuxostat were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). 12 healthy Chinese volunteers were enrolled and completed 3 treatment periods. After oral administration of single doses of 40, 80, and 120 mg of febuxostat, the mean (SD) Cmax was 2,835.43 (1,136.41), 5,356.75 (1,711.33), and 7,718.21 (2,446.34) ng/mL, respectively; the AUC0-48h was 8,821.10 (3,018.35), 17,854.46 (5,113.28), and 30,832.05 (10,992.20) ng×h/ mL; the AUC0-∞ was 8,990.33 (3,046.14), 18,193.58 (5,160.80), and 31,466.93 (1,1074.74) ng×h/mL; the t1/2 was 5.95 (2.71), 9.41 (7.47), and 12.34 (10.34) hours; the Cl/F was 4.81 (1.18), 4.70 (1.21), and 4.18(1.19) L/h; and the Vz/F was 39.66 (16.69), 62.72 (51.41), and 73.41 (64.84) L. After administration of multiple doses of 40 and 80 mg febuxostat, the mean (SD) Cmax,ss was 2,762.38 (1,331.96) and 5,047.27 (1,456.57) ng/mL; the Cmin,ss was 124.10 (6.32) and 46.93 (15.86) ng/mL; the AUCss,0-τ was 8,525.49 (2,160.64) and 16,757.12 (4,223.17) ng×h /mL; the steadystate plasma concentration (Css) was 355.23 (90.03) and 698.21 (175.97) ng/mL; the t1/2 was 7.68 (3.30) and 11.33 (6.94) hours; the Cl/F was 4.99 (1.30) and 5.05 (1.22) L/h; and the Vz/F was 54.10 (24.10) and 85.51 (65.99) L. No serious AEs were reported, and there were no discontinuations due to AEs. The PK of febuxostat exhibited dose proportional kinetics from 40 to 120 mg dose. After multiple doses, the pharmacokinetic parameters of febuxostat were consistent with those after single doses. There was no accumulation in febuxostat exposure in healthy Chinese between multiple doses and single dose. At the doses studied, febuxostat appeared to be well tolerated in these healthy volunteers.
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Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy
Richardson, Paul; Mitsiades, Constantine; Laubach, Jacob; Schlossman, Robert; Ghobrial, Irene; Hideshima, Teru; Munshi, Nikhil; Anderson, Kenneth
2010-01-01
Introduction: Multiple myeloma (MM) is a relatively common and incurable hematological malignancy. Currently, there is no single standard therapy, with choice of treatment dependent on individual patient factors. Lenalidomide is an immunomodulatory drug with potent antitumor, antiangiogenic, immunomodulatory, and proapoptotic activity in MM. Aims: To evaluate the evidence for the use of lenalidomide in its current indication in relapsed or refractory MM, and additionally its investigational use for the treatment of newly diagnosed MM. Evidence review: In patients with relapsed and refractory MM, adding lenalidomide to high-dose dexamethasone significantly improves response rates and time-to-progression, relative to high-dose dexamethasone alone. This translates into a significant extension of overall survival (with a median extension of 9.1 months in a pivotal phase III study). Outcome is independent of patient age, number of previous therapies, type of previous therapy (including thalidomide or autologous stem cell transplantation), renal impairment, and β2-microglobulin level. Evidence suggests that combining lenalidomide with low-dose dexamethasone improves outcomes in patients with newly diagnosed disease and is superior to lenalidomide combined with high-dose dexamethasone. Myelosuppression is the predominant toxicity observed, although some studies have shown high incidences of venous thromboembolism in the absence of prophylactic antithrombotic anticoagulation therapy. There is currently only limited evidence regarding the health economics of lenalidomide. Role in therapy: The encouraging results obtained with lenalidomide alone and in combination with dexamethasone in patients with relapsed or refractory MM have led to its adoption as a recommended therapy in patients who have received at least one prior treatment. Emerging evidence supports the ongoing investigation of lenalidomide in combination with low-dose dexamethasone, and in other combinations including bortezomib, for use both in relapsed, refractory, and newly diagnosed MM. PMID:20694078
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Taylor, Paige A., E-mail: pataylor@mdanderson.org; Kry, Stephen F.; Alvarez, Paola
Purpose: The purpose of this study was to summarize the findings of anthropomorphic proton phantom irradiations analyzed by the Imaging and Radiation Oncology Core Houston QA Center (IROC Houston). Methods and Materials: A total of 103 phantoms were irradiated by proton therapy centers participating in clinical trials. The anthropomorphic phantoms simulated heterogeneous anatomy of a head, liver, lung, prostate, and spine. Treatment plans included those for scattered, uniform scanning, and pencil beam scanning beam delivery modalities using 5 different treatment planning systems. For every phantom irradiation, point doses and planar doses were measured using thermoluminescent dosimeters (TLD) and film, respectively. Differencesmore » between measured and planned doses were studied as a function of phantom, beam delivery modality, motion, repeat attempt, treatment planning system, and date of irradiation. Results: The phantom pass rate (overall, 79%) was high for simple phantoms and lower for phantoms that introduced higher levels of difficulty, such as motion, multiple targets, or increased heterogeneity. All treatment planning systems overestimated dose to the target, compared to TLD measurements. Errors in range calculation resulted in several failed phantoms. There was no correlation between treatment planning system and pass rate. The pass rates for each individual phantom are not improving over time, but when individual institutions received feedback about failed phantom irradiations, pass rates did improve. Conclusions: The proton phantom pass rates are not as high as desired and emphasize potential deficiencies in proton therapy planning and/or delivery. There are many areas for improvement with the proton phantom irradiations, such as treatment planning system dose agreement, range calculations, accounting for motion, and irradiation of multiple targets.« less
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Belogurov, Alexey; Zakharov, Konstantin; Lomakin, Yakov; Surkov, Kirill; Avtushenko, Sergey; Kruglyakov, Peter; Smirnov, Ivan; Makshakov, Gleb; Lockshin, Curtis; Gregoriadis, Gregory; Genkin, Dmitry; Gabibov, Alexander; Evdoshenko, Evgeniy
2016-10-01
Previously, we showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP 46-62 , MBP 124-139 and MBP 147-170 (Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including Expanded Disability Status Scale score, magnetic resonance imaging results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection. Xemys was safe and well tolerated when administered for 6 weeks to a maximum single dose of 900 μg. Expanded Disability Status Scale scores and numbers of T2-weighted and new gadolinium-enhancing lesions on magnetic resonance imaging were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and interleukin-7 decreased, whereas the level of tumor necrosis factor-α increased. These results provide evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.
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NASA Astrophysics Data System (ADS)
McCall, Keisha C.
Identification and monitoring of sub-tumor targets will be a critical step for optimal design and evaluation of cancer therapies in general and biologically targeted radiotherapy (dose-painting) in particular. Quantitative PET imaging may be an important tool for these applications. Currently radiotherapy planning accounts for tumor motion by applying geometric margins. These margins create a motion envelope to encompass the most probable positions of the tumor, while also maintaining the appropriate tumor control and normal tissue complication probabilities. This motion envelope is effective for uniform dose prescriptions where the therapeutic dose is conformed to the external margins of the tumor. However, much research is needed to establish the equivalent margins for non-uniform fields, where multiple biological targets are present and each target is prescribed its own dose level. Additionally, the size of the biological targets and close proximity make it impractical to apply planning margins on the sub-tumor level. Also, the extent of high dose regions must be limited to avoid excessive dose to the surrounding tissue. As such, this research project is an investigation of the uncertainty within quantitative PET images of moving and displaced dose-painting targets, and an investigation of the residual errors that remain after motion management. This included characterization of the changes in PET voxel-values as objects are moved relative to the discrete sampling interval of PET imaging systems (SPECIFIC AIM 1). Additionally, the repeatability of PET distributions and the delineating dose-painting targets were measured (SPECIFIC AIM 2). The effect of imaging uncertainty on the dose distributions designed using these images (SPECIFIC AIM 3) has also been investigated. This project also included analysis of methods to minimize motion during PET imaging and reduce the dosimetric impact of motion/position-induced imaging uncertainty (SPECIFIC AIM 4).
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Mayer, Kenneth H; Seaton, Kelly E; Huang, Yunda; Grunenberg, Nicole; Isaacs, Abby; Allen, Mary; Ledgerwood, Julie E; Frank, Ian; Sobieszczyk, Magdalena E; Baden, Lindsey R; Rodriguez, Benigno; Van Tieu, Hong; Tomaras, Georgia D; Deal, Aaron; Goodman, Derrick; Bailer, Robert T; Ferrari, Guido; Jensen, Ryan; Hural, John; Graham, Barney S; Mascola, John R; Corey, Lawrence; Montefiori, David C
2017-11-01
VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed. HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 μg/ml (95% CI: 1,033, 1,340) and 420 μg/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 μg/ml (95% CI: 10, 27) and 6 μg/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration [IC50] > 5 μg/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits. VRC01 administered as either an IV infusion (10-40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants' sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials. Clinical Trials Registration: NCT02165267.
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Cheng, Chen; Lin, Jia-zhen; Li, Li; Yang, Jun-ling; Jia, Wei-wei; Huang, Yu-hong; Du, Fei-fei; Wang, Feng-qing; Li, Mei-juan; Li, Yan-fen; Xu, Fang; Zhang, Na-ting; Olaleye, Olajide E; Sun, Yan; Li, Jian; Sun, Chang-hai; Zhang, Gui-ping; Li, Chuan
2016-04-01
Monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides. Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro. A total of 18 monoterpene glycosides were detected in XueBiJing injection (content levels, 0.001-2.47 mmol/L), and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorin increased proportionally as the dose was increased. Rat lung, heart, and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability. Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.
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Polyamine Analogues as Novel Anti-HER Family Agents in Human Breast Cancer
2007-09-01
Davidson NE, & Casero RA Jr. Spermine oxidase SMO(PAOh1), not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Elevated levels of all three naturally occurring polyamines, spermine , spermidine and...protein in multiple human breast cancer cell lines. This suppression is both time and dose dependent. A relationship between oligoamine structure , growth
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In vitro biotransformation rates in fish liver S9: effect of dosing techniques.
Lee, Yung-Shan; Lee, Danny H Y; Delafoulhouze, Maximilien; Otton, S Victoria; Moore, Margo M; Kennedy, Chris J; Gobas, Frank A P C
2014-08-01
In vitro biotransformation assays are currently being explored to improve estimates of bioconcentration factors of potentially bioaccumulative organic chemicals in fish. The present study compares thin-film and solvent-delivery dosing techniques as well as single versus multiple chemical dosing for measuring biotransformation rates of selected polycyclic aromatic hydrocarbons in rainbow trout (Oncorhynchus mykiss) liver S9. The findings show that biotransformation rates of very hydrophobic substances can be accurately measured in thin-film sorbent-dosing assays from concentration-time profiles in the incubation medium but not from those in the sorbent phase because of low chemical film-to-incubation-medium mass-transfer rates at the incubation temperature of 13.5 °C required for trout liver assays. Biotransformation rates determined by thin-film dosing were greater than those determined by solvent-delivery dosing for chrysene (octanol-water partition coefficient [KOW ] =10(5.60) ) and benzo[a]pyrene (KOW =10(6.04) ), whereas there were no statistical differences in pyrene (KOW =10(5.18) ) biotransformation rates between the 2 methods. In sorbent delivery-based assays, simultaneous multiple-chemical dosing produced biotransformation rates that were not statistically different from those measured in single-chemical dosing experiments for pyrene and benzo[a]pyrene but not for chrysene. In solvent-delivery experiments, multiple-chemical dosing produced biotransformation rates that were much smaller than those in single-chemical dosing experiments for all test chemicals. While thin-film sorbent-phase and solvent delivery-based dosing methods are both suitable methods for measuring biotransformation rates of substances of intermediate hydrophobicity, thin-film sorbent-phase dosing may be more suitable for superhydrophobic chemicals. © 2014 SETAC.
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Snajderova, Marta; Blair, Jo; Pournara, Effie; Pedersen, Birgitte Tønnes; Petit, Isabelle Oliver
2017-01-01
Objective To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; Nbib960128) between 2006 and 2016. Design This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n = 425/61/316/119), France (n = 1404/188/970/206), Germany (n = 2603/351/1387/411) and the UK (n = 259/60/87/35). Methods GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications. Results In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown (P < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%). Conclusions GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations. PMID:28522645
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Current response of a TlBr detector to {sup 137}Cs {gamma}-ray radiation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Gazizov, I. M., E-mail: gazizov@isotop.dubna.ru; Zaletin, V. M.; Kukushkin, V. M.
2011-05-15
The current response of a TlBr detector to {sup 137}Cs {gamma}-ray radiation has been studied in the dose-rate range 0.033-3.84 Gy/min and within the voltage range 1-300 V; the detectors are based on pure and doped TlBr crystals grown from the melt by the Bridgman-Stockbarger method. The mass fraction of Pb or Ca introduced into the TlBr crystals was 1-10 ppm for Pb and 150 ppm for Ca. The current response of nominally undoped TlBr samples was nearly linear over two decades of studied dose rates. Deep hole levels associated with cationic vacancies V{sub c}{sup -} determine the dependence ofmore » the current response on the voltage in the high electric fields. The parameters of the carriers' transport {mu}{tau} are determined. The TlBr crystals grown in vacuum and in the bromine vapor exhibit a large mobility-lifetime product of 4.3 Multiplication-Sign 10{sup -4} and 6.4 Multiplication-Sign 10{sup -5} cm{sup 2}V{sup -1}, respectively. The value of {mu}{tau} is in the range (4-9) Multiplication-Sign 10{sup -5} cm{sup 2}V{sup -1} for crystals doped with a divalent cation.« less
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Kaynar, Mehmet; Tekinarslan, Erdem; Keskin, Suat; Buldu, İbrahim; Sönmez, Mehmet Giray; Karatag, Tuna; Istanbulluoglu, Mustafa Okan
2015-01-01
To determine and evaluate the effective radiation exposure during a one year follow-up of urolithiasis patients following the SWL (extracorporeal shock wave lithotripsy) treatment. Total Effective Radiation Exposure (ERE) doses for each of the 129 patients: 44 kidney stone patients, 41 ureter stone patients, and 44 multiple stone location patients were calculated by adding up the radiation doses of each ionizing radiation session including images (IVU, KUB, CT) throughout a one year follow-up period following the SWL. Total mean ERE values for the kidney stone group was calculated as 15, 91 mSv (5.10-27.60), for the ureter group as 13.32 mSv (5.10-24.70), and in the multiple stone location group as 27.02 mSv (9.41-54.85). There was no statistically significant differences between the kidney and ureter groups in terms of the ERE dose values (p = 0.221) (p >0.05). In the comparison of the kidney and ureter stone groups with the multiple stone location group; however, there was a statistically significant difference (p = 0.000) (p <0.05). ERE doses should be a factor to be considered right at the initiation of any diagnostic and/or therapeutic procedure. Especially in the case of multiple stone locations, due to the high exposure to ionized radiation, different imaging modalities with low dose and/or totally without a dose should be employed in the diagnosis, treatment, and follow-up bearing the aim to optimize diagnosis while minimizing the radiation dose as much as possible.
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Baird, Joanne M.; Kim, Young Joo; Rajora, Kuwar B.; D’Silva, Delma; Podolinsky, Lin; Mazefsky, Carla; Minshew, Nancy
2014-01-01
We examined whether different doses of therapeutic riding influenced parent-nominated target behaviors of children with autism spectrum disorder (ASD) (a) during the session (b) at home, and (c) in the community. We used a single subject multiple Baseline, multiple case design, with dosing of 1, 3, and 5 times/week. Three boys with ASD, 6–8 years of age participated, and counts of target behaviors were collected in each setting and phase of the study. Compared to Baseline, 70 % of the target behaviors were better during Intervention and improvement was retained in 63 % of the behaviors during Withdrawal. Increased doses of therapeutic riding were significant for magnitude of change, and the effect of the therapeutic riding sessions generalized to home and community. PMID:24091469
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Pharmacokinetics of multiple doses of transdermal flunixin meglumine in adult Holstein dairy cows.
Kleinhenz, M D; Gorden, P J; Smith, J S; Schleining, J A; Kleinhenz, K E; Wulf, L L; Sidhu, P K; Rea, D; Coetzee, J F
2018-06-01
A transdermal formulation of the nonsteroidal anti-inflammatory drug, flunixin meglumine, has been approved in the United States and Canada for single-dose administration. Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33 mg/kg every 24 hr for three total treatments. Plasma flunixin concentrations were determined using high-pressure liquid chromatography with mass spectroscopy (HPLC-MS). Pharmacokinetic analysis was completed on each individual animal with noncompartmental methods using computer software. The time to maximum drug concentration (Tmax) was 2.81 hr, and the maximum drug concentration was 1.08 μg/ml. The mean terminal half-life (T½) was determined to be 5.20 hr. Clearance per fraction absorbed (Cl/F) was calculated to be 0.294 L/hr kg -1 , and volume of distribution of fraction (Vz/F) absorbed was 2.20 L/kg. The mean accumulation factor was 1.10 after three doses. This indicates changes in dosing may not be required when giving multiple doses of flunixin transdermal. Further work is required to investigate the clinical efficacy of transdermal flunixin after multiple daily doses. © 2018 John Wiley & Sons Ltd.
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Effects of refractive index mismatch in optical CT imaging of polymer gel dosimeters.
Manjappa, Rakesh; Makki S, Sharath; Kumar, Rajesh; Kanhirodan, Rajan
2015-02-01
Proposing an image reconstruction technique, algebraic reconstruction technique-refraction correction (ART-rc). The proposed method takes care of refractive index mismatches present in gel dosimeter scanner at the boundary, and also corrects for the interior ray refraction. Polymer gel dosimeters with high dose regions have higher refractive index and optical density compared to the background medium, these changes in refractive index at high dose results in interior ray bending. The inclusion of the effects of refraction is an important step in reconstruction of optical density in gel dosimeters. The proposed ray tracing algorithm models the interior multiple refraction at the inhomogeneities. Jacob's ray tracing algorithm has been modified to calculate the pathlengths of the ray that traverses through the higher dose regions. The algorithm computes the length of the ray in each pixel along its path and is used as the weight matrix. Algebraic reconstruction technique and pixel based reconstruction algorithms are used for solving the reconstruction problem. The proposed method is tested with numerical phantoms for various noise levels. The experimental dosimetric results are also presented. The results show that the proposed scheme ART-rc is able to reconstruct optical density inside the dosimeter better than the results obtained using filtered backprojection and conventional algebraic reconstruction approaches. The quantitative improvement using ART-rc is evaluated using gamma-index. The refraction errors due to regions of different refractive indices are discussed. The effects of modeling of interior refraction in the dose region are presented. The errors propagated due to multiple refraction effects have been modeled and the improvements in reconstruction using proposed model is presented. The refractive index of the dosimeter has a mismatch with the surrounding medium (for dry air or water scanning). The algorithm reconstructs the dose profiles by estimating refractive indices of multiple inhomogeneities having different refractive indices and optical densities embedded in the dosimeter. This is achieved by tracking the path of the ray that traverses through the dosimeter. Extensive simulation studies have been carried out and results are found to be matching that of experimental results.
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Effects of refractive index mismatch in optical CT imaging of polymer gel dosimeters
DOE Office of Scientific and Technical Information (OSTI.GOV)
Manjappa, Rakesh; Makki S, Sharath; Kanhirodan, Rajan, E-mail: rajan@physics.iisc.ernet.in
2015-02-15
Purpose: Proposing an image reconstruction technique, algebraic reconstruction technique-refraction correction (ART-rc). The proposed method takes care of refractive index mismatches present in gel dosimeter scanner at the boundary, and also corrects for the interior ray refraction. Polymer gel dosimeters with high dose regions have higher refractive index and optical density compared to the background medium, these changes in refractive index at high dose results in interior ray bending. Methods: The inclusion of the effects of refraction is an important step in reconstruction of optical density in gel dosimeters. The proposed ray tracing algorithm models the interior multiple refraction at themore » inhomogeneities. Jacob’s ray tracing algorithm has been modified to calculate the pathlengths of the ray that traverses through the higher dose regions. The algorithm computes the length of the ray in each pixel along its path and is used as the weight matrix. Algebraic reconstruction technique and pixel based reconstruction algorithms are used for solving the reconstruction problem. The proposed method is tested with numerical phantoms for various noise levels. The experimental dosimetric results are also presented. Results: The results show that the proposed scheme ART-rc is able to reconstruct optical density inside the dosimeter better than the results obtained using filtered backprojection and conventional algebraic reconstruction approaches. The quantitative improvement using ART-rc is evaluated using gamma-index. The refraction errors due to regions of different refractive indices are discussed. The effects of modeling of interior refraction in the dose region are presented. Conclusions: The errors propagated due to multiple refraction effects have been modeled and the improvements in reconstruction using proposed model is presented. The refractive index of the dosimeter has a mismatch with the surrounding medium (for dry air or water scanning). The algorithm reconstructs the dose profiles by estimating refractive indices of multiple inhomogeneities having different refractive indices and optical densities embedded in the dosimeter. This is achieved by tracking the path of the ray that traverses through the dosimeter. Extensive simulation studies have been carried out and results are found to be matching that of experimental results.« less
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Methotrexate Is a JAK/STAT Pathway Inhibitor
Thomas, Sally; Fisher, Katherine H.; Snowden, John A.; Danson, Sarah J.; Brown, Stephen; Zeidler, Martin P.
2015-01-01
Background The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains. Methods & Findings We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin. Conclusions Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential. PMID:26131691
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Radiotherapy in the treatment of multiple myeloma.
Bosch, A; Frias, Z
1988-12-01
Fifty-nine patients with multiple myeloma referred for treatment of painful bony lesions received irradiation to 95 local areas, and 16 of the 59 were irradiated using hemibody techniques. Pain relief was obtained in practically all of the irradiated regions. Most local areas were treated to doses of 3000 cGy in 10 to 15 fractions. Patients with generalized pain due to multiple site involvement were treated with single dose hemibody irradiation, to doses of 600 cGy to the upper hemibody, and of 800 cGy to the lower hemibody. This treatment was well tolerated and side effects minimal. Median survival from diagnosis was 30 months and the survival at 1, 3, and 5 years was 80%, 42%, and 12% respectively. Key articles on radiation therapy of multiple myeloma are reviewed and discussed. Since all patients eventually relapse after chemotherapy, the role of radiotherapy using present techniques should be fully evaluated and considered as an alternative in the primary treatment of multiple myeloma.
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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.
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Dose-finding design for multi-drug combinations
Wages, Nolan A; Conaway, Mark R; O'Quigley, John
2012-01-01
Background Most of the current designs used for Phase I dose finding trials in oncology will either involve only a single cytotoxic agent or will impose some implicit ordering among the doses. The goal of the studies is to estimate the maximum tolerated dose (MTD), the highest dose that can be administered with an acceptable level of toxicity. A key working assumption of these methods is the monotonicity of the dose–toxicity curve. Purpose Here we consider situations in which the monotonicity assumption may fail. These studies are becoming increasingly common in practice, most notably, in phase I trials that involve combinations of agents. Our focus is on studies where there exist pairs of treatment combinations for which the ordering of the probabilities of a dose-limiting toxicity cannot be known a priori. Methods We describe a new dose-finding design which can be used for multiple-drug trials and can be applied to this kind of problem. Our methods proceed by laying out all possible orderings of toxicity probabilities that are consistent with the known orderings among treatment combinations and allowing the continual reassessment method (CRM) to provide efficient estimates of the MTD within these orders. The design can be seen to simplify to the CRM when the full ordering is known. Results We study the properties of the design via simulations that provide comparisons to the Bayesian approach to partial orders (POCRM) of Wages, Conaway, and O'Quigley. The POCRM was shown to perform well when compared to other suggested methods for partial orders. Therefore, we comapre our approach to it in order to assess the performance of the new design. Limitations A limitation concerns the number of possible orders. There are dose-finding studies with combinations of agents that can lead to a large number of possible orders. In this case, it may not be feasible to work with all possible orders. Conclusions The proposed design demonstrates the ability to effectively estimate MTD combinations in partially ordered dosefinding studies. Because it relaxes the monotonicity assumption, it can be considered a multivariate generalization of the CRM. Hence, it can serve as a link between single and multiple-agent dosefinding trials. PMID:21652689
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Fedotova, Julia; Dudnichenko, Tatyana; Kruzliak, Peter; Puchavskaya, Zhanna
2016-12-01
Vitamine D (VD) has important functions in the human brain and may play a role in affective-related disorders. VD receptors are expressed in multiple brain regions associated with depressive disorders. The aim of the preclinical study was to examine the effects of chronic cholecalciferol administration (1.0, 2.5 or 5.0mg/kg/day,s.c., once daily, for 14days) on the depression-like behavior and corticosterone levels in the blood samples following ovariectomy in female rats. Cholecalciferol was administered to the ovariectomized (OVX) rats and OVX rats treated with 17β-estradiol (17β-E 2 , 0.5μg/rat,s.c., once daily, for 14days). Depression-like behavior and spontaneous locomotor activity were assessed in the forced swimming test (FST) and the open field test (OFT), respectively. The corticosterone levels in the blood serum before and after FST were measured in all experimental groups. Treatment with cholecalciferol in high dose (5.0mg/kg/day,s.c.) significantly decreased the immobility time of OVX rats in the FST. Co-administration of cholecalciferol in high dose with 17β-E 2 exerted a markedly synergistic antidepressant-like effect in the OVX rats on the same model of depression-like behavior testing. Cholecalciferol in high dose (5.0mg/kg/day,s.c.) administered alone or together with 17β-E 2 significantly enhanced frequency of grooming for the OVX rats in the OFT. Moreover, cholecalciferol in high dose administered alone or together with 17β-E 2 significantly decreased the elevated corticosterone levels in the blood serum of OVX rats following the FST. These results indicate that Cholecalciferol in high dose has a marked antidepressant-like effect in the adult female rats with low levels of estrogen. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
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Oswald, S; zu Schwabedissen, HE Meyer; Nassif, A; Modess, C; Desta, Z; Ogburn, ET; Mostertz, J; Keiser, M; Jia, J; Hubeny, A; Ulrich, A; Runge, D; Marinova, M; Lütjohann, D; Kroemer, HK; Siegmund, W
2013-01-01
Hypercholesterolemia frequently occurs in patients treated with efavirenz who cannot be treated adequately with statins because of drug interactions. These patients may benefit from cholesterol-lowering therapy with ezetimibe. This study determined the influence of single-dose and multiple-dose efavirenz (400 mg/day for 9 days) on the pharmacokinetics and sterol-lowering of ezetimibe (10 mg) in 12 healthy subjects. In addition, the influence of efavirenz on genome-wide intestinal expression and in vitro function of ABCB1, ABCC2, UGT1A1, and OATP1B1 was studied. Efavirenz (multiple dose) had no influence on the pharmacokinetics and lipid-lowering functions of ezetimibe. Intestinal expression of enzymes and transporters (e.g., ABCB1, ABCC2, and UGT1A1) was not affected by chronic efavirenz. Efavirenz (single dose) slightly increased ezetimibe absorption and markedly decreased exposure to ezetimibe-glucuronide (single dose and multiple dose), which may be explained by inhibition of UGT1A1 and ABCB1 (in vitro data). Ezetimibe had no effect on the disposition of efavirenz. Consequently, ezetimibe may be a safe and efficient therapeutic option in patients with HIV infection. PMID:22297387
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Recalculation of dose for each fraction of treatment on TomoTherapy.
Thomas, Simon J; Romanchikova, Marina; Harrison, Karl; Parker, Michael A; Bates, Amy M; Scaife, Jessica E; Sutcliffe, Michael P F; Burnet, Neil G
2016-01-01
The VoxTox study, linking delivered dose to toxicity requires recalculation of typically 20-37 fractions per patient, for nearly 2000 patients. This requires a non-interactive interface permitting batch calculation with multiple computers. Data are extracted from the TomoTherapy(®) archive and processed using the computational task-management system GANGA. Doses are calculated for each fraction of radiotherapy using the daily megavoltage (MV) CT images. The calculated dose cube is saved as a digital imaging and communications in medicine RTDOSE object, which can then be read by utilities that calculate dose-volume histograms or dose surface maps. The rectum is delineated on daily MV images using an implementation of the Chan-Vese algorithm. On a cluster of up to 117 central processing units, dose cubes for all fractions of 151 patients took 12 days to calculate. Outlining the rectum on all slices and fractions on 151 patients took 7 h. We also present results of the Hounsfield unit (HU) calibration of TomoTherapy MV images, measured over an 8-year period, showing that the HU calibration has become less variable over time, with no large changes observed after 2011. We have developed a system for automatic dose recalculation of TomoTherapy dose distributions. This does not tie up the clinically needed planning system but can be run on a cluster of independent machines, enabling recalculation of delivered dose without user intervention. The use of a task management system for automation of dose calculation and outlining enables work to be scaled up to the level required for large studies.
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Christophi, George P.; Christophi, Jennifer A.; Gruber, Ross C.; Mihai, Cornelia; Mejico, Luis J.; Massa, Paul T.; Jubelt, Burk
2012-01-01
Interferon-β (IFN-β) is a current effective treatment for multiple sclerosis (MS) and exerts its therapeutic effects by down-modulating the systemic immune response and cytokine signaling. In clinical practice there are several formulations of interferon including a low dose of IFN-β 1a formulation of 30μg IM once weekly (Avonex) and a high dose formulation of 44 μg SC three times weekly (Rebif). Recent studies suggest that Rebif is more efficacious compared to Avonex in preventing relapses and decreasing MRI activity in relapsing remitting MS (RRMS) patients. This study examines whether there are quantitative gene expression changes in interferon-treated RRMS patients that can explain the difference in efficacy and side effects between Rebif and Avonex. Herein, RRMS patients were treated for three months with IFN-β 1a and the levels of plasma cytokines and gene expression in peripheral blood mononuclear cells were examined. Thirty-two normal subjects were compared to thirty-two RRMS patients, of which ten were treated with Rebif and ten with Avonex. Rebif and Avonex both significantly and equally suppressed plasma TNF-α and IL-6 levels. Rebif suppressed IL-13 significantly more than Avonex. Rebif also significantly suppressed the levels of the chemokines CCL17 and RANTES, the protease ADAM8, and COX-2 at a higher degree compared to Avonex. The STAT1-inducible genes IP-10 and caspase 1 were significantly increased with Rebif compared to Avonex. In conclusion, the higher dosed, more frequently administered IFN-β 1a Rebif when compared to IFN β-1a Avonex has more potent immunomodulatory effects. These quantitative results might relate to efficacy and side-effect profile of the two IFN-β 1a formulations and provide prospective practical clinical tools to monitor treatment and adjust dosage. PMID:21658727
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Burke, J M; Miller, J E
2006-06-30
High levels of anthelmintic resistance in gastrointestinal nematodes (GIN) of small ruminants have created the need for alternative approaches to parasite control. Copper oxide wire particles (COWP; 2g) have proven effective in decreasing GIN infection in lambs. However, the risk of copper toxicity has limited the usefulness of this approach. Recently, smaller doses (0.5 and 1g) have proven effective in GIN control, reducing the risk of toxicity. The objective of this study was to examine the effectiveness and risk of toxicity using multiple small doses of COWP for GIN control in lambs between weaning and market weight. Dorper crossbred ram lambs were orally administered levamisole (Levasol, 8.0mg/kg; n=8), 0.5g (n=9), or 1g COWP (n=9) at weaning (Day 0; 118+/-2 days of age; late May 2005) and again at 6-week intervals for a total of four treatments. A pooled fecal culture determined that Haemonchus contortus was the predominant gastrointestinal parasite at weaning. Lambs grazed bermudagrass pastures and were supplemented with up to 500g corn/soybean meal and free choice trace mineralized salt. Fecal egg counts (FEC), packed cell volume (PCV), and plasma aspartate aminotransferase (AST) activity were determined every 14 days and lambs weighed every 28 days. GIN infection reached a peak at Day 42 (high FEC, low PCV). COWP effectively reduced FEC on Days 0 and 42 compared with the previous week, but did not reduce FEC on Days 84 and 126 (treatment by time interaction, P<0.005). Plasma AST activity and weight gains were similar among treatment groups throughout the study period. Concentrations of copper in the liver on Day 155 were greater in COWP-treated lambs (P<0.001), but all concentrations were normal. Multiple doses of COWP were as effective as levamisole for control of H. contortus without risk of copper toxicity.
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2014-01-01
Background In complex large-scale experiments, in addition to simultaneously considering a large number of features, multiple hypotheses are often being tested for each feature. This leads to a problem of multi-dimensional multiple testing. For example, in gene expression studies over ordered categories (such as time-course or dose-response experiments), interest is often in testing differential expression across several categories for each gene. In this paper, we consider a framework for testing multiple sets of hypothesis, which can be applied to a wide range of problems. Results We adopt the concept of the overall false discovery rate (OFDR) for controlling false discoveries on the hypothesis set level. Based on an existing procedure for identifying differentially expressed gene sets, we discuss a general two-step hierarchical hypothesis set testing procedure, which controls the overall false discovery rate under independence across hypothesis sets. In addition, we discuss the concept of the mixed-directional false discovery rate (mdFDR), and extend the general procedure to enable directional decisions for two-sided alternatives. We applied the framework to the case of microarray time-course/dose-response experiments, and proposed three procedures for testing differential expression and making multiple directional decisions for each gene. Simulation studies confirm the control of the OFDR and mdFDR by the proposed procedures under independence and positive correlations across genes. Simulation results also show that two of our new procedures achieve higher power than previous methods. Finally, the proposed methodology is applied to a microarray dose-response study, to identify 17 β-estradiol sensitive genes in breast cancer cells that are induced at low concentrations. Conclusions The framework we discuss provides a platform for multiple testing procedures covering situations involving two (or potentially more) sources of multiplicity. The framework is easy to use and adaptable to various practical settings that frequently occur in large-scale experiments. Procedures generated from the framework are shown to maintain control of the OFDR and mdFDR, quantities that are especially relevant in the case of multiple hypothesis set testing. The procedures work well in both simulations and real datasets, and are shown to have better power than existing methods. PMID:24731138
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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
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Total marrow irradiation using Helical TomoTherapy
NASA Astrophysics Data System (ADS)
Garcia-Fernandez, Lourdes Maria
Clinical dose response data of human tumours are limited or restricted to a radiation dose range determined by the level of toxicity to the normal tissues. This is the case for the most common disseminated plasma cell neoplasm, multiple myeloma, where the maximum dose deliverable to the entire bony skeleton using a standard total body irradiation (TBI) technique is limited to about 12 Gy. This study is part of scientific background of a phase I/II dose escalation clinical trial for multiple myeloma using image-guided intensity modulated radiotherapy (IG-IMRT) to deliver high dose to the entire volume of bone marrow with Helical TomoTherapy (HT). This relatively new technology can deliver highly conformal dose distributions to complex target shapes while reducing the dose to critical normal tissues. In this study tools for comparing and predicting the effectiveness of different approaches to total marrow irradiation (TMI) using HT were provided. The expected dose response for plasma cell neoplasms was computed and a radiobiological evaluation of different treatment cohorts in a dose escalating study was performed. Normal tissue complication probability (NTCP) and tumour control probability (TCP) models were applied to an actual TMI treatment plan for a patient and the implications of using different longitudinal field widths were assessed. The optimum dose was ˜39 Gy for which a predicted tumour control of 95% (+/-3%) was obtained, with a predicted 3% (0, 8%) occurrence of radiation pneumonitis. Tissue sparing was seen by using smaller field widths only in the organs of the head. This suggests it would be beneficial to use the small fields in the head only since using small fields for the whole treatment would lead to long treatment times. In TMI it may be necessary to junction two longitudinally adjacent treatment volumes to form a contiguous planning target volume PTV. For instance, this is the case when a different SUP-INF spatial resolution is required or when the PTV length exceeds the bed travel distance. In this work, the dosimetric challenges associated with junctioning longitudinally adjacent PTVs with HT were analyzed and the feasibility of PTV junctioning was demonstrated. The benefits of spatially dividing or splitting the treatment into a few sub-treatments along the longitudinal direction were also investigated.
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Estimating the lifetime risk of cancer associated with multiple CT scans.
Ivanov, V K; Kashcheev, V V; Chekin, S Yu; Menyaylo, A N; Pryakhin, E A; Tsyb, A F; Mettler, F A
2014-12-01
Multiple CT scans are often done on the same patient resulting in an increased risk of cancer. Prior publications have estimated risks on a population basis and often using an effective dose. Simply adding up the risks from single scans does not correctly account for the survival function. A methodology for estimating personal radiation risks attributed to multiple CT imaging using organ doses is presented in this article. The estimated magnitude of the attributable risk fraction for the possible development of radiation-induced cancer indicates the necessity for strong clinical justification when ordering multiple CT scans.
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Multiple Consecutive Infections Might Explain the Lack of Protection by BCG
Cardona, Pere-Joan; Vilaplana, Cristina
2014-01-01
Although contacts between tuberculosis patients may result in multiple consecutive infections (MCI), no experimental animal models consider this fact when used in basic studies. Moreover, the current TB vaccine (BCG) has demonstrated a limited protection in humans. In this study we evaluate the effect of tuberculosis MCI by way of a simple mathematical analysis using data from the low dose aerosol murine experimental model. The results show that a higher number of, or shorter intervals between, multiple consecutive infections reduce the protective effect of BCG. This is due to both the increase in bacillary load at the stationary level of the infection, and the protective immune response induced by the infection itself. This factor must therefore be taken into account when designing new prophylactic strategies as candidate vaccines for the replacement of BCG. PMID:24740286
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Multiple consecutive infections might explain the lack of protection by BCG.
Cardona, Pere-Joan; Vilaplana, Cristina
2014-01-01
Although contacts between tuberculosis patients may result in multiple consecutive infections (MCI), no experimental animal models consider this fact when used in basic studies. Moreover, the current TB vaccine (BCG) has demonstrated a limited protection in humans. In this study we evaluate the effect of tuberculosis MCI by way of a simple mathematical analysis using data from the low dose aerosol murine experimental model. The results show that a higher number of, or shorter intervals between, multiple consecutive infections reduce the protective effect of BCG. This is due to both the increase in bacillary load at the stationary level of the infection, and the protective immune response induced by the infection itself. This factor must therefore be taken into account when designing new prophylactic strategies as candidate vaccines for the replacement of BCG.
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Clinical and biological features of multiple myeloma involving the gastrointestinal system.
Talamo, Giampaolo; Cavallo, Federica; Zangari, Maurizio; Barlogie, Bart; Lee, Choon-Kee; Pineda-Roman, Mauricio; Kiwan, Elias; Krishna, Somashekar; Tricot, Guido
2006-07-01
We report 24 cases of multiple myeloma (MM) with involvement of the gastrointestinal (GI) system. We found a strong association with high A lactate dehydrogenase levels, plasmablastic morphology, and A unfavorable karyotype. GI involvement at the time of initial diagnosis was much rarer than later in the course of the disease. The A median survival after diagnosis of GI involvement was 7 months. Among 13 patients treated with stem cell transplantation, the response rate was 92%, and median progression-free survival was 4 months. We conclude that MM involving the GI system is associated with adverse biological features and with short-lasting remissions, even after A high-dose chemotherapy.
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Looking into future: challenges in radiation protection in medicine.
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.
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Myocardial protection induced by fentanyl in pigs exposed to high-dose adrenaline.
da Luz, Vinicius Fernando; Otsuki, Denise Aya; Gonzalez, Maria Margarita Castro; Negri, Elnara Marcia; Caldini, Elia Garcia; Damaceno-Rodrigues, Nilsa Regina; Malbouisson, Luiz Marcelo Sá; Viana, Bruno Gonçalves; Vane, Matheus Fachini; Carmona, Maria Jose Carvalho
2015-10-01
The use of high doses of adrenaline is common in critical patients, especially during cardiac arrest. During these situations, myocardial dysfunction can be a result of multiple factors, including adrenaline use. In addition, opioids have been shown to have anti-arrhythmic and anti-ischemic mechanisms that may confer cardiac protection. This study aimed to evaluate the effects of fentanyl on myocardial function in pigs exposed to high-dose adrenaline. After institutional ethics committee approval, 26 pigs were randomly allocated to receive either 20 μg/kg fentanyl (n = 10; fentanyl group) administered 5 min before five doses of adrenaline (20 μg/kg), equivalent-volume saline (n = 10; saline group) using the same adrenaline dosing protocol, or neither fentanyl nor adrenaline (n = 6; sham group). The fentanyl group showed lower levels of troponin at the end of the sixth hour compared with the saline group (1.91 ± 1.47 vs 5.44 ± 5.35 ng/mL, P = 0.019). Transmission electron microscopy and immunohistochemistry also showed less myocardial injury in the fentanyl group. The conclusion was reached that fentanyl attenuates myocardial injury caused by high-dose adrenaline without blunting the hemodynamic effect of adrenaline. © 2015 Wiley Publishing Asia Pty Ltd.
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Heise, Tim; Jordan, Jens; Wanner, Christoph; Heer, Martina; Macha, Sreeraj; Mattheus, Michaela; Lund, Søren S; Woerle, Hans J; Broedl, Uli C
2016-10-01
Our aim was to investigate the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on urinary and serum glucose and electrolytes, urinary volume, osmolality, and the renin-angiotensin system in patients with type 2 diabetes. In an open-label study, 22 patients receiving metformin (median age 56 years; range 40-65 years) received empagliflozin 25 mg once daily for 5 days. Food, fluid, and sodium intake were standardized for 3 days before and during treatment. Twenty patients completed treatment. After single and multiple doses of empagliflozin, mean (SE) changes from baseline in 24-hour urinary glucose excretion were 463.3 (57.3) mmol/d and 599.5 (60.0) mmol/d, respectively (83.5 [10.3] g/d and 108.0 [10.8] g/d, respectively) (both P < 0.001), and in fasting serum glucose concentration were -1.8 (0.4) mmol/L and -1.1 (0.3) mmol/L, respectively (both P < 0.001). After a single dose, mean (SE) change from baseline in urine sodium excretion was 45.3 (9.6) mmol/d (P < 0.001), and in urine volume was 341.0 (140.5) g/d (P = 0.025), but there were no changes compared with baseline in either parameter after multiple doses. There were no changes in plasma renin or serum aldosterone with single or multiple doses of empagliflozin. There was a nonsignificant reduction in weight after a single dose of empagliflozin and a mean (SE) change of -1.4 (0.5) kg after multiple doses (P = 0.020). Empagliflozin 25 mg increased urinary glucose excretion and decreased serum glucose and weight with transient natriuresis and increases in urine volume, without significant changes in the renin-angiotensin system. Clinicaltrials.gov Identifier: NCT01276288. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.
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2014-01-01
Background The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Methods Adults (n = 198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n = 101) or matching placebo lozenges (n = 97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Results Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P <0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P <0.01). There were no serious adverse events. Conclusions Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. Trial registration This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010. PMID:24988909
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Date, Abhijit A.; Long, Julie M.; Nochii, Tomonori; Belshan, Michael; Shibata, Annemarie; Vincent, Heather; Baker, Caroline E.; Thayer, William O.; Kraus, Guenter; Lachaud-Durand, Sophie; Williams, Peter; Destache, Christopher J.; Garcia, J. Victor
2015-01-01
Vaginal HIV transmission accounts for the majority of new infections worldwide. Currently, multiple efforts to prevent HIV transmission are based on pre-exposure prophylaxis with various antiretroviral drugs. Here, we describe two novel nanoformulations of the reverse transcriptase inhibitor rilpivirine for pericoital and coitus-independent HIV prevention. Topically applied rilpivirine, encapsulated in PLGA nanoparticles, was delivered in a thermosensitive gel, which becomes solid at body temperature. PLGA nanoparticles with encapsulated rilpivirine coated the reproductive tract and offered significant protection to BLT humanized mice from a vaginal high-dose HIV-1 challenge. A different nanosuspension of crystalline rilpivirine (RPV LA), administered intramuscularly, protected BLT mice from a single vaginal high-dose HIV-1 challenge one week after drug administration. Using transmitted/founder viruses, which were previously shown to establish de novo infection in humans, we demonstrated that RPV LA offers significant protection from two consecutive high-dose HIV-1 challenges one and four weeks after drug administration. In this experiment, we also showed that, in certain cases, even in the presence of drug, HIV infection could occur without overt or detectable systemic replication until levels of drug were reduced. We also showed that infection in the presence of drug can result in acquisition of multiple viruses after subsequent exposures. These observations have important implications for the implementation of long-acting antiretroviral formulations for HIV prevention. They provide first evidence that occult infections can occur, despite the presence of sustained levels of antiretroviral drugs. Together, our results demonstrate that topically- or systemically administered rilpivirine offers significant coitus-dependent or coitus-independent protection from HIV infection. PMID:26271040
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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,…
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Stathakis, S; Defoor, D; Saenz, D
Purpose: Stereotactic radiosurgery (SRS) outcomes are related to the delivered dose to the target and to surrounding tissue. We have commissioned a Monte Carlo based dose calculation algorithm to recalculated the delivered dose planned using pencil beam calculation dose engine. Methods: Twenty consecutive previously treated patients have been selected for this study. All plans were generated using the iPlan treatment planning system (TPS) and calculated using the pencil beam algorithm. Each patient plan consisted of 1 to 3 targets and treated using dynamically conformal arcs or intensity modulated beams. Multi-target treatments were delivered using multiple isocenters, one for each target.more » These plans were recalculated for the purpose of this study using a single isocenter. The CT image sets along with the plan, doses and structures were DICOM exported to Monaco TPS and the dose was recalculated using the same voxel resolution and monitor units. Benchmark data was also generated prior to patient calculations to assess the accuracy of the two TPS against measurements using a micro ionization chamber in solid water. Results: Good agreement, within −0.4% for Monaco and +2.2% for iPlan were observed for measurements in water phantom. Doses in patient geometry revealed up to 9.6% differences for single target plans and 9.3% for multiple-target-multiple-isocenter plans. The average dose differences for multi-target-single-isocenter plans were approximately 1.4%. Similar differences were observed for the OARs and integral dose. Conclusion: Accuracy of the beam is crucial for the dose calculation especially in the case of small fields such as those used in SRS treatments. A superior dose calculation algorithm such as Monte Carlo, with properly commissioned beam models, which is unaffected by the lack of electronic equilibrium should be preferred for the calculation of small fields to improve accuracy.« less
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Yang, Qiang; Ma, Yanling; Zhao, Yongxue; She, Zhennan; Wang, Long; Li, Jie; Wang, Chunling; Deng, Yihui
2013-01-01
Background Sequential low-dose chemotherapy has received great attention for its unique advantages in attenuating multidrug resistance of tumor cells. Nevertheless, it runs the risk of producing new problems associated with the accelerated blood clearance phenomenon, especially with multiple injections of PEGylated liposomes. Methods Liposomes were labeled with fluorescent phospholipids of 1,2-dipalmitoyl-snglycero-3-phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) and epirubicin (EPI). The pharmacokinetics profile and biodistribution of the drug and liposome carrier following multiple injections were determined. Meanwhile, the antitumor effect of sequential low-dose chemotherapy was tested. To clarify this unexpected phenomenon, the production of polyethylene glycol (PEG)-specific immunoglobulin M (IgM), drug release, and residual complement activity experiments were conducted in serum. Results The first or sequential injections of PEGylated liposomes within a certain dose range induced the rapid clearance of subsequently injected PEGylated liposomal EPI. Of note, the clearance of EPI was two- to three-fold faster than the liposome itself, and a large amount of EPI was released from liposomes in the first 30 minutes in a complement-activation, direct-dependent manner. The therapeutic efficacy of liposomal EPI following 10 days of sequential injections in S180 tumor-bearing mice of 0.75 mg EPI/kg body weight was almost completely abolished between the sixth and tenth day of the sequential injections, even although the subsequently injected doses were doubled. The level of PEG-specific IgM in the blood increased rapidly, with a larger amount of complement being activated while the concentration of EPI in blood and tumor tissue was significantly reduced. Conclusion Our investigation implied that the accelerated blood clearance phenomenon and its accompanying rapid leakage and clearance of drug following sequential low-dose injections may reverse the unique pharmacokinetic–toxicity profile of liposomes which deserved our attention. Therefore, a more reasonable treatment regime should be selected to lessen or even eliminate this phenomenon. PMID:23576868
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Minocha, Mukul; Tran, Jonathan Q; Sheridan, James P; Othman, Ahmed A
2016-01-01
Daclizumab high-yield process (DAC HYP) is a humanized monoclonal antibody that selectively blocks the α-subunit (CD25) of the high-affinity interleukin-2 receptors, and has shown robust efficacy as a treatment for multiple sclerosis (MS). This work quantitatively characterized the relationship between DAC HYP serum concentrations and saturation of CD25 expressed on antigen-rich target T cells in blood. Serial pharmacokinetic and 968 CD25 measurements from three double-blind, randomized, placebo-controlled, phase I studies of DAC HYP (50-300 mg subcutaneous and 200-400 mg intravenous doses or placebo) in healthy volunteers (n = 95) were analyzed using nonlinear mixed-effects modeling. CD25 occupancy was determined using flow cytometry and a fluorescently-labeled DAC HYP-competing antibody. CD25 occupancy was described using a direct inhibitory sigmoidal maximum effect (E max) model (where DAC HYP fully inhibited CD25 labeling with competing antibody). Two IC50 (serum concentration corresponding to 50 % of maximal inhibition) parameters were used to describe rapid CD25 saturation at initiation of dosing and apparently slower desaturation during DAC HYP washout. Parameter estimates (95 % bootstrap confidence intervals) were: baseline CD25 labeling, 47 % (45-48); DAC HYP IC50(saturation), 0.023 µg/mL (0.005-0.073); IC50(desaturation) 0.86 µg/mL (0.74-0.98); Hill coefficient 5.6 (4.3-6.8). Based on the developed model, the 150 mg monthly subcutaneous regimen of DAC HYP in subjects with MS is predicted to saturate CD25 on target effector T cells within a few hours of dosing and maintain CD25 saturation during the entire dosing interval. Free CD25 levels return to baseline within 4-6 months of the last DAC HYP dose.
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Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers
Chiesa, Joseph; Lückermann, Mark; Fischer, Carsten; Dalhoff, Axel; Fuhr, Uwe
2017-01-01
ABSTRACT Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.) PMID:28784673
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Chandorkar, Gurudatt; Zhan, Qiao; Donovan, Julie; Rege, Shruta; Patino, Hernando
2017-03-28
Surotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile-associated diarrhea, has demonstrated minimal intestinal absorption in animal models. Safety, tolerability, and plasma pharmacokinetics of single and multiple ascending oral doses (SAD/MAD) of surotomycin in healthy volunteers were characterized in two randomized, double-blind, placebo-controlled, phase 1 studies. Participants were sequentially enrolled into one of four SAD (500, 1000, 2000, 4000 mg surotomycin) or three MAD (250, 500, 1000 mg surotomycin twice/day for 14 days) cohorts. Ten subjects were randomized 4:1 into each cohort to receive surotomycin or placebo. Surotomycin plasma concentrations rose as dose increased (maximum plasma concentration [C max ]: 10.5, 21.5, 66.6, and 86.7 ng/mL). Systemic levels were generally low, with peak median surotomycin plasma concentrations observed 6-12 h after the first dose. In the MAD study, surotomycin plasma concentrations were higher on day 14 (C max : 25.5, 37.6, and 93.5 ng/mL) than on day 1 (C max : 6.8, 11.0, and 21.1 ng/mL for increasing doses), indicating accumulation. In the SAD study, <0.01% of the administered dose was recovered in urine. Mean surotomycin stool concentration from the 1000 mg MAD cohort was 6394 μg/g on day 5. Both cohorts were well tolerated with all adverse events reported as mild to moderate. Both SAD and MAD studies of surotomycin demonstrated minimal systemic exposure, with feces the primary route of elimination following oral administration; consistent with observations with similar compounds, such as fidaxomicin. Results of these phase 1 studies support the continued clinical development of surotomycin for the treatment of Clostridium difficile-associated diarrhea. NCT02835118 and NCT02835105 . Retrospectively registered, July 13 2016.
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NASA Astrophysics Data System (ADS)
Lehnert, T.; Korkusuz, H.; Khan, F.; Vogl, T. J.; Mack, M. G.
2008-03-01
In this study, image quality was based on required clinical criteria, in order to investigate to what degree entrance dose could be lowered and what kind of added filtration can be used without impinging on radiologist confidence levels in diagnosing. Images were taken of extremities from a cadaver using stepwise decreasing dose levels and variation of added filtration (no filtration, aluminum, aluminum/copper) under digital projection radiography (Kodak DirectView DR7500). The starting point dose level for all body parts imaged was the current x-ray technique. Two experienced and two resident radiologists were presented the images in a blinded fashion and rated each with an image quality score from 1 to 9 indicated very satisfied and 1 as very unsatisfied indicating loss of diagnostic value. The readers were not aware of which dose level and added filtration corresponded to which image. Dose levels considered were 100%, 75%, 50% and 25% of the normal and customary x-ray techniques used for the particular body part and projection. Images were reviewed on a clinical diagnostic workstation with no time limits imposed. Readers were also able to change the image presentation by adjusting the window width and level. Without added filtration image quality mean score was rated with 6.3 (dose level 100%), 6.2 (dose level 75%), 5.3 (dose level 50%) and with 4.4 (dose level 25%). An added aluminum filtration induced an image quality mean score of 6.3 (dose level 100%), 6.0 (dose level 75%), 5.1 (dose level 50%) and of 4.2 (dose level 25%). Using aluminum/copper filtration image quality mean score was rated with 6.0 (dose level 100%), 6.1 (dose level 75%), 5.0 (dose level 50%) and with 3.8 (dose level 25%). Regardless of the added filtration a differentiation between dose levels 100% and 75% was possible in 38.9%, between dose levels 75% and 50% in 66.7%, and between dose levels 50% and 25% in 70.0% of the cases. It is possible, in the case of extremities, to lower entrance doses up to 75 % of the normal value, a reduction of 25% in dose, under simultaneous use of added aluminum or aluminum/copper filtration, without comprising the diagnostic value required.
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miR-26b enhances radiosensitivity of hepatocellular carcinoma cells by targeting EphA2
Jin, Qiao; Li, Xiang Jun; Cao, Pei Guo
2016-01-01
Objective(s): Although low-dose radiotherapy (RT) that involves low collateral damage is more suitable for hepatocellular carcinoma (HCC) than traditional high-dose RT, but to achieve satisfactory therapeutic effect with low-dose RT, it is necessary to sensitize HCC cells to irradiation. This study was aimed to determine whether radiosensitivity of HCC cells can be enhanced using miR-26b by targeting erythropoietin producing human hepatocelluar A2 (EphA2). Materials and Methods: The levels of miR-26b and EphA2 expression in multiple HCC cell lines were assessed by qPCR and western blotting, respectively, and compared with those in a hepatic cell line. HCC 97H cells were transfected with miR-26b mimics, EphA2-ShRNA or EphA2 over-expression vector before exposure to low-dose irradiation. Results: Different degrees of miR-26b down-regulation and EphA2 up-regulation were observed in all HCC cell lines, among which the HCC 97H cell line expressed the lowest level of miR-26b and highest level of EphA2. EphA2 was verified as the target of miR-26b by dual luciferase reporter assay. HCC 97H cells transfected with miR-26b mimics or EphA2-ShRNA reduced the expression of EphA2 protein, with significantly lower cell proliferation rate and cell invasion ability and higher apoptosis rate in response to low-dose irradiation than those in the non-transfected cells. These results were reversed after EphA2 was overexpressed by transfection with the EphA2 overexpression vector. Co-transfection with miR-26b mimics and EphA2 overexpression vector barely altered EphA2 expression level and cell response to low-dose irradiation. Conclusion: These data suggest that miR-26b enhances radiosensitivity of HCC 97H cells by targeting EphA2 protein. PMID:27746866
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Vasir, Baldev; Uhl, Lynne; Blotta, Simona; MacNamara, Claire; Somaiya, Poorvi; Wu, Zekui; Joyce, Robin; Levine, James D.; Dombagoda, Dilani; Yuan, Yan Emily; Francoeur, Karen; Fitzgerald, Donna; Richardson, Paul; Weller, Edie; Anderson, Kenneth; Kufe, Donald; Munshi, Nikhil; Avigan, David
2011-01-01
We have developed a tumor vaccine in which patient-derived myeloma cells are chemically fused with autologous dendritic cells (DCs) such that a broad spectrum of myeloma-associated antigens are presented in the context of DC-mediated costimulation. We have completed a phase 1 study in which patients with multiple myeloma underwent serial vaccination with the DC/multiple myeloma fusions in conjunction with granulocyte-macrophage colony-stimulating factor. DCs were generated from adherent mononuclear cells cultured with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-α and fused with myeloma cells obtained from marrow aspirates. Vaccine generation was successful in 17 of 18 patients. Successive cohorts were treated with 1 × 106, 2 × 106, and 4 × 106 fusion cells, respectively, with 10 patients treated at the highest dose level. Vaccination was well tolerated, without evidence of dose-limiting toxicity. Vaccination resulted in the expansion of circulating CD4 and CD8 lymphocytes reactive with autologous myeloma cells in 11 of 15 evaluable patients. Humoral responses were documented by SEREX (Serologic Analysis of Recombinant cDNA Expression Libraries) analysis. A majority of patients with advanced disease demonstrated disease stabilization, with 3 patients showing ongoing stable disease at 12, 25, and 41 months, respectively. Vaccination with DC/multiple myeloma fusions was feasible and well tolerated and resulted in antitumor immune responses and disease stabilization in a majority of patients. PMID:21030562
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Precise let-7 expression levels balance organ regeneration against tumor suppression
Wu, Linwei; Nguyen, Liem H; Zhou, Kejin; de Soysa, T Yvanka; Li, Lin; Miller, Jason B; Tian, Jianmin; Locker, Joseph; Zhang, Shuyuan; Shinoda, Gen; Seligson, Marc T; Zeitels, Lauren R; Acharya, Asha; Wang, Sam C; Mendell, Joshua T; He, Xiaoshun; Nishino, Jinsuke; Morrison, Sean J; Siegwart, Daniel J; Daley, George Q; Shyh-Chang, Ng; Zhu, Hao
2015-01-01
The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics. DOI: http://dx.doi.org/10.7554/eLife.09431.001 PMID:26445246
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Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy.
Landen, Jaren W; Cohen, Sharon; Billing, Clare B; Cronenberger, Carol; Styren, Scot; Burstein, Aaron H; Sattler, Catherine; Lee, Jae-Hong; Jack, Clifford R; Kantarci, Kejal; Schwartz, Pamela F; Duggan, William T; Zhao, Qinying; Sprenger, Ken; Bednar, Martin M; Binneman, Brendon
2017-09-01
Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ 1-x and Aβ 1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.
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Biberoglu, Ebru H; Tanrıkulu, Filiz; Erdem, Mehmet; Erdem, Ahmet; Biberoglu, Kutay Omer
2016-01-01
Vaginal progesterone (P) has been suggested to be used for luteal phase support (LPS) in controlled ovarian stimulation (COH)-intrauterine insemination (IUI) cycles, however, no concensus exists about the best P dose. Therefore, considering the fecundability rate as the primary end point, our main objective was to find the optimal dose of P in COH-IUI cycles, comparing the two groups of women, each of which comprised of 100 women either on 300 mg or 600 mg of intravaginal P tablets, in a prospective randomized study design. The mean age of the women, duration of infertility, basal and day of hCG injection hormone levels in the female and sperm parameters were similar in the two study groups. Also, duration and dose of gonadotropin given, number of follicles, endometrial thickness, the total, ongoing and multiple pregnancy rates were comparable in both groups. We, therefore, claim that 300 mg of intravaginal micronized P should be the maximum dose of LPS in IUI cycles.
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Shared dosimetry error in epidemiological dose-response analyses
Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; ...
2015-03-23
Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takesmore » up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed.« less
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Dovio, Andrea; Perazzolo, Laura; Osella, Giangiacomo; Ventura, Massimo; Termine, Angela; Milano, Eva; Bertolotto, Antonio; Angeli, Alberto
2004-10-01
Glucocorticoid (GC)-induced osteoporosis is the leading form of secondary osteoporosis. Bone loss can be rapid. However, longitudinal studies at the very beginning of treatment are scarce. Patients relapsing from multiple sclerosis are treated with high-dose, short-term iv GCs. A number of them are young, without concomitant disease affecting bone and with no substantial impairment of mobility. Such patients were selected for the present study. Thirteen patients suffering from multiple sclerosis [11 females, two males; age 32 +/- 2 yr (mean +/- se)] and receiving iv methylprednisolone 15 mg/kg daily for 10 d completed the study. We measured serum osteocalcin (OC), aminoterminal propeptide of type I collagen (PINP), bone isoform of alkaline phosphatase (bALP), carboxyterminal telopeptide of type I collagen (CTX), and urinary calcium/creatinine ratio (uCa/Cr) during the 10-d cycle and 3 months later. Dual-energy x-ray absorptiometry and calcaneal quantitative ultrasonometry were performed before and 6 months after therapy. We found an immediate, impressive fall of OC and PINP (-80 +/- 3 and -54 +/- 5% at d 2, respectively), which persisted throughout the whole treatment period (P < 0.0001 for both markers). bALP levels showed only a modest decrease at d 6 (-19 +/- 7%, P < 0.05), with subsequent return to baseline in d 7-10. After 3 months, OC, PINP, and bALP levels rose to +51 +/- 22, +37 +/- 16 (not significant), and +61 +/- 17% (P < 0.01) with respect to baseline, respectively. uCa/Cr and CTX showed a progressive, marked increase during treatment, peaking at d 7-9 (+92 +/- 44 and +149 +/- 63%, respectively), with subsequent decrement at d 10 (P < 0.01 and P < 0.05, respectively) despite continuing GC administration. After 3 months, uCa/Cr and CTX levels were also higher than baseline. No change in quantitative ultrasonometry parameters and bone mineral density was observed 6 months after therapy. In conclusion, high-dose, short-term iv GC regimens cause an immediate and persistent decrease in bone formation and a rapid and transient increase of bone resorption. Our data also support the concept that discontinuation of such regimens is followed by a high bone turnover phase.
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Thermoluminescence dosimetry and its applications in medicine--Part 2: History and applications.
Kron, T
1995-03-01
Thermoluminescence dosimetry (TLD) has been available for dosimetry of ionising radiation for nearly 100 years. The variety of materials and their different physical forms allow the determination of different radiation qualities over a wide range of absorbed dose. This makes TL dosimeters useful in radiation protection where dose levels of microGy are monitored as well as in radiotherapy where doses up to several Gray are to be measured. The major advantages of TL detectors are their small physical size and that no cables or auxiliary equipment is required during the dose assessment. Therefore TLD is a good method for point dose measurements in phantoms as well as for in vivo dosimetry on patients during radiotherapy treatment. As an integrative dosimetric technique, it can be applied to personal dosimetry and it lends itself to the determination of dose distributions due to multiple or moving radiation sources (e.g. conformal and dynamic radiotherapy, computed tomography). In addition, TL dosimeters are easy to transport, and they can be mailed. This makes them well suited for intercomparison of doses delivered in different institutions. The present article aims at describing the various applications TLD has found in medicine by taking into consideration the physics and practice of TLD measurements which have been discussed in the first part of this review (Australas. Phys. Eng. Sci. Med. 17: 175-199, 1994).
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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.
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Welsch, C W; DeHoog, J V
1988-04-15
The effect of caffeine (430-500 mg/liter of drinking water) on the initiation and promotion phases of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a chemically defined diet containing standard (5%) or high (20%) levels of fat (corn oil) was examined. In the initiation studies, caffeine and the standard or high fat diet treatments were provided for 34 days, from 24-29 days of age to 58-63 days of age. Three days prior to termination of caffeine-fat diet treatments, each rat received a single dose of DMBA. In the promotion studies, caffeine and the standard or high fat diets were provided commencing 3 days after a single dose of DMBA (at 56-61 days of age) and until termination of the study. Caffeine consumption, during the initiation phase significantly (P less than 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat), in rats fed either a standard or high fat diet. In the promotion studies, prolonged consumption of caffeine in rats fed either a standard or high fat diet did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, an apparent increase in mammary carcinoma multiplicity was observed; this increase in mammary carcinoma multiplicity did not, however, reach the 5% level of statistical probability. When caffeine was administered during both the initiation and promotion phases, no significant effect on mammary carcinoma multiplicity was observed. Treatment of rats during the initiation or promotion phases with caffeinated coffee (via drinking water) mimicked the mammary tumor modulating activities of caffeine. Decaffeinated coffee consumption did not effect either the initiation or promotion phases of this tumorigenic process. In both the initiation and promotion studies, caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency period of mammary tumor appearance. Thus, in female rats fed a chemically defined standard or high fat diet, caffeine consumption can significantly influence chemical carcinogenesis of the mammary gland; an effect that is dependent upon the duration and time-span of caffeine administration.
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Ogutu, Bernhards R; Newton, Charles R J C; Muchohi, Simon N; Otieno, Godfrey O; Kokwaro, Gilbert O
2002-01-01
Aims Some children with malaria and convulsions also have concurrent bacterial meningitis. Chloramphenicol is used to treat the latter whereas phenytoin is used for convulsions. Since chloramphenicol inhibits the metabolism of phenytoin in vivo, we studied the effects of chloramphenicol on phenytoin pharmacokinetics in children with malaria. Methods Multiple intravenous (i.v.) doses of chloramphenicol succinate (CAP) (25 mg kg−1 6 hourly for 72 h) and a single intramuscular (i.m.) seizure prophylactic dose of fosphenytoin (18 mg kg−1 phenytoin sodium equivalents) were concomitantly administered to 15 African children with malaria. Control children (n= 13) with malaria received a similar dose of fosphenytoin and multiple i.v. doses (25 mg kg−1 8 hourly for 72 h) of cefotaxime (CEF). Blood pressure, heart rate, respiratory rate, oxygen saturation, level of consciousness and convulsion episodes were monitored. Cerebrospinal fluid (CSF) and plasma phenytoin concentrations were determined. Results The area under the plasma unbound phenytoin concentration-time curve (AUC(0,∞); means (CAP, CEF): 58.5, 47.6 µg ml−1 h; 95% CI for difference between means: −35.0, 11.4), the peak unbound phenytoin concentrations (Cmax; medians: 1.12, 1.29 µg ml−1; 95% CI: −0.5, 0.04), the times to Cmax(tmax; medians: 4.0, 4.0 h; 95% CI: −2.0, 3.7), the CSF:plasma phenytoin ratios (means: 0.21, 0.22; 95% CI: −0.8, 0.10), the fraction of phenytoin unbound (means: 0.06, 0.09; 95% CI: −0.01, 0.07) and the cardiovascular parameters were not significantly different between CAP and CEF groups. However, mean terminal elimination half-life (t1/2,z) was significantly longer (23.7, 15.5 h; 95% CI: 1.71, 14.98) in the CAP group compared with the CEF group. Seventy per cent of the children had no convulsions during the study period. Conclusions Concomitant administration of chloramphenicol and a single i.m. dose of fosphenytoin alters the t1/2,z but not the other pharmacokinetic parameters or clinical effects of phenytoin in African children with severe malaria. Moreover, a single i.m. dose of fosphenytoin provides anticonvulsant prophylaxis in the majority of the children over 72 h. However, a larger study would be needed to investigate the effect of concomitant administration of multiple doses of the two drugs in this population of patients. PMID:12492612
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Nontransmission of deoxynivalenol (vomitoxin) to milk following oral administration to dairy cows.
Prelusky, D B; Trenholm, H L; Lawrence, G A; Scott, P M
1984-10-01
The absorption of deoxynivalenol (DON; vomitoxin), a trichothecene mycotoxin produced by Fusarium species, was studied in the dairy cow. Serum and milk DON levels were quantitated following a single oral dose of 920 mg DON to each of two lactating cows of similar weight. Maximum blood levels for the two animals following DON administration were 200 and 90 ng/ml serum, occurring at times 4.7 and 3.5 hr, respectively. By 24 hr after dosing only trace levels (less than 2 ng/ml) were still detectable. DON in its conjugated form accounted for 24-46% of the total levels present in serum. Free and conjugated DON were also present in cow's milk, but only extremely low amounts (less than 4 ng/ml) were detected. Detection of DON was carried out utilizing Sep-Pak C18 extraction cartridges for isolation, with additional purification of the sample achieved by passing the extract through a short charcoal/alumina column. The extract was then reacted with N-heptafluorobutyrylimidazole prior to quantitation of the resulting DON-tris-heptafluorobutyrate derivative by combined gas chromatography-quadrupole mass spectrometry, using multiple selected ion monitoring. Detection limits were as low as 1 ng/ml (1 ppb).
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Ng, Juki; Chwalisz, Kristof; Carter, David C; Klein, Cheri E
2017-05-01
Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women. We evaluated the pharmacokinetics and pharmacodynamics of elagolix. This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days. Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events. Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women. Copyright © 2017 Endocrine Society
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Prenatal exposure to allergen, DNA methylation, and allergy in grandoffspring mice.
Niedzwiecki, M; Zhu, H; Corson, L; Grunig, G; Factor, P H; Chu, S; Jiang, H; Miller, R L
2012-07-01
Prenatal allergen exposure has been linked to both induction and protection of allergic sensitization in offspring. We hypothesized that prenatal exposure of mice (F0) to Aspergillus fumigatus (A. fumigatus) would be associated with decreased immunoglobulin (Ig) E and airway eosinophilia and alterations in CpG methylation of T-helper genes in third-generation mice (F2). Female BALB/c mice were sensitized to A. fumigatus (62.5, 125, 1250 μg, or saline) and re-exposed to the same dose on days 7 and 14 (early) or days 12 and 17 (late) gestation. Grandoffspring were treated with A. fumigatus (62.5 μg) at 9 weeks. IgE, IgG(1) , and IgG(2a) levels and cell counts from bronchoalveolar lavage fluid were determined. Lung DNA was pyrosequenced at multiple sites in the interferon (IFN)-γ and interleukin (IL)-4 promoters. Grandoffspring of mothers dosed with 1250 μg early during pregnancy developed increased airway eosinophilia (P < 0.05). Grandoffspring of mothers dosed late in pregnancy developed lower IgE (P < 0.05) and airway eosinophilia (P < 0.05). Grandoffspring of mothers dosed early had lower methylation at IL-4 CpG(-408) and CpG(-393) compared to late dosed mice (P < 0.005 across all doses). Few correlations were found between methylation levels and airway eosinophilia and IgE. Prenatal exposure to A. fumigatus late during pregnancy, but not early, was associated with lower IgE and airway eosinophilia in grandoffspring. Prenatal exposure to A. fumigatus was associated with changes in CpG methylation in the IFN-γ and IL-4 promoters that did not correlate consistently with indicators of allergic sensitization. © 2012 John Wiley & Sons A/S.
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Safety of multiple stereotactic radiosurgery treatments for multiple brain lesions.
Hillard, Virany H; Shih, Lynn L; Chin, Shing; Moorthy, Chitti R; Benzil, Deborah L
2003-07-01
Stereotactic radiosurgery (SRS) is a widely used therapy for multiple brain lesions, and studies have clearly established the safety and efficacy of single-dose SRS. However, as patient survival has increased, the recurrence of tumors and the development of metastases to new sites within the brain have made it desirable to repeat treatments over time. The cumulative toxicity of multi-isocenter, multiple treatments has not been well defined. We have retrospectively studied 10 patients who received multiple SRS treatments for multiple brain lesions to assess the cumulative toxicity of these treatments. In a retrospective review of all patients treated with SRS using the X-knife (Radionics, Burlington, MA) at Westchester Medical Center/New York Medical College between December 1995 and December 2000, 10 patients were identified who received at least two treatments to at least 3 isocenters and had a minimum follow-up period of 6 months. Image fusion technique was used to determine cumulative doses to targeted lesions, whole brain and critical brain structures. Toxicities and complications were identified by chart and radiological review. The average of the maximum doses (cGy) to a point within the whole brain was 2402 (range 1617-3953); to the brainstem, 1059 (range 48-4126); to the right optic nerve, 223 (range 14-1012); to the left optic nerve, 159 (range 17-475); and to the optic chiasm, 219 (range 15-909). There were no focal neurological toxicities, including visual disturbances, cranial nerve palsies, or ataxia in any of the 10 patients. There were also no global toxicities, including cognitive decline or secondary tumors. Only one patient developed seizures that were difficult to control in association with radiation necrosis. Multiple SRS treatments at the cumulative doses used in our study are a safe therapy for patients with multiple brain lesions.
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Cianferotti, Luisella; Bertoldo, Francesco; Bischoff-Ferrari, Heike A; Bruyere, Olivier; Cooper, Cyrus; Cutolo, Maurizio; Kanis, John A; Kaufman, Jean-Marc; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa
2017-05-01
Optimal vitamin D status promotes skeletal health and is recommended with specific treatment in individuals at high risk for fragility fractures. A growing body of literature has provided indirect and some direct evidence for possible extraskeletal vitamin D-related effects. Members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis have reviewed the main evidence for possible proven benefits of vitamin D supplementation in adults at risk of or with overt chronic extra-skeletal diseases, providing recommendations and guidelines for future studies in this field. Robust mechanistic evidence is available from in vitro studies and in vivo animal studies, usually employing cholecalciferol, calcidiol or calcitriol in pharmacologic rather than physiologic doses. Although many cross-sectional and prospective association studies in humans have shown that low 25-hydroxyvitamin D levels (i.e., <50 nmol/L) are consistently associated with chronic diseases, further strengthened by a dose-response relationship, several meta-analyses of clinical trials have shown contradictory results. Overall, large randomized controlled trials with sufficient doses of vitamin D are missing, and available small to moderate-size trials often included people with baseline levels of serum 25-hydroxyvitamin D levels >50 nmol/L, did not simultaneously assess multiple outcomes, and did not report overall safety (e.g., falls). Thus, no recommendations can be made to date for the use of vitamin D supplementation in general, parental compounds, or non-hypercalcemic vitamin D analogs in the prevention and treatment of extra-skeletal chronic diseases. Moreover, attainment of serum 25-hydroxyvitamin D levels well above the threshold desired for bone health cannot be recommended based on current evidence, since safety has yet to be confirmed. Finally, the promising findings from mechanistic studies, large cohort studies, and small clinical trials obtained for autoimmune diseases (including type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), cardiovascular disorders, and overall reduction in mortality require further confirmation.
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Swallow, E A; Aref, M W; Chen, N; Byiringiro, I; Hammond, M A; McCarthy, B P; Territo, P R; Kamocka, M M; Winfree, S; Dunn, K W; Moe, S M; Allen, M R
2018-06-11
This work examines the skeletal accumulation of fluorescently tagged zoledronate in an animal model of chronic kidney disease. The results show higher accumulation in 24-h post-dose animals with lower kidney function due to greater amounts of binding at individual surfaces. Chronic kidney disease (CKD) patients suffer from increased rates of skeletal-related mortality from changes driven by biochemical abnormalities. Bisphosphonates are commonly used in reducing fracture risk in a variety of diseases, yet their use is not recommended in advanced stages of CKD. This study aimed to characterize the accumulation of a single dose of fluorescently tagged zoledronate (FAM-ZOL) in the setting of reduced kidney function. At 25 weeks of age, FAM-ZOL was administered to normal and CKD rats. Twenty-four hours later, multiple bones were collected and assessed using bulk fluorescence imaging, two-photon imaging, and dynamic histomorphometry. CKD animals had significantly higher levels of FAM-ZOL accumulation in the proximal tibia, radius, and ulna, but not in lumbar vertebral body or mandible, based on multiple measurement modalities. Although a majority of trabecular bone surfaces were covered with FAM-ZOL in both normal and CKD animals, the latter had significantly higher levels of fluorescence per unit bone surface in the proximal tibia. These results provide new data regarding how reduced kidney function affects drug accumulation in rat bone.
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Tekinarslan, Erdem; Keskin, Suat; Buldu, İbrahim; Sönmez, Mehmet Giray; Karatag, Tuna; Istanbulluoglu, Mustafa Okan
2015-01-01
Introduction To determine and evaluate the effective radiation exposure during a one year follow-up of urolithiasis patients following the SWL (extracorporeal shock wave lithotripsy) treatment. Material and methods Total Effective Radiation Exposure (ERE) doses for each of the 129 patients: 44 kidney stone patients, 41 ureter stone patients, and 44 multiple stone location patients were calculated by adding up the radiation doses of each ionizing radiation session including images (IVU, KUB, CT) throughout a one year follow-up period following the SWL. Results Total mean ERE values for the kidney stone group was calculated as 15, 91 mSv (5.10-27.60), for the ureter group as 13.32 mSv (5.10-24.70), and in the multiple stone location group as 27.02 mSv (9.41-54.85). There was no statistically significant differences between the kidney and ureter groups in terms of the ERE dose values (p = 0.221) (p >0.05). In the comparison of the kidney and ureter stone groups with the multiple stone location group; however, there was a statistically significant difference (p = 0.000) (p <0.05). Conclusions ERE doses should be a factor to be considered right at the initiation of any diagnostic and/or therapeutic procedure. Especially in the case of multiple stone locations, due to the high exposure to ionized radiation, different imaging modalities with low dose and/or totally without a dose should be employed in the diagnosis, treatment, and follow-up bearing the aim to optimize diagnosis while minimizing the radiation dose as much as possible. PMID:26568880
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Tangen, Jon-Magnus; Tierens, Anne; Caers, Jo; Binsfeld, Marilene; Olstad, Ole Kristoffer; Trøseid, Anne-Marie Siebke; Wang, Junbai; Tjønnfjord, Geir Erland; Hetland, Geir
2015-01-01
Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous stem cell support were randomized in a double blinded fashion to receive adjuvant treatment with the mushroom extract AndoSan, containing 82% of Agaricus blazei Murrill (19 patients) or placebo (21 patients). Intake of the study product started on the day of stem cell mobilizing chemotherapy and continued until the end of aplasia after high dose chemotherapy, a period of about seven weeks. Thirty-three patients were evaluable for all study endpoints, while all 40 included patients were evaluable for survival endpoints. In the leukapheresis product harvested after stem cell mobilisation, increased percentages of Treg cells and plasmacytoid dendritic cells were found in patients receiving AndoSan. Also, in this group, a significant increase of serum levels of IL-1ra, IL-5, and IL-7 at the end of treatment was found. Whole genome microarray showed increased expression of immunoglobulin genes, Killer Immunoglobulin Receptor (KIR) genes, and HLA genes in the Agaricus group. Furthermore, AndoSan displayed a concentration dependent antiproliferative effect on mouse myeloma cells in vitro. There were no statistically significant differences in treatment response, overall survival, and time to new treatment. The study was registered with Clinicaltrials.gov NCT00970021.
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Tierens, Anne; Caers, Jo; Binsfeld, Marilene; Olstad, Ole Kristoffer; Trøseid, Anne-Marie Siebke; Wang, Junbai; Tjønnfjord, Geir Erland; Hetland, Geir
2015-01-01
Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous stem cell support were randomized in a double blinded fashion to receive adjuvant treatment with the mushroom extract AndoSan, containing 82% of Agaricus blazei Murrill (19 patients) or placebo (21 patients). Intake of the study product started on the day of stem cell mobilizing chemotherapy and continued until the end of aplasia after high dose chemotherapy, a period of about seven weeks. Thirty-three patients were evaluable for all study endpoints, while all 40 included patients were evaluable for survival endpoints. In the leukapheresis product harvested after stem cell mobilisation, increased percentages of Treg cells and plasmacytoid dendritic cells were found in patients receiving AndoSan. Also, in this group, a significant increase of serum levels of IL-1ra, IL-5, and IL-7 at the end of treatment was found. Whole genome microarray showed increased expression of immunoglobulin genes, Killer Immunoglobulin Receptor (KIR) genes, and HLA genes in the Agaricus group. Furthermore, AndoSan displayed a concentration dependent antiproliferative effect on mouse myeloma cells in vitro. There were no statistically significant differences in treatment response, overall survival, and time to new treatment. The study was registered with Clinicaltrials.gov NCT00970021. PMID:25664323
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Blake, Mary Kay; Carr, Brittany J; Mauldin, Glenna E
2016-02-01
Clinically significant hypersensitivity reactions (HSRs) to the chemotherapy drug L-asparaginase are reported in humans and dogs, but frequency in small animals is not well-defined. This study retrospectively evaluated the frequency of HSR to L-asparaginase given by IM injection to dogs and cats with lymphoid malignancies. The medical records of all dogs and cats treated with at least 1 dose of L-asparaginase chemotherapy over a 5-year period were reviewed. A total of 370 doses of L-asparaginase were administered to the dogs, with 88 of 142 dogs receiving multiple doses, and 6 dogs experiencing an HSR. A total of 197 doses were administered to the cats, with 33 of 68 cats receiving multiple doses, and no cats experiencing an HSR. Hypersensitivity reactions were documented in 4.2% of dogs, and in association with 1.6% of L-asparaginase doses administered. These results show that HSRs occur uncommonly among dogs and cats, even with repeated dosing.
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Blake, Mary Kay; Carr, Brittany J.; Mauldin, Glenna E.
2016-01-01
Clinically significant hypersensitivity reactions (HSRs) to the chemotherapy drug L-asparaginase are reported in humans and dogs, but frequency in small animals is not well-defined. This study retrospectively evaluated the frequency of HSR to L-asparaginase given by IM injection to dogs and cats with lymphoid malignancies. The medical records of all dogs and cats treated with at least 1 dose of L-asparaginase chemotherapy over a 5-year period were reviewed. A total of 370 doses of L-asparaginase were administered to the dogs, with 88 of 142 dogs receiving multiple doses, and 6 dogs experiencing an HSR. A total of 197 doses were administered to the cats, with 33 of 68 cats receiving multiple doses, and no cats experiencing an HSR. Hypersensitivity reactions were documented in 4.2% of dogs, and in association with 1.6% of L-asparaginase doses administered. These results show that HSRs occur uncommonly among dogs and cats, even with repeated dosing. PMID:26834270
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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.
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Bello-Bello, Jericó J; Chavez-Santoscoy, Rocío A; Lecona-Guzmán, Carlos A; Bogdanchikova, Nina; Salinas-Ruíz, Josafhat; Gómez-Merino, Fernando Carlos; Pestryakov, Alexey
2017-01-01
Hormesis is considered a dose-response phenomenon characterized by growth stimulation at low doses and inhibition at high doses. The hormetic response by silver nanoparticles (AgNPs) on in vitro multiplication of sugarcane was evaluated using a temporary immersion system. Sugarcane shoots were used as explants cultured in Murashige and Skoog medium with AgNPs at concentrations of 0, 25, 50, 100, and 200 mg/L. Shoot multiplication rate and length were used to determine hormetic response. Total content of phenolic compounds of sugarcane, mineral nutrition, and reactive oxygen species (ROS) was determined. Results were presented as a dose-response curve. Stimulation phase growth was observed at 50 mg/L AgNPs, whereas inhibition phase was detected at 200 mg/L AgNPs. Mineral nutrient analysis showed changes in macronutrient and micronutrient contents due to the effect of AgNPs. Moreover, AgNPs induced ROS production and increased total phenolic content, with a dose-dependent effect. Results suggested that the production of ROS and mineral nutrition are key mechanisms of AgNP-induced hormesis and that phenolic accumulation was obtained as a response of the plant to stress produced by high doses of AgNPs. Therefore, small doses of AgNPs in the culture medium could be an efficient strategy for commercial micropropagation.
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Che, Magnus M; Conti, Michele; Boylan, Megan; Sciuto, Alfred M; Gordon, Richard K; Nambiar, Madhusoodana P
2008-07-01
We determined acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in the bronchoalveolar lavage fluid (BALF) following inhalation exposure to chemical threat nerve agent (CTNA) sarin. Age- and weight-matched male guinea pigs were exposed to five different doses of sarin (169.3, 338.7, 508, 677.4, and 846.5 mg/m(3)) using a microinstillation inhalation exposure technique for 4 min. The technique involves aerosolization of the agent in the trachea using a microcatheter with a center hole that delivers the agent and multiple peripheral holes that pumps air to aerosolize the agent at the tip. Animals exposed to higher doses of sarin occasionally developed seizures and succumbed to death within 15 min after exposure. The LCt(50) for sarin using the microinstillation technique was determined to be close to 677.4 mg/m(3). Ear blood AChE activity showed a dose-dependent inhibition at 15 min postexposure. The inhibition of blood AChE remained constant over 35 and 55 min after sarin exposure indicating that there was no lung depot effect. Cardiac blood AChE and butyrylcholinesterase (BChE) activity in surviving animals euthanized at 24 h postexposure showed a dose-dependent inhibition with an inhibition of 60% at 677.4 and 846.5 mg/m(3) sarin exposure. AChE and BChE activity in bronchoalveolar lavage fluid (BALF) showed a slight increase at 338.7 to 677.4 mg/m(3) sarin exposure but a marginal inhibition at 169.3 mg/m(3). In contrast, the AChE protein levels determined by immunoblotting showed an increase at 169.3 mg/m(3) in the BALF. The BALF protein level, a biomarker of lung injury, was increased maximally at 338.7 mg/m(3) and that increase was dropped with an increase in the dose of sarin. The BALF protein levels correlated with the AChE and BChE activity. These data suggest that sarin microinstillation inhalation exposure results in respiratory toxicity and lung injury characterized by changes in lavage AChE, BChE, and protein levels.
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Urinary Phenylacetylglutamine as Dosing Biomarker for Patients with Urea Cycle Disorders
Mokhtarani, M; Diaz, GA; Rhead, W; Lichter-Konecki, U; Bartley, J; Feigenbaum, A; Longo, N; Berquist, W; Berry, SA; Gallagher, R; Bartholomew, D; Harding, CO; Korson, MS; McCandless, SE; Smith, W; Vockley, J; Bart, S; Kronn, D; Zori, R; Cederbaum, S; Dorrani, N; Merritt, JL; Sreenath-Nagamani, Sandesh; Summar, M; LeMons, C; Dickinson, K; Coakley, DF; Moors, TL; Lee, B; Scharschmidt, BF
2013-01-01
We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). Study Design These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6–17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. Results Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5–31.8 g/day and of sodium phenylbutyrate ranging from 1.3–31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% –5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% -to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r=0.730, p<0.001) or as total 24-hour excretion (r=0.791 p<0.001), followed by plasma phenylacetylglutamine AUC24-hour, plasma phenylacetic acid AUC24-hour and phenylbutyric acid AUC24-hour. Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. Conclusion The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring. PMID:22958974
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Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders.
Mokhtarani, M; Diaz, G A; Rhead, W; Lichter-Konecki, U; Bartley, J; Feigenbaum, A; Longo, N; Berquist, W; Berry, S A; Gallagher, R; Bartholomew, D; Harding, C O; Korson, M S; McCandless, S E; Smith, W; Vockley, J; Bart, S; Kronn, D; Zori, R; Cederbaum, S; Dorrani, N; Merritt, J L; Sreenath-Nagamani, Sandesh; Summar, M; Lemons, C; Dickinson, K; Coakley, D F; Moors, T L; Lee, B; Scharschmidt, B F
2012-11-01
We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring. Copyright © 2012 Elsevier Inc. All rights reserved.
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Radiotherapy in the treatment of solitary plasmacytoma.
Jyothirmayi, R; Gangadharan, V P; Nair, M K; Rajan, B
1997-05-01
Solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EMP) are rare. High local control rates are reported with radiotherapy, although the optimal dose and extent of radiotherapy portals remains controversial. Between 1983 and 1993, 30 patients with solitary plasmacytoma were seen at the Regional Cancer Centre, Trivandrum, India. 23 patients had SPB and seven EMP. The mean age was 52 years and the male to female ratio 3.2:1. Diagnosis of SPB was confirmed by biopsy in 16 patients and tumour excision in seven. 20 patients received megavoltage radiotherapy to the bone lesion with limited margins, and one received chemotherapy. Two patients who underwent complete tumour excision received no further treatment. All seven patients with EMP received megavoltage radiotherapy, four following biopsy and three after tumour excision. Local control was achieved in all patients with SPB. Nine progressed to multiple myeloma and one developed a solitary plasmacytoma in another bone. Six patients with EMP achieved local control. Three later progressed to multiple myeloma and one had local relapse. Median time to relapse was 28 months in SPB and 30 months in EMP. 5-year overall survival rates were 82% and 57% for patients with SPB and EMP, respectively. The corresponding progression free survival rates were 55% and 50%, respectively. Age, sex, site of tumour, serum M protein and haemoglobin levels did not significantly influence progression free survival. The extent of surgery, radiotherapy dose or time to relapse were not significant prognostic factors. Radiotherapy appears to be an effective modality of treatment of solitary plasmacytoma. No dose-response relationship is observed, and high local control rates are achieved with limited portals. Progression to multiple myeloma is the commonest pattern of failure, although no prognostic factors for progression are identified. The role of chemotherapy in preventing disease progression needs further evaluation.
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Valcke, Mathieu; Haddad, Sami
2015-01-01
The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to "low" (RfC-like) or "high" (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant "low" exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16-24%, vs. 12-15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO's CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For "high" exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11-16% to 2-6%) and TODD (CV= 12-13% to 7-9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Dong, P; Ma, L
Purpose: To study the feasibility of treating multiple brain tumors withlarge number of noncoplanar IMRT beams. Methods: Thirty beams are selected from 390 deliverable beams separated by six degree in 4pi space. Beam selection optimization is based on a column generation algorithm. MLC leaf size is 2 mm. Dose matrices are calculated with collapsed cone convolution and superposition method in a 2 mm by 2mm by 2 mm grid. Twelve brain tumors of various shapes, sizes and locations are used to generate four plans treating 3, 6, 9 and 12 tumors. The radiation dose was 20 Gy prescribed to themore » 100% isodose line. Dose Volume Histograms for tumor and brain were compared. Results: All results are based on a 2 mm by 2 mm by 2 mm CT grid. For 3, 6, 9 and 12 tumor plans, minimum tumor doses are all 20 Gy. Mean tumor dose are 20.0, 20.1, 20.1 and 20.1 Gy. Maximum tumor dose are 23.3, 23.6, 25.4 and 25.4 Gy. Mean ventricles dose are 0.7, 1.7, 2.4 and 3.1 Gy.Mean subventricular zone dose are 0.8, 1.3, 2.2 and 3.2 Gy. Average Equivalent uniform dose (gEUD) values for tumor are 20.1, 20.1, 20.2 and 20.2 Gy. The conformity index (CI) values are close to 1 for all 4 plans. The gradient index (GI) values are 2.50, 2.05, 2.09 and 2.19. Conclusion: Compared with published Gamma Knife treatment studies, noncoplanar IMRT treatment plan is superior in terms of dose conformity. Due to maximum limit of beams per plan, Gamma knife has to treat multiple tumors separately in different plans. Noncoplanar IMRT plans theoretically can be delivered in a single plan on any modern linac with an automated couch and image guidance. This warrants further study of using noncoplanar IMRT as a viable treatment solution for multiple brain tumors.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Ben-Josef, Edgar, E-mail: edgar.ben-josef@uphs.upenn.edu; Schipper, Mathew; Francis, Isaac R.
2012-12-01
Purpose: Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). Methods and Materials: Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of {>=}1500/mm{sup 3}, platelets {>=}100,000/mm{sup 3}, creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase {<=}2.5 Multiplication-Sign upper limit of normal. FDR-G (1000 mg/m{sup 2}/100 min intravenously) wasmore » given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) {>=}3, neutropenic fever, or deterioration in performance status to {>=}3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. Results: Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. Conclusions: High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Weir, V; Zhang, J
2016-06-15
Purpose: Iterative reconstruction (IR) algorithms have been adopted by medical centers in the past several years. IR has a potential to substantially reduce patient dose while maintaining or improving image quality. This study characterizes dose reductions in clinical settings for CT examinations using IR. Methods: We retrospectively analyzed dose information from patients who underwent abdomen/pelvis CT examinations with and without contrast media in multiple locations of our Healthcare system. A total of 743 patients scanned with ASIR on 64 slice GE lightspeed VCTs at three sites, and 30 patients scanned with SAFIRE on a Siemens 128 slice Definition Flash inmore » one site was retrieved. For comparison, patient data (n=291) from a GE scanner and patient data (n=61) from two Siemens scanners where filtered back-projection (FBP) was used was collected retrospectively. 30% and 10% ASIR, and SAFIRE Level 2 was used. CTDIvol, Dose-length-product (DLP), weight and height from all patients was recorded. Body mass index (BMI) was calculated accordingly. To convert CTDIvol to SSDE, AP and lateral dimensions at the mid-liver level was measured for each patient. Results: Compared with FBP, 30% ASIR reduces dose by 44.1% (SSDE: 12.19mGy vs. 21.83mGy), while 10% ASIR reduced dose by 20.6% (SSDE 17.32mGy vs. 21.83). Use of SAFIRE reduced dose by 61.4% (SSDE: 8.77mGy vs. 22.7mGy). The geometric mean for patients scanned with ASIR was larger than for patients scanned with FBP (geometric mean is 297.48 mmm vs. 284.76 mm). The same trend was observed for the Siemens scanner where SAFIRE was used (geometric mean: 316 mm with SAFIRE vs. 239 mm with FBP). Patient size differences suggest that further dose reduction is possible. Conclusion: Our data confirmed that in clinical practice IR can significantly reduce dose to patients who undergo CT examinations, while meeting diagnostic requirements for image quality.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Zablotska, Lydia B., E-mail: Lydia.Zablotska@ucsf.edu; Lane, Rachel S.D.; Frost, Stanley E.
Uranium workers are chronically exposed to low levels of radon decay products (RDP) and gamma (γ) radiation. Risks of leukemia from acute and high doses of γ-radiation are well-characterized, but risks from lower doses and dose-rates and from RDP exposures are controversial. Few studies have evaluated risks of other hematologic cancers in uranium workers. The purpose of this study was to analyze radiation-related risks of hematologic cancers in the cohort of Eldorado uranium miners and processors first employed in 1932–1980 in relation to cumulative RDP exposures and γ-ray doses. The average cumulative RDP exposure was 100.2 working level months andmore » the average cumulative whole-body γ-radiation dose was 52.2 millisievert. We identified 101 deaths and 160 cases of hematologic cancers in the cohort. Overall, male workers had lower mortality and cancer incidence rates for all outcomes compared with the general Canadian male population, a likely healthy worker effect. No statistically significant association between RDP exposure or γ-ray doses, or a combination of both, and mortality or incidence of any hematologic cancer was found. We observed consistent but non-statistically significant increases in risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma (HL) incidence and non-Hodgkin lymphoma (NHL) mortality with increasing γ-ray doses. These findings are consistent with recent studies of increased risks of CLL and NHL incidence after γ-radiation exposure. Further research is necessary to understand risks of other hematologic cancers from low-dose exposures to γ-radiation. - Highlights: • We analyzed long-term follow-up for hematologic cancers of the Eldorado uranium workers. • Workers were exposed to a unique combination of radon decay products (RDP) and gamma (γ) ray doses. • Exposures to RDP and γ-ray doses were not associated with significantly increased risks of cancers. • Radiation risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma were increased. • Study findings provide additional support for radiation-related risks of CLL.« less
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Nirogi, Ramakrishna; Mudigonda, Koteshwara; Bhyrapuneni, Gopinadh; Muddana, Nageswara Rao; Goyal, Vinod Kumar; Pandey, Santosh Kumar; Palacharla, Raghava Choudary
2018-05-01
SUVN-502, a selective 5-HT6 receptor antagonist, was found to be active in preclinical models of cognitive deterioration suggesting a potential role in the treatment of dementia related to Alzheimer's disease. The objective of this study was to characterize the safety, tolerability and pharmacokinetics of SUVN-502 in healthy young adults and elderly subjects following single and multiple oral doses. Single doses (5, 15, 50, 100 and 200 mg SUVN-502) and multiple doses (50, 100 and 130 mg SUVN-502 once daily for 7 days) were evaluated in healthy young adults and multiple doses (50 and 100 mg SUVN-502 once daily for 14 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food, gender and age on SUVN-502 pharmacokinetics (100 mg single dose) was evaluated using an open-label, two-period, randomized, fed and fasted in a crossover design. SUVN-502 and M1 (major metabolite of SUVN-502) were monitored using validated analytical methods. SUVN-502 is safe and well tolerated up to the highest tested single dose of 200 mg in healthy young adults and multiple doses up to 130 mg for 7 days and 100 mg for 14 days in healthy young adults and elderly subjects, respectively. Exposures of SUVN-502 and M1 were more than dose-proportional over the evaluated dose range. Food and gender did not have a clinically meaningful effect on SUVN-502 exposure. The mean SUVN-502 total (AUC 0-∞ , and AUC 0-last ) and peak exposures (C max ) were 2.9- and 2.2-fold higher, respectively, in elderly subjects compared to young subjects. Steady-state was achieved for SUVN-502 and M1 within 7 days after once-daily dosing of SUVN-502. SUVN-502 exhibited an acceptable safety, tolerability and pharmacokinetic profile in healthy young adults and elderly subjects. Based on the above results, 50 and 100 mg once-daily doses of SUVN-502 were advanced to Phase 2 evaluation in patients with moderate AD.
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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.
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San Miguel, Jesus F.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine; Renner, Christoph; Bahlis, Nizar Jacques; Yu, Xin; Teasdale, Terri; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Dimopoulos, Meletios A.
2015-01-01
Pomalidomide is a distinct oral IMiD® immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. PMID:26160879
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Laurora, Irene; Wang, Yuan
2016-10-01
Extended-release (ER) naproxen sodium provides pain relief for up to 24 hours with a single dose (660 mg/day). Its pharmacokinetic profile after single and multiple dosing was compared to immediate release (IR) naproxen sodium in two randomized, open-label, crossover studies, under fasting and fed conditions. Eligible healthy subjects were randomized to ER naproxen sodium 660-mg tablet once daily or IR naproxen sodium 220-mg tablet twice daily (440 mg initially, followed by 220 mg 12 hours later). Primary variables: pharmacokinetic parameters after singleday administration (day 1) and at steady state after multiple-day administration (day 6). Total exposure was comparable for both treatments under fasting and fed conditions. After fasting: peak naproxen concentrations were slightly lower with ER naproxen sodium than with IR naproxen sodium but were reached at a similar time. Fed conditions: mean peak concentrations were comparable but reached after a longer time with ER vs. IR naproxen sodium. ER naproxen sodium was well tolerated, with a similar safety profile to IR naproxen sodium. The total exposure of ER naproxen sodium (660 mg) is comparable to IR naproxen sodium (220 mg) when administered at the maximum over the counter (OTC) dose of 660-mg daily dose on a single day and over multiple days. The rate of absorption is delayed under fed conditions.
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Pharmacokinetic interactions of efavirenz and voriconazole in healthy volunteers
Damle, Bharat; LaBadie, Robert; Crownover, Penelope; Glue, Paul
2008-01-01
AIMS Co-administration of standard-dose voriconazole and efavirenz results in a substantial decrease in voriconazole levels, while concurrently increasing efavirenz levels. Hence, concomitant use of standard doses of these drugs was initially contraindicated. This study assessed different dose combinations of efavirenz and voriconazole, with the goal of attaining a dose combination that provides systemic exposures similar to standard-dose monotherapy with each drug. METHODS This was an open-label, four-treatment, multiple-dose, fixed-sequence study in 16 healthy males. Steady-state pharmacokinetics were assessed following two test treatments (voriconazole 300 mg q12 h + efavirenz 300 mg q24 h and voriconazole 400 mg q12 h + efavirenz 300 mg q24 h) and compared with standard-dose monotherapy (voriconazole 200 mg q12 h or efavirenz 600 mg q24 h). RESULTS Dose adjustment to voriconazole 300 mg q12 h with efavirenz 300 mg q24 h decreased voriconazole area under the concentration–time curve (AUCτ) and maximum concentration (Cmax), with changes of −55% [90% confidence interval (CI) −62, −45] and −36% (90% CI −49, −21), respectively, when compared with monotherapy. Voriconazole 400 mg q12 h plus efavirenz 300 mg q24 h decreased voriconazole AUCτ (−7%; 90% CI −23, 13) and increased Cmax (23%; 90% CI −1, 53), while increasing efavirenz AUCτ (17%; 90% CI 6, 29) and not changing Cmax when compared with the respective monotherapy regimens. No serious adverse events were observed with voriconazole plus efavirenz. CONCLUSIONS When co-administered, voriconazole dose should be increased to 400 mg q12 h and efavirenz dose decreased to 300 mg q24 h in order to provide systemic exposures similar to standard-dose monotherapy. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Efavirenz 400 mg q24 h reduces exposure to voriconazole 200 mg q12 h when the two drugs are co-administered.Furthermore, voriconazole increases the systemic exposure of efavirenz.Co-administration was therefore initially contraindicated. WHAT THIS STUDY ADDS The doses of efavirenz and voriconazole can be adjusted to provide adequate exposure to both drugs when the two are co-administered, without compromising safety.Appropriate adjustment of doses for both drugs may thus represent an alternative to a mere contraindication. PMID:18294336
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Improved Chemical Control of Chagas Disease Vectors in the Dry Chaco Region
CECERE, MARÍA CARLA; VAZQUEZ-PROKOPEC, GONZALO M.; CEBALLOS, LEONARDO A.; BORAGNO, SILVANA; ZÁRATE, JOAQUÍN E.; KITRON, URIEL; GÜRTLER, RICARDO E.
2013-01-01
The effectiveness of two doses of suspension concentrate (SC) pyrethroid insecticides in suppressing peridomestic populations of Triatoma infestans (Klug) was evaluated in 28 rural communities located in Santiago del Estero province, northwestern Argentina, including 388 houses and 1,516 identified sites. Four treatments were randomly assigned to peridomiciles within each community: 5% SC β-cypermethrin at standard (S, 50 mg active ingredient [AI]/m2) and double dose (2S), and 2.5% SC deltamethrin at standard (D, 25 mg [AI]/m2) and double dose (2D). Simultaneously, we assessed the effects of both pyrethroids applied at standard doses against domestic infestations. Bug infestation at the site level was assessed by timed manual collections with a dislodging agent at baseline, 13 and 21 mo postspraying (MPS). In domiciles, D and S nearly suppressed all T. infestans infestations up to 21 MPS. In peridomestic sites infested before interventions, multiple logistic regression analysis showed that site-level reinfestation at 13 MPS was significantly lower for treatment 2D (1%) than for other treatments, whereas 2S (6%), D (5%), and S (14%) did not differ significantly between them. The risk of reinfestation after spraying was significantly greater in goat or pig corrals than in other peridomestic ecotopes (in which treatments did not differ significantly), and in sites infested before interventions than in uninfested sites. The application of SC deltamethrin at double dose in goat or pig corrals may suppress T. infestans foci and achieve more sustained effects in the dry Chaco. PMID:23540129
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Hemmerle, Ann M.; Dickerson, Jonathan W.; Herring, Nicole R.; Schaefer, Tori L.; Vorhees, Charles V.; Williams, Michael T.; Seroogy, Kim B.
2014-01-01
(±)3,4-Methylenedioxymethamphetamine (MDMA), a widely used drug of abuse, rapidly reduces serotonin levels in the brain when ingested or administered in sufficient quantities, resulting in deficits in complex route-based learning, spatial learning, and reference memory. Neurotrophins are important for survival and preservation of neurons in the adult brain, including serotonergic neurons. In this study, we examined the effects of MDMA on the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their respective high-affinity receptors, tropomyosin receptor kinase (trk)B and trkC, in multiple regions of the rat brain. A serotonergic-depleting dose of MDMA (10 mg/kg × 4 at 2-hour intervals on a single day) was administered to adult Sprague-Dawley rats, and brains were examined 1, 7, or 24 hours after the last dose. Messenger RNA levels of BDNF, NT-3, trkB, and trkC were analyzed by using in situ hybridization with cRNA probes. The prefrontal cortex was particularly vulnerable to MDMA-induced alterations in that BDNF, NT-3, trkB, and trkC mRNAs were all upregulated at multiple time points. MDMA-treated animals had increased BDNF expression in the frontal, parietal, piriform, and entorhinal cortices, increased NT-3 expression in the anterior cingulate cortex, and elevated trkC in the entorhinal cortex. In the nigrostriatal system, BDNF expression was upregulated in the substantia nigra pars compacta, and trkB was elevated in the striatum in MDMA-treated animals. Both neurotrophins and trkB were differentially regulated in several regions of the hippocampal formation. These findings suggest a possible role for neurotrophin signaling in the learning and memory deficits seen following MDMA treatment. PMID:22237931
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Karlson, Björn W; Dellborg, Mikael; Gullestad, Lars; Aberg, Jan; Sugg, Jennifer; Herlitz, Johan
2014-01-01
Previous metoprolol studies in myocardial infarction patients were performed with immediate-release (IR) metoprolol. This study aims to evaluate if extended-release metoprolol CR/XL once daily gives a similar β-blockade over 24 h compared to multiple dosing of metoprolol IR. After 2 days of routine metoprolol treatment, 27 patients with suspected acute myocardial infarction were randomized to open-label treatment with metoprolol IR (50 mg four times daily or 100 mg twice daily) or metoprolol CR/XL 200 mg once daily for 3 days. Metoprolol CR/XL 200 mg once daily gave more pronounced suppression of peak heart rate, with lower peak and less variation in peak to trough plasma levels. There were no differences in AUC between the CR/XL and IR formulations, although the trough plasma metoprolol levels were comparable for metoprolol CR/XL 200 mg once daily and metoprolol IR 50 mg four times daily, but lower for metoprolol IR 100 mg twice daily. Both treatments were well tolerated. Metoprolol CR/XL 200 mg once daily showed lower peak and less variation in peak to trough plasma levels compared to multiple dosing of metoprolol IR with the same AUC. This was accompanied by a more uniform β-blockade over time, which was reflected by heart rate, and a more pronounced suppression of peak heart rate with similar tolerability. This suggests metoprolol CR/XL may be used as an alternative to metoprolol IR in patients with myocardial infarction. © 2013 S. Karger AG, Basel.
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Dose-response relationships for a wide range of in vivo and in vitro continuous datasets are well-described by a four-parameter exponential or Hill model, based on a recent analysis of multiple historical dose-response datasets, mostly with more than five dose groups (Slob and Se...
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Yiin, James H; Anderson, Jeri L; Bertke, Stephen J; Tollerud, David J
2018-05-09
To examine dose-response relationships between internal uranium exposures and select outcomes among a cohort of uranium enrichment workers. Cox regression was conducted to examine associations between selected health outcomes and cumulative internal uranium with consideration for external ionizing radiation, work-related medical X-rays and contaminant radionuclides technetium ( 99 Tc) and plutonium ( 239 Pu) as potential confounders. Elevated and monotonically increasing mortality risks were observed for kidney cancer, chronic renal diseases, and multiple myeloma, and the association with internal uranium absorbed organ dose was statistically significant for multiple myeloma. Adjustment for potential confounders had minimal impact on the risk estimates. Kidney cancer, chronic renal disease, and multiple myeloma mortality risks were elevated with increasing internal uranium absorbed organ dose. The findings add to evidence of an association between internal exposure to uranium and cancer. Future investigation includes a study of cancer incidence in this cohort. © 2018 Wiley Periodicals, Inc.
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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
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Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian
2016-05-01
In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.
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Dose critical in-vivo detection of anti-cancer drug levels in blood
Miller, Holly H.; Hirschfeld, deceased, Tomas B.
1991-01-01
A method and apparatus are disclosed for the in vivo and in vitro detection and measurement of dose critical levels of DNA-binding anti-cancer drug levels in biological fluids. The apparatus comprises a laser based fiber optic sensor (optrode) which utilizes the secondary interactions between the drug and an intercalating fluorochrome bound to a probe DNA, which in turn is attached to the fiber tip at one end thereof. The other end of the optical fiber is attached to an illumination source, detector and recorder. The fluorescence intensity is measured as a function of the drug concentration and its binding constant to the probe DNA. Anticancer drugs which lend themselves to analysis by the use of the method and the optrode of the present invention include doxorubicin, daunorubicin, carminomycin, aclacinomycin, chlorambucil, cyclophosphamide, methotrexate, 5-uracil, arabinosyl cytosine, mitomycin, cis-platinum 11 diamine dichloride procarbazine, vinblastine vincristine and the like. The present method and device are suitable for the continuous monitoring of the levels of these and other anticancer drugs in biological fluids such as blood, serum, urine and the like. The optrode of the instant invention also enables the measurement of the levels of these drugs from a remote location and from multiple samples.
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Einstein, Andrew J.; Weiner, Shepard D.; Bernheim, Adam; Kulon, Michal; Bokhari, Sabahat; Johnson, Lynne L.; Moses, Jeffrey W.; Balter, Stephen
2013-01-01
Context Myocardial perfusion imaging (MPI) is the single medical test with the highest radiation burden to the US population. While many patients undergoing MPI receive repeat MPI testing, or additional procedures involving ionizing radiation, no data are available characterizing their total longitudinal radiation burden and relating radiation burden with reasons for testing. Objective To characterize procedure counts, cumulative estimated effective doses of radiation, and clinical indications, for patients undergoing MPI. Design, Setting, Patients Retrospective cohort study evaluating, for 1097 consecutive patients undergoing index MPI during the first 100 days of 2006 at Columbia University Medical Center, all preceding medical imaging procedures involving ionizing radiation undergone beginning October 1988, and all subsequent procedures through June 2008, at that center. Main Outcome Measures Cumulative estimated effective dose of radiation, number of procedures involving radiation, and indications for testing. Results Patients underwent a median (interquartile range, mean) of 15 (6–32, 23.9) procedures involving radiation exposure; 4 (2–8, 6.5) were high-dose (≥3 mSv, i.e. one year's background radiation), including 1 (1–2, 1.8) MPI studies per patient. 31% of patients received cumulative estimated effective dose from all medical sources >100mSv. Multiple MPIs were performed in 39% of patients, for whom cumulative estimated effective dose was 121 (81–189, 149) mSv. Men and whites had higher cumulative estimated effective doses, and there was a trend towards men being more likely to undergo multiple MPIs than women (40.8% vs. 36.6%, Odds ratio 1.29, 95% confidence interval 0.98–1.69). Over 80% of initial and 90% of repeat MPI exams were performed in patients with known cardiac disease or symptoms consistent with it. Conclusion In this institution, multiple testing with MPI was very common, and in many patients associated with very high cumulative estimated doses of radiation. PMID:21078807
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Multiple metals predict prolactin and thyrotropin (TSH) levels in men
DOE Office of Scientific and Technical Information (OSTI.GOV)
Meeker, John D., E-mail: meekerj@umich.edu; Rossano, Mary G.; Protas, Bridget
2009-10-15
Exposure to a number of metals can affect neuroendocrine and thyroid signaling, which can result in adverse effects on development, behavior, metabolism, reproduction, and other functions. The present study assessed the relationship between metal concentrations in blood and serum prolactin (PRL) and thyrotropin (TSH) levels, markers of dopaminergic, and thyroid function, respectively, among men participating in a study of environmental influences on male reproductive health. Blood samples from 219 men were analyzed for concentrations of 11 metals and serum levels of PRL and TSH. In multiple linear regression models adjusted for age, BMI and smoking, PRL was inversely associated withmore » arsenic, cadmium, copper, lead, manganese, molybdenum, and zinc, but positively associated with chromium. Several of these associations (Cd, Pb, Mo) are consistent with limited studies in humans or animals, and a number of the relationships (Cr, Cu, Pb, Mo) remained when additionally considering multiple metals in the model. Lead and copper were associated with non-monotonic decrease in TSH, while arsenic was associated with a dose-dependent increase in TSH. For arsenic these findings were consistent with recent experimental studies where arsenic inhibited enzymes involved in thyroid hormone synthesis and signaling. More research is needed for a better understanding of the role of metals in neuroendocrine and thyroid function and related health implications.« less
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Wallace, Adam N; Vyhmeister, Ross; Bagade, Swapnil; Chatterjee, Arindam; Hicks, Brandon; Ramirez-Giraldo, Juan Carlos; McKinstry, Robert C
2015-06-01
Cerebrospinal fluid shunts are primarily used for the treatment of hydrocephalus. Shunt complications may necessitate multiple non-contrast head CT scans resulting in potentially high levels of radiation dose starting at an early age. A new head CT protocol using automatic exposure control and automated tube potential selection has been implemented at our institution to reduce radiation exposure. The purpose of this study was to evaluate the reduction in radiation dose achieved by this protocol compared with a protocol with fixed parameters. A retrospective sample of 60 non-contrast head CT scans assessing for cerebrospinal fluid shunt malfunction was identified, 30 of which were performed with each protocol. The radiation doses of the two protocols were compared using the volume CT dose index and dose length product. The diagnostic acceptability and quality of each scan were evaluated by three independent readers. The new protocol lowered the average volume CT dose index from 15.2 to 9.2 mGy representing a 39 % reduction (P < 0.01; 95 % CI 35-44 %) and lowered the dose length product from 259.5 to 151.2 mGy/cm representing a 42 % reduction (P < 0.01; 95 % CI 34-50 %). The new protocol produced diagnostically acceptable scans with comparable image quality to the fixed parameter protocol. A pediatric shunt non-contrast head CT protocol using automatic exposure control and automated tube potential selection reduced patient radiation dose compared with a fixed parameter protocol while producing diagnostic images of comparable quality.
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Poulos, Christine; Kinter, Elizabeth; Yang, Jui-Chen; Bridges, John F P; Posner, Joshua; Gleißner, Erika; Mühlbacher, Axel; Kieseier, Bernd
2016-03-01
The aim of this study was to assess the relative importance of features of a hypothetical injectable disease-modifying treatment for patients with multiple sclerosis using a discrete-choice experiment. German residents at least 18 years of age with a self-reported physician diagnosis of multiple sclerosis completed a 25-30 minute online discrete-choice experiment. Patients were asked to choose one of two hypothetical injectable treatments for multiple sclerosis, defined by different levels of six attributes (disability progression, the number of relapses in the next 4 years, injection time, frequency of injections, presence of flu-like symptoms, and presence of injection-site reactions). The data were analyzed using a random-parameters logit model. Of 202 adults who completed the survey, results from 189 were used in the analysis. Approximately 50% of all patients reported a diagnosis of relapsing-remitting multiple sclerosis, and 31% reported secondary progressive multiple sclerosis. Approximately 71% of patients had current or prior experience with injectable multiple sclerosis medication. Approximately 53% had experienced flu-like symptoms caused by their medication, and 47% had experienced mild injection-site reactions. At least one significant difference was seen between levels in all attributes, except injection time. The greatest change in relative importance between levels of an attribute was years until symptoms get worse from 1 to 4 years. The magnitude of this difference was about twice that of relapses in the next 4 years, frequency of injections, and flu-like symptoms. Most attributes examined in this experiment had an influence on patient preference. Patients placed a significant value on improvements in the frequency of dosing and disability progression. Results suggest that changes in injection frequency can be as important as changes in efficacy and safety attributes. Understanding which attributes of injectable therapies influence patient preference could potentially improve outcomes and adherence in patients with multiple sclerosis.
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Staerk, L; Gerds, T A; Lip, G Y H; Ozenne, B; Bonde, A N; Lamberts, M; Fosbøl, E L; Torp-Pedersen, C; Gislason, G H; Olesen, J B
2018-01-01
Comparative data of non-vitamin K antagonist oral anticoagulants (NOAC) are lacking in patients with atrial fibrillation (AF). We compared effectiveness and safety of standard and reduced dose NOAC in AF patients. Using Danish nationwide registries, we included all oral anticoagulant-naïve AF patients who initiated NOAC treatment (2012-2016). Outcome-specific and mortality-specific multiple Cox regressions were combined to compute average treatment effects as 1-year standardized differences in stroke and bleeding risks (g-formula). Amongst 31 522 AF patients, the distribution of NOAC/dose was as follows: dabigatran standard dose (22.4%), dabigatran-reduced dose (14.0%), rivaroxaban standard dose (21.8%), rivaroxaban reduced dose (6.7%), apixaban standard dose (22.9%), and apixaban reduced dose (12.2%). The 1-year standardized absolute risks of stroke/thromboembolism were 1.73-1.98% and 2.51-2.78% with standard and reduced NOAC dose, respectively, without statistically significant differences between NOACs for given dose level. Comparing standard doses, the 1-year standardized absolute risk (95% CI) for major bleeding was for rivaroxaban 2.78% (2.42-3.17%); corresponding absolute risk differences (95% CI) were for dabigatran -0.93% (-1.45% to -0.38%) and apixaban, -0.54% (-0.99% to -0.05%). The results for major bleeding were similar for reduced NOAC dose. The 1-year standardized absolute risk (95% CI) for intracranial bleeding was for standard dose dabigatran 0.19% (0.22-0.50%); corresponding absolute risk differences (95% CI) were for rivaroxaban 0.23% (0.06-0.41%) and apixaban, 0.18% (0.01-0.34%). Standard and reduced dose NOACs, respectively, showed no significant risk difference for associated stroke/thromboembolism. Rivaroxaban was associated with higher bleeding risk compared with dabigatran and apixaban and dabigatran was associated with lower intracranial bleeding risk compared with rivaroxaban and apixaban. © 2017 The Association for the Publication of the Journal of Internal Medicine.
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Popescu, Cristina; Draghici, George A.; Andrica, Florina-Maria; Privistirescu, Ionela A.; Gergen, Iosif I.; Stöger, Reinhard
2017-01-01
5-methylcytosine (5mC) is a key epigenetic mark which influences gene expression and phenotype. In vertebrates, this epigenetic mark is sensitive to Cd exposure, but there is no information linking such an event with changes in global 5mC levels in terrestrial gastropods despite their importance as excellentecotoxicological bioindicators of metal contamination. Therefore, we first evaluated total 5mC content in DNA of the hepatopancreas of adult Cantareus aspersus with the aim to determine whether this epigenetic mark is responsive to Cd exposure. The experiment was conducted under laboratory conditions and involved a continuous exposure, multiple dose- and time-point (14, 28, and 56 days) study design. Hepatopancreas cadmium levels were measured using Flame Atomic Absorption Spectrometry and the percentage of 5-mC in samples using an ELISA-based colorimetric assay. Snail death rates were also assessed. Our results, for the first time, reveal the presence of 5mC in C. aspersus and provide evidence for Cd-induced changes in global 5mC levels in DNA of gastropods and mollusks. Although less sensitive than tissue accumulation, DNA methylation levels responded in a dose- and time-dependent manner to dietary cadmium, with exposure dose having a much stronger effect than exposure duration. An obvious trend of increasing 5mC levels was observed starting at 28 days of exposure to the second highest dose and this trend persisted at the two highest treatments for close to one month, when the experiment was terminated after 56 days. Moreover, a strong association was identified between Cd concentrations in the hepatopancreas and DNA methylation levels in this organ. These data indicate an overall trend towards DNA hypermethylation with elevated Cd exposure. No consistent lethal effect was observed, irrespective of time point and Cd-dosage. Overall, our findings suggest that the total 5mC content in DNA of the hepatopancreas of land snails is responsive to sublethal Cd exposure and give new insights into invertebrate environmental epigenetics. PMID:28877233
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Single-Dose and Multiple-Dose Pharmacokinetics of Nicotine 6 mg Gum.
Hansson, Anna; Rasmussen, Thomas; Kraiczi, Holger
2017-04-01
Under-dosing is a recognized problem with current nicotine replacement therapy (NRT). Therefore, a new 6mg nicotine gum has been developed. To compare the nicotine uptake from the 6mg gum versus currently available NRT products, two pharmacokinetic studies were performed. In one randomized crossover study, 44 healthy adult smokers received single doses of 6, 4, and 2mg nicotine gum, and 4mg nicotine lozenge on separate occasions. In a separate randomized crossover multiple-dose study over 11 hours, 50 healthy adult smokers received one 6mg gum every hour and 90 minutes, respectively, one 4mg gum every hour, and one 4mg lozenge every hour. In both studies, blood samples were collected over 12 hours to determine single-dose and multiple-dose pharmacokinetic variables. In the single-dose study, the amount of nicotine released from the 2, 4, and 6mg gums (1.44, 3.36, and 4.94mg) as well as the resulting maximum concentration and area under the curve (5.9, 10.1, and 13.8ng/mL, and 17.1, 30.7, 46.2ng/mL × h, respectively) increased with dose. The maximum concentration and area under the curve of the 6mg gum were 44% and 30% greater, respectively, than those for 4mg lozenge. Upon hourly administration, the steady-state average plasma nicotine concentration with 6mg gum (37.4ng/mL) was significantly higher than those for 4mg lozenge (28.3ng/mL) and 4mg gum (27.1ng/mL). Nicotine delivery via the 6mg gum results in higher plasma nicotine concentrations after a single dose and at steady state than with currently available oral NRT. Under-dosing is a recognized problem with current NRT. Therefore, a new 6mg nicotine gum has been developed. Our studies show that upon single-dose and multiple-dose administration, the 6mg gum releases and delivers more nicotine to the systemic circulation than 2mg gum, 4mg gum, and 4mg lozenge. Thus, each 6mg nicotine gum provides a higher degree of nicotine substitution and/or lasts for a longer period of time than currently available nicotine gums and lozenges. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Glucuronidation and Sulfation Kinetics of Diflunisal in Man.
NASA Astrophysics Data System (ADS)
Loewen, Gordon Rapheal
Diflunisal is a nonsteroidal anti-inflammatory drug used in the treatment of arthritis and musculoskeletal pain. Diflunisal exhibits concentration- and dose-dependent kinetics, the mechanism of which has not been determined. The purpose of this study was to determine the mechanism(s) responsible for non-linear disposition of diflunisal and to examine environmental factors which may affect the elimination of diflunisal. The metabolites of diflunisal, including a new metabolite, the sulphate conjugate, were purified by column and semi-preparative high pressure liquid chromatography. Assays for the quantitation of diflunisal and conjugates in urine and diflunisal in plasma were developed. Plasma protein binding of diflunisal in blank plasma and in plasma obtained following multiple doses of diflunisal was determined by equilibrium dialysis. Total body clearance of diflunisal decreased when dose increased from 100 to 750 mg. Total clearance increased when dose increased from 750 to 1000 mg. The percent of recovered dose eliminated as the acyl glucuronide decreased and the percent eliminated as the sulphate increased with increasing dose of diflunisal. Plasma protein binding of diflunisal was concentration dependent over a range of diflunisal plasma concentrations of 3 to 257 mug/ml. Total clearance, and to a lesser degree, unbound clearance of diflunisal were decreased following multiple dose administration of 250 and 500 mg diflunisal. Percent of recovered dose eliminated as the acyl glucuronide decreased and percent eliminated as the sulphate conjugate increased following multiple dosing. Plasma protein binding of diflunisal was similar in blank plasma and plasma obtained at steady state. Unbound clearance of diflunisal exceeded liver plasma flow. Frequency distributions of the elimination of the conjugates of diflunisal were normally distributed. Sex, smoking, and use of vitamins or oral contraceptives were identified as factors which may affect the elimination of diflunisal.
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Patten, Denise K; Schultz, Bob G; Berlau, Daniel J
2018-03-01
Chronic inflammatory diseases are complex to treat and have an impact on a large number of patients. Due to the difficulty of treating these diseases and the great impact on quality of life, patients often seek off-label, complimentary, or alternative medicines to gain relief from symptoms. Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia, and other diseases. Naltrexone is a mu-opioid receptor antagonist indicated by the U.S. Food and Drug Administration for opioid and alcohol dependence. It is hypothesized that lower than standard doses of naltrexone inhibit cellular proliferation of T and B cells and block Toll-like receptor 4, resulting in an analgesic and antiinflammatory effect. It is the purpose of this review to examine the evidence of the safety, tolerability, and efficacy of low-dose naltrexone for use in chronic pain and inflammatory conditions. Currently, evidence supports the safety and tolerability of low-dose naltrexone in multiple sclerosis, fibromyalgia, and Crohn's disease. Fewer studies support the efficacy of low-dose naltrexone, with most of these focusing on subjective measures such as quality of life or self-reported pain. These studies do demonstrate that low-dose naltrexone has subjective benefits over placebo, but evidence for more objective measures is limited. However, further randomized controlled trials are needed to determine the efficacy of low-dose naltrexone due to insufficient evidence supporting its use in these disease states. This review provides practitioners with the extent of low-dose naltrexone evidence so that they can be cognizant of situations where it may not be the most appropriate therapy. © 2018 Pharmacotherapy Publications, Inc.
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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.
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Mark, Tomer M; Guarneri, Danielle; Forsberg, Peter; Rossi, Adriana; Pearse, Roger; Perry, Arthur; Pekle, Karen; Tegnestam, Linda; Greenberg, June; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; Van Besien, Koen; Ely, Scott; Jayabalan, David; Sherbenou, Daniel; Coleman, Morton; Niesvizky, Ruben
2017-06-01
Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Low-dose right unilateral electroconvulsive therapy (ECT): effectiveness of the first treatment.
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.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Bowers, M; Robertson, S; Moore, J
Purpose: Late toxicity from radiation to critical structures limits the possible dose in Radiation Therapy. Perfectly conformal treatment of a target is not realizable, so the clinician must accept a certain level of collateral radiation to nearby OARs. But how much? General guidelines exist for healthy tissue sparing which guide RT treatment planning, but are these guidelines good enough to create the optimal plan given the individualized patient anatomy? We propose a means to evaluate the planned dose level to an OAR using a multi-institutional data-store of previously treated patients, so a clinician might reconsider planning objectives. Methods: The toolmore » is built on Oncospace, a federated data-store system, which consists of planning data import, web based analysis tools, and a database containing:1) DVHs: dose by percent volume delivered to each ROI for each patient previously treated and included in the database.2) Overlap Volume Histograms (OVHs): Anatomical measure defined as the percent volume of an ROI within a given distance to target structures.Clinicians know what OARs are important to spare. For any ROI, Oncospace knows for which patients’ anatomy that ROI was harder to plan in the past (the OVH is less). The planned dose should be close to the least dose of previous patients. The tool displays the dose those OARs were subjected to, and the clinician can make a determination about the planning objectives used.Multiple institutions contribute to the Oncospace Consortium, and their DVH and OVH data are combined and color coded in the output. Results: The Oncospace website provides a plan quality display tool which identifies harder to treat patients, and graphically displays the dose delivered to them for comparison with the proposed plan. Conclusion: The Oncospace Consortium manages a data-store of previously treated patients which can be used for quality checking new plans. Grant funding by Elekta.« less
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Basaria, Shehzad; Collins, Lauren; Dillon, E. Lichar; Orwoll, Katie; Storer, Thomas W.; Miciek, Renee; Ulloor, Jagadish; Zhang, Anqi; Eder, Richard; Zientek, Heather; Gordon, Gilad; Kazmi, Syed; Sheffield-Moore, Melinda
2013-01-01
Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. Methods. In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations. PMID:22459616
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Elens, Laure; van Schaik, Ron H; Panin, Nadtha; de Meyer, Martine; Wallemacq, Pierre; Lison, Dominique; Mourad, Michel; Haufroid, Vincent
2011-10-01
CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the immunosuppressants tacrolimus (Tac) and cyclosporine (CsA). The objective of the study was to assess the potential influence of a new functional SNP in CYP3A4 on the pharmacokinetic parameters assessed by dose requirements and trough blood levels of both calcineurin inhibitors (CNI) in stable renal transplant patients. A total of 99 stable renal transplant patients receiving either Tac (n = 49) or CsA (n = 50) were genotyped for the CYP3A4 intron 6 C>T (rs35599367) and CYP3A5*3 SNPs. Trough blood levels ([Tac](0) or [CsA](0) in ng/ml), dose-adjusted [Tac](0) or [CsA](0) (ng/ml per mg/kg bodyweight) as well as doses (mg/kg bodyweight) required to achieve target concentrations were compared among patients according to allelic status for CYP3A4 and CYP3A5. Dose-adjusted concentrations were 2.0- and 1.6-fold higher in T-variant allele carriers for the CYP3A4 intron 6 C>T SNP compared with homozygous CC for Tac and CsA, respectively. When CYP3A4/CYP3A5 genotypes were combined, the difference was even more striking as the so-defined CYP3A poor metabolizer group presented dose-adjusted concentration 1.6- and 4.1-fold higher for Tac, and 1.5- and 2.2-fold higher for CsA than the intermediate metabolizer and extensive metabolizer groups, respectively. Multiple linear regression analysis revealed that, taken together, both CYP3A4 intron 6 and CYP3A5*3 SNPs explained more than 60 and 20% of the variability observed in dose-adjusted [Tac](0) and [CsA](0), respectively. The CYP3A4 intron 6 C>T polymorphism is associated with altered Tac and CsA metabolism. CYP3A4 intron 6 C>T along with CYP3A5*3 (especially for Tac) pharmacogenetic testing performed just before transplantation may help identifying patients at risk of CNI overexposure and contribute to limit CNI-related nephrotoxicity by refining the starting dose according to their genotype. Original submitted 5 May 2011; Revision submitted 29 June 2011.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Algan, O; Giem, J; Young, J
Purpose: To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiotherapy utilizing a single isocenter (SI) versus multiple isocenter (MI) in patients with multiple intracranial metastases. Methods: Seven patients imaged with MRI including SPGR sequence and diagnosed with 2–3 brain metastases were included in this retrospective study. Two sets of stereotactic IMRT treatment plans, (MI vs SI), were generated. The hippocampus was contoured on SPGR sequences and doses received by the hippocampus and whole brain were calculated. The prescribed dose was 25Gy in 5 fractions. The two groups were compared using t-testmore » analysis. Results: There were 17 lesions in 7 patients. The median tumor, right hippocampus, left hippocampus and brain volumes were: 3.37cc, 2.56cc, 3.28cc, and 1417cc respectively. In comparing the two treatment plans, there was no difference in the PTV coverage except in the tail of the DVH curve. All tumors had V95 > 99.5%. The only statistically significant parameter was the V100 (72% vs 45%, p=0.002, favoring MI). All other evaluated parameters including the V95 and V98 did not reveal any statistically significant differences. None of the evaluated dosimetric parameters for the hippocampus (V100, V80, V60, V40, V20, V10, D100, D90, D70, D50, D30, D10) revealed any statistically significant differences (all p-values > 0.31) between MI and SI plans. The total brain dose was slightly higher in the SI plans, especially in the lower dose regions, although this difference was not statistically significant. Utilizing brain-sub-PTV volumes did not change these results. Conclusion: The use of SI treatment planning for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain compared to MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.« less
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Cheng, Hao-Wen; Lo, Wei-Lun; Kuo, Chun-Yuan; Su, Yu-Kai; Tsai, Jo-Ting; Lin, Jia-Wei; Wang, Yu-Jen; Pan, David Hung-Chi
2017-11-01
In Gamma Knife forward treatment planning, normalization effect may be observed when multiple shots are used for treating large lesions. This effect can reduce the proportion of coverage of high-value isodose lines within targets. The aim of this study was to evaluate the performance of forward treatment planning techniques using the Leksell Gamma Knife for the normalization effect reduction. We adjusted the shot positions and weightings to optimize the dose distribution and reduce the overlap of high-value isodose lines from each shot, thereby mitigating the normalization effect during treatment planning. The new collimation system, Leksell Gamma Knife Perfexion, which contains eight movable sectors, provides an additional means to reduce the normalization effect by using composite shots. We propose different techniques in forward treatment planning that can reduce the normalization effect. Reducing the normalization effect increases the coverage proportion of higher isodose lines within targets, making the high-dose region within targets more uniform and increasing the mean dose to targets. Because of the increase in the mean dose to the target after reducing the normalization effect, we can set the prescribed marginal dose at a higher isodose level and reduce the maximum dose, thereby lowering the risk of complications. © 2017 Shuang Ho Hospital-Taipei Medical University. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.
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Antifungal activity of HWA-138 and amphotericin B in experimental systemic candidiasis.
Wasan, K M; Vadiei, K; Luke, D R; Keyhani, A; White, R A; McQueen, T J; Mehta, R; Lopez-Berestein, G
1991-01-01
HWA-138, a pentoxifylline analog, has been shown to increase yeast urinary clearance and to reduce yeast counts in the kidneys of rats infected with Candida albicans. Furthermore, HWA-138 has also been shown to prevent amphotericin B-induced acute renal failure in rats. We report here on the effects of HWA-138 alone and in combination with amphotericin B in the treatment of systemic candidiasis in mice. When single doses of HWA-138 were administered intravenously (10, 25, or 50 mg/kg of body weight) into infected mice, no significant improvement in survival was observed. In infected mice treated intravenously with multiple doses of HWA-138 (10, 25, or 50 mg/kg once daily for 5 consecutive days), a significant increase in survival time was seen only in animals also receiving 25 mg of HWA-138 per kg (14 +/- 3 days test versus 9 +/- 1 days control; P less than 0.05). The coadministration of subtherapeutic doses of amphotericin B and HWA-138 resulted in increased survival time. Combination therapy with amphotericin B (0.1-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) resulted in a significant increase in survival time over controls (19 +/- 4, 19 +/- 5, and 21 +/- 9 days, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P < 0.05). Variance analysis of these findings indicate synergistic activity between amphotericin B and HWA-138 in the treatment of experimental candidiasis in mice. PMID:1759826
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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.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Vikraman, S; Rajesh, Thiyagarajan; Karrthick, Kp
2015-06-15
Purpose: The purpose of this study was to evaluate multiple brain metastases stereotactic treatment planning of Cyberknife versus linac using dose volume based indices. Methods: Fifteen multiple brain metastases patients were taken for this study from Cyberknife Multiplan TPSv4.6.0. All these patients underwent stereotactic treatment in Cyberknife. For each patient VMAT stereotactic treatment plan was generated in MONACO TPSv5.0 using Elekta beam modulator MLC and matched the delivered plan. A median dose of 8.5Gy(range 7–12Gy) per fraction was prescribed. Tumor volume was in the range of 0.06–4.33cc. Treatment plan quality was critically evaluated by comparing DVH indices such as D98,more » D95, CI, and HI for target volumes. Maximum point doses and volume doses were evaluated for critical organs. Results: For each case, target coverage of D98 was achieved with 100% prescription dose with SD of 0.29% and 0.41% in Linac and Cyberknife respectively. The average conformity index(CI) of 1.26±0.0796 SD for Cyberknife and 1.92±0.60SD for linac were observed. Better homogeneity Index (HI) of 1.17±0.09SD was observed in linac as compared to Cyberknife HI of 1.24±0.05SD.All the critical organ doses were well within tolerance limit in both linac and Cyberknife plans. There is no significant difference of maximum point doses for brainstem and optic chiasm. Treatment time and number of monitor units are more in Cyberknife compared to linac. The average volume receiving 12Gy in whole brain was 6% and 12% for Cyberknife and linac respectively. 1000cc of whole brain received 60% lesser dose in Linac compared to Cyberknife in all cases. Conclusion: The study shows that dosimetrically comparable plans are achievable Cyberknife and Linac. However, a better conformity, target coverage, lesser OAR dose is achieved with Cyberknife due to greater degrees of freedom with robotic gantry and smaller collimator for multiple targets.« less
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Impact of the Tips From Former Smokers Campaign on Population-Level Smoking Cessation, 2012–2015
Davis, Kevin C.; Beistle, Diane; King, Brian A.; Duke, Jennifer; Rodes, Robert; Graffunder, Corinne
2018-01-01
This study provides estimates of the long-term cumulative impact of the Centers for Disease Control and Prevention’s national tobacco education campaign, Tips From Former Smokers (Tips), on population-level smoking cessation. We used recently published estimates of the association between increased Tips campaign media doses and quit attempts to calculate campaign-attributable population sustained (6-month) quits during 2012–2015. Tips led to approximately 522,000 sustained quits during 2012–2015. These findings indicate that the Tips campaign’s comprehensive approach to combining evidence-based messages with the promotion of cessation resources was successful in achieving substantial long-term cigarette cessation at the population level over multiple years. PMID:29862960
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Low-dose dasatinib rescues cardiac function in Noonan syndrome
Yi, Jae-Sung; Huang, Yan; Kwaczala, Andrea T.; Kuo, Ivana Y.; Ehrlich, Barbara E.; Campbell, Stuart G.; Giordano, Frank J.; Bennett, Anton M.
2016-01-01
Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in the PTPN11 gene encoding for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. In contrast, NS with multiple lentigines (NSML) is caused by mutations that inactivate SHP2, but it exhibits some overlapping abnormalities with NS. Protein zero-related (PZR) is a SHP2-binding protein that is hyper-tyrosyl phosphorylated in the hearts of mice from NS and NSML, suggesting that PZR and the tyrosine kinase that catalyzes its phosphorylation represent common targets for these diseases. We show that the tyrosine kinase inhibitor, dasatinib, at doses orders of magnitude lower than that used for its anticancer activities inhibited PZR tyrosyl phosphorylation in the hearts of NS mice. Low-dose dasatinib treatment of NS mice markedly improved cardiomyocyte contractility and functionality. Remarkably, a low dose of dasatinib reversed the expression levels of molecular markers of cardiomyopathy and reduced cardiac fibrosis in NS and NSML mice. These results suggest that PZR/SHP2 signaling is a common target of both NS and NSML and that low-dose dasatinib may represent a unifying therapy for the treatment of PTPN11-related cardiomyopathies. PMID:27942593
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Thomas, Evan M; Popple, Richard A; Wu, Xingen; Clark, Grant M; Markert, James M; Guthrie, Barton L; Yuan, Yu; Dobelbower, Michael C; Spencer, Sharon A; Fiveash, John B
2014-10-01
Volumetric modulated arc therapy (VMAT) has been shown to be feasible for radiosurgical treatment of multiple cranial lesions with a single isocenter. To investigate whether equivalent radiosurgical plan quality and reduced delivery time could be achieved in VMAT for patients with multiple intracranial targets previously treated with Gamma Knife (GK) radiosurgery. We identified 28 GK treatments of multiple metastases. These were replanned for multiarc and single-arc, single-isocenter VMAT (RapidArc) in Eclipse. The prescription for all targets was standardized to 18 Gy. Each plan was normalized for 100% prescription dose to 99% to 100% of target volume. Plan quality was analyzed by target conformity (Radiation Therapy Oncology Group and Paddick conformity indices [CIs]), dose falloff (area under the dose-volume histogram curve), as well as the V4.5, V9, V12, and V18 isodose volumes. Other end points included beam-on and treatment time. Compared with GK, multiarc VMAT improved median plan conformity (CIVMAT = 1.14, CIGK = 1.65; P < .001) with no significant difference in median dose falloff (P = .269), 12 Gy isodose volume (P = .500), or low isodose spill (P = .49). Multiarc VMAT plans were associated with markedly reduced treatment time. A predictive model of the 12 Gy isodose volume as a function of tumor number and volume was also developed. For multiple target stereotactic radiosurgery, 4-arc VMAT produced clinically equivalent conformity, dose falloff, 12 Gy isodose volume, and low isodose spill, and reduced treatment time compared with GK. Because of its similar plan quality and increased delivery efficiency, single-isocenter VMAT radiosurgery may constitute an attractive alternative to multi-isocenter radiosurgery for some patients.
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Pickhardt, Perry J; Lubner, Meghan G; Kim, David H; Tang, Jie; Ruma, Julie A; del Rio, Alejandro Muñoz; Chen, Guang-Hong
2012-12-01
The purpose of this study was to report preliminary results of an ongoing prospective trial of ultralow-dose abdominal MDCT. Imaging with standard-dose contrast-enhanced (n = 21) and unenhanced (n = 24) clinical abdominal MDCT protocols was immediately followed by ultralow-dose imaging of a matched series of 45 consecutively registered adults (mean age, 57.9 years; mean body mass index, 28.5). The ultralow-dose images were reconstructed with filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and model-based iterative reconstruction (MBIR). Standard-dose series were reconstructed with FBP (reference standard). Image noise was measured at multiple predefined sites. Two blinded abdominal radiologists interpreted randomly presented ultralow-dose images for multilevel subjective image quality (5-point scale) and depiction of organ-based focal lesions. Mean dose reduction relative to the standard series was 74% (median, 78%; range, 57-88%; mean effective dose, 1.90 mSv). Mean multiorgan image noise for low-dose MBIR was 14.7 ± 2.6 HU, significantly lower than standard-dose FBP (28.9 ± 9.9 HU), low-dose FBP (59.2 ± 23.3 HU), and ASIR (45.6 ± 14.1 HU) (p < 0.001). The mean subjective image quality score for low-dose MBIR (3.0 ± 0.5) was significantly higher than for low-dose FBP (1.6 ± 0.7) and ASIR (1.8 ± 0.7) (p < 0.001). Readers identified 213 focal noncalcific lesions with standard-dose FBP. Pooled lesion detection was higher for low-dose MBIR (79.3% [169/213]) compared with low-dose FBP (66.2% [141/213]) and ASIR (62.0% [132/213]) (p < 0.05). MBIR shows great potential for substantially reducing radiation doses at routine abdominal CT. Both FBP and ASIR are limited in this regard owing to reduced image quality and diagnostic capability. Further investigation is needed to determine the optimal dose level for MBIR that maintains adequate diagnostic performance. In general, objective and subjective image quality measurements do not necessarily correlate with diagnostic performance at ultralow-dose CT.
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Fujimoto, Koichi; Kanazawa, Katsunori; Takemoto, Koji; Urasaki, Kokichi; Ueda, Yutaka; Ubukata, Kimiko; Sunakawa, Keisuke
2013-08-01
The purpose of this study was to investigate the relationship between efficacy and percentage of time above the MIC (%T>MIC) in the cerebrospinal fluid (CSF) for different dosing regimens of meropenem against an experimental lethal meningitis model in guinea pigs with type b β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (Hib BLNAR). Guinea pigs were intrathecally inoculated with 10(8) CFU/head of Hib BLNAR 8 h before the start of therapy. A single dose of 20, 40, or 80 mg/kg meropenem or multiple doses of 40 mg/kg meropenem were subcutaneously administered. Numbers of bacteria in CSF were counted 8 h after the start of therapy. Meropenem concentration in serum and CSF were determined in infected guinea pigs receiving a single dose of 40 mg/kg. In the single-dose regimen, 40 and 80 mg/kg meropenem significantly reduced the number of bacteria in CSF compared with the control, but 20 mg/kg meropenem did not. The %T>MIC for an 8-h period of 20, 40, and 80 mg/kg meropenem were 41, 52, and 62, respectively. Two and four doses of 40 mg/kg meropenem, for both of which %T>MIC was calculated as 100, had similar efficacy and were significantly superior to a single-dose of 40 mg/kg. In conclusion, meropenem had high efficacy when %T>MIC in the CSF was increased because of the high dose level and shortening of the dosing interval in a guinea pig meningitis model caused by Hib BLNAR, suggesting that high and frequent doses of meropenem are useful for treatment of meningitis with Hib BLNAR.
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Inequalities in full immunization coverage: trends in low- and middle-income countries
Barros, Aluísio JD; Wong, Kerry LM; Johnson, Hope L; Pariyo, George; França, Giovanny VA; Wehrmeister, Fernando C; Victora, Cesar G
2016-01-01
Abstract Objective To investigate disparities in full immunization coverage across and within 86 low- and middle-income countries. Methods In May 2015, using data from the most recent Demographic and Health Surveys and Multiple Indicator Cluster Surveys, we investigated inequalities in full immunization coverage – i.e. one dose of bacille Calmette-Guérin vaccine, one dose of measles vaccine, three doses of vaccine against diphtheria, pertussis and tetanus and three doses of polio vaccine – in 86 low- or middle-income countries. We then investigated temporal trends in the level and inequality of such coverage in eight of the countries. Findings In each of the World Health Organization’s regions, it appeared that about 56–69% of eligible children in the low- and middle-income countries had received full immunization. However, within each region, the mean recorded level of such coverage varied greatly. In the African Region, for example, it varied from 11.4% in Chad to 90.3% in Rwanda. We detected pro-rich inequality in such coverage in 45 of the 83 countries for which the relevant data were available and pro-urban inequality in 35 of the 86 study countries. Among the countries in which we investigated coverage trends, Madagascar and Mozambique appeared to have made the greatest progress in improving levels of full immunization coverage over the last two decades, particularly among the poorest quintiles of their populations. Conclusion Most low- and middle-income countries are affected by pro-rich and pro-urban inequalities in full immunization coverage that are not apparent when only national mean values of such coverage are reported. PMID:27821882
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Perkins, Sarah; Verschoyle, Richard D; Hill, Kirsti; Parveen, Ifat; Threadgill, Michael D; Sharma, Ricky A; Williams, Marion L; Steward, William P; Gescher, Andreas J
2002-06-01
Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/+ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/+ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated. Levels of curcumin and metabolites were determined by high-performance liquid chromatography in plasma, tissues, and feces of mice after either long-term ingestion of dietary curcumin or a single dose of [(14)C]curcumin (100 mg/kg) via the i.p. route. Whereas curcumin at 0.1% in the diet was without effect, at 0.2 and 0.5%, it reduced adenoma multiplicity by 39 and 40%, respectively, compared with untreated mice. Hematocrit values in untreated Min/+ mice were drastically reduced compared with those in wild-type C57Bl/6J mice. Dietary curcumin partially restored the suppressed hematocrit. Traces of curcumin were detected in the plasma. Its concentration in the small intestinal mucosa, between 39 and 240 nmol/g of tissue, reflects differences in dietary concentration. [(14)C]Curcumin disappeared rapidly from tissues and plasma within 2-8 h after dosing. Curcumin may be useful in the chemoprevention of human intestinal malignancies related to Apc mutations. The comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. A clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation.
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Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.
McGuire, Brendan M; Zupanets, Igor A; Lowe, Mark E; Xiao, Xunjun; Syplyviy, Vasyliy A; Monteleone, Jon; Gargosky, Sharron; Dickinson, Klara; Martinez, Antonia; Mokhtarani, Masoud; Scharschmidt, Bruce F
2010-06-01
Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.
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Pharmacology and Safety of Glycerol Phenylbutyrate in Healthy Adults and Adults with Cirrhosis
MCGuire, Brendan M.; Zupanets, Igor A.; Lowe, Mark E.; Xiao, Xunjun; Syplyviy, Vasyliy A.; Monteleone, Jon; Gargosky, Sharron; Dickinson, Klara; Martinez, Antonia; Mokhtarani, Masoud; Scharschmidt, Bruce F.
2013-01-01
Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. Conclusion GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted. PMID:20512995
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Diethylene glycol in health products sold over-the-counter and imported from Asian countries.
Schier, Joshua G; Barr, Dana B; Li, Zheng; Wolkin, Amy F; Baker, Samuel E; Lewis, Lauren S; McGeehin, Michael A
2011-03-01
Diethylene glycol (DEG), a chemical that has been implicated in multiple medication-associated mass poisonings, can result in renal and neurological toxicity if ingested. Three previous such mass poisonings implicated Chinese manufacturers as the origin of contaminated ingredients. No literature exists on potential DEG or triethylene glycol (TEG), a related compound, contamination of health products imported from Asian countries to the USA. Our primary objective was to quantitatively assess the amount of DEG present in a convenience sampling of these health products. The study's secondary objectives were to: (1) evaluate for, and quantify TEG levels in these samples; (2) compare DEG and TEG levels in these products directly to levels in medications implicated in previous similar mass poisonings; and (3) to estimate DEG dose (in mg/kg) based on the manufacturer's instructions and compare these values to toxic doses from past mass poisonings and the literature. A quantitative assessment of DEG and TEG was performed in a convenience sampling of over-the-counter health products imported from Asian countries. Results were converted to volume to volume (v/v) % and compared with DEG levels in medications implicated in previous mass poisonings. Estimated doses (based on the manufacturer's instructions) of each product with detectable levels of DEG for a 70 kg adult were compared to toxic doses of DEG reported in the literature. Seventeen of 85 (20%) samples were not able to be analyzed for DEG or TEG due to technical reasons. Fifteen of 68 (22%) samples successfully tested had detectable levels of DEG (mean, 18.8 μg/ml; range, 0.791-110.1 μg/ml; and volume to volume (v/v) range, 0.00007-0.01%). Two of 68 (3%) samples had TEG levels of 12.8 and 20.2 μg/ml or 0.0012% and 0.0018% TEG v/v. The product with the highest DEG% by v/v was 810 times less than the product involved in the Panama DEG mass poisoning (8.1%). The lowest reported toxic dose from a past DEG mass poisoning (14 mg/kg) was more than 150 times higher than the highest daily dose estimated in our study (0.09 mg/kg). Sixty-eight of 85 (80%) samples were able to be successfully analyzed for DEG and TEG. DEG and TEG were detectable in 15/68 (22%) and 2/68 (3%) samples, respectively. Based on current standards, these levels probably do not represent an acute public health threat. Additional research focusing on why DEG is found in these products and on the minimum amount of DEG needed to result in toxicity is needed. © American College of Medical Toxicology 2010
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DOSE-DEPENDENT TRANSITIONS IN MECHANISMS OF TOXICITY: CASE STUDIES
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 ...
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Martin, Paul; Cheung, S Y Amy; Yen, Mark; Han, David; Gillen, Michael
2016-01-01
The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. Mean maximum plasma concentration (C max) and area under total plasma concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses. Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.
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The Importance of Gestational Sac Size of Ectopic Pregnancy in Response to Single-Dose Methotrexate
Kimiaei, Parichehr; Khani, Zahra; Marefian, Azadeh; Gholampour Ghavamabadi, Maryam; Salimnejad, Maryam
2013-01-01
This retrospective cohort study was designed in a selective group of 185 patients diagnosed with and treated for ectopic pregnancy. Intramuscular administration of a single dose of methotrexate (50 mg/m2) was performed to measure predictors of failure or resistance to treatment necessitating surgical intervention. During the time of treatment with a single dose of MTX, 20 patients (10.8%) failed to response, in which 6 of 20 (30%) indicated side effects to MTX and rupture of the ectopic pregnancy. Remaining cases (n = 14) showed resistance to the drug; the level of β-hCG did not fall at least 15% during 7 days after treatment and necessitated laparotomy. In backward-step analysis by multiple logistic regressions of various types of predictor factors, size of gestational sac (coefficient = 1.91, OR = 6.78, 95% confidence interval = 3.18–8.22) and baseline level β-hCG (coefficient = 1.60, OR = 5.0, 95% confidence interval = 4.26–6.72) had significant correlation with leading EP patients failing to response to MTX. This study suggests that further investigation for finding relative contraindications of MTX treatment in EP women should be considered on the gestational sac size because other variables are in the causal pathway of this variable. PMID:23762575
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Dose-Related Effects of Alcohol on Cognitive Functioning
Dry, Matthew J.; Burns, Nicholas R.; Nettelbeck, Ted; Farquharson, Aaron L.; White, Jason M.
2012-01-01
We assessed the suitability of six applied tests of cognitive functioning to provide a single marker for dose-related alcohol intoxication. Numerous studies have demonstrated that alcohol has a deleterious effect on specific areas of cognitive processing but few have compared the effects of alcohol across a wide range of different cognitive processes. Adult participants (N = 56, 32 males, 24 females aged 18–45 years) were randomized to control or alcohol treatments within a mixed design experiment involving multiple-dosages at approximately one hour intervals (attained mean blood alcohol concentrations (BACs) of 0.00, 0.048, 0.082 and 0.10%), employing a battery of six psychometric tests; the Useful Field of View test (UFOV; processing speed together with directed attention); the Self-Ordered Pointing Task (SOPT; working memory); Inspection Time (IT; speed of processing independent from motor responding); the Traveling Salesperson Problem (TSP; strategic optimization); the Sustained Attention to Response Task (SART; vigilance, response inhibition and psychomotor function); and the Trail-Making Test (TMT; cognitive flexibility and psychomotor function). Results demonstrated that impairment is not uniform across different domains of cognitive processing and that both the size of the alcohol effect and the magnitude of effect change across different dose levels are quantitatively different for different cognitive processes. Only IT met the criteria for a marker for wide-spread application: reliable dose-related decline in a basic process as a function of rising BAC level and easy to use non-invasive task properties. PMID:23209840
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Molnar, Anna; Fu, Shanlin; Lewis, John; Allsop, David J; Copeland, Jan
2014-05-01
Sativex(®) is an oromucosal spray used to treat spasticity in multiple sclerosis sufferers in some European countries, the United Kingdom, Canada and New Zealand. The drug has also recently been registered by the Therapeutic Goods Administration (TGA) in Australia for treatment of multiple sclerosis. Sativex(®) contains high concentrations of Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), with the former being the subject of random roadside drug tests across Australia to detect cannabis use. This pilot study aims to determine whether or not patients taking Sativex(®) will test positive to THC using these roadside screening tests. Detectable levels of THC, CBD and cannabinol (CBN) in their oral fluid were also confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study was a double-blind, placebo controlled design. Oral fluid was tested prior to and immediately after dosing with either Sativex(®) or placebo at intervals up to 2h after the dose. Two Sativex(®) doses were studied. The low dose contained 5.4mg THC, the high dose 21.6mg THC. Results indicate that the primary screening test used in Australian roadside drug testing, the DrugWipe(®) II Twin, often gave a false negative response for THC, even with high concentrations present. However, secondary screening test, Cozart(®) DDS (used by police after a DrugWipe test gives a positive result), gave true positive results in all cases where patients were being treated with Sativex(®). Confirmatory testing showed high concentrations of THC and CBD (>5356ng/mL THC and >3826ng/mL CBD) in the oral fluid shortly after dosing and also elevated concentrations of CBN. Levels dropped quickly but remained at detectable concentrations (>67.6ng/mL) two hours after drug administration. The average concentration ratio of THC/CBD across all positive samples was 1.10 (%RSD 19.9) reflecting the composition of the Sativex(®) spray. In conclusion, Sativex(®) users may test positive for THC by roadside drug testing within 2-3h of use. Confirmatory analysis can identify Sativex(®) treatment through use of THC/CBD ratios, however, these ratios would unlikely be sufficient to differentiate non-medicinal cannabis use from Sativex(®) use if both are taken concurrently. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.
Scherz, Michael W; Brossard, Patrick; D'Ambrosio, Daniele; Ipek, Murat; Dingemanse, Jasper
2015-06-01
Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval. © 2015, The American College of Clinical Pharmacology.
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Blankenstein, Oliver; Snajderova, Marta; Blair, Jo; Pournara, Effie; Pedersen, Birgitte Tønnes; Petit, Isabelle Oliver
2017-08-01
To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; Nbib960128) between 2006 and 2016. This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n = 425/61/316/119), France ( n = 1404/188/970/206), Germany ( n = 2603/351/1387/411) and the UK ( n = 259/60/87/35). GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications. In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown ( P < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%). GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations. © 2017 The authors.
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Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs.
Shen, Chenlin; Huang, Xiaohui; Li, Jun; Zhang, Ping; Li, Lin; Zhang, Wei; Hu, Tingting; Pappoe, Faustina; Huang, Jihan; Tang, Haiqin
2016-01-01
1. Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin-aspirin therapy, the safety and side effect of combined therapy remains unclear. 2. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses. 3. Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC(0-t)) and maximum plasma concentration (Cmax) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC(0-t) and Cmax and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC(0-t) and Emax of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin. 4. Coadministration of warfarin had no markedly effects on the AUC(0-t) and Cmax of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC(0-t) and Emax of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin. 5. Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug-drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin-aspirin drug interactions in healthy volunteers or patients.
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Wheelock, C E; Wolfe, M F; Olsen, H; Tjeerdema, R S; Sowby, M L
1999-04-01
Hsp60 induction was selected as a sublethal endpoint of toxicity for Brachionus plicatilis exposed to a water accommodated fraction (WAF) of Prudhoe Bay crude oil (PBCO), a PBCO/dispersant (Corexit 9527(R)) fraction and Corexit 9527(R) alone. To examine the effect of multiple stressors, exposures modeled San Francisco Bay, where copper levels are approximately 5 microgram/L, salinity is 22 per thousand, significant oil transport and refining occurs, and petroleum releases have occurred historically. Rotifers were exposed to copper at 5 microgram/L for 24 h, followed by one of the oil/dispersant preparations for 24 h. Batch-cultured rotifers were used in this study to model wild populations instead of cysts. SDS-PAGE with Western Blotting using hsp60-specific antibodies and chemiluminescent detection were used to isolate, identify, and measure induced hsp60 as a percentage of control values. Both PBCO/dispersant and dispersant alone preparations induced significant levels of hsp60. However, hsp60 expression was reduced to that of controls at high WAF concentrations, suggesting interference with protein synthesis. Rotifers that had been preexposed to copper maintained elevated levels of hsp60 upon treatment with WAF at all concentrations. Results suggest that induction of hsp60 by chronic low-level exposure may serve as a protective mechanism against subsequent or multiple stressors and that hsp60 levels are not additive for the toxicants tested in this study, giving no dose-response relationship. The methods employed in this study could be useful for quantifying hsp60 levels in wild rotifer populations.
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Multiple comparisons permutation test for image based data mining in radiotherapy.
Chen, Chun; Witte, Marnix; Heemsbergen, Wilma; van Herk, Marcel
2013-12-23
: Comparing incidental dose distributions (i.e. images) of patients with different outcomes is a straightforward way to explore dose-response hypotheses in radiotherapy. In this paper, we introduced a permutation test that compares images, such as dose distributions from radiotherapy, while tackling the multiple comparisons problem. A test statistic Tmax was proposed that summarizes the differences between the images into a single value and a permutation procedure was employed to compute the adjusted p-value. We demonstrated the method in two retrospective studies: a prostate study that relates 3D dose distributions to failure, and an esophagus study that relates 2D surface dose distributions of the esophagus to acute esophagus toxicity. As a result, we were able to identify suspicious regions that are significantly associated with failure (prostate study) or toxicity (esophagus study). Permutation testing allows direct comparison of images from different patient categories and is a useful tool for data mining in radiotherapy.
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Cvrčková, Fatima; Luštinec, Jiří; Žárský, Viktor
2015-01-01
We usually expect the dose-response curves of biological responses to quantifiable stimuli to be simple, either monotonic or exhibiting a single maximum or minimum. Deviations are often viewed as experimental noise. However, detailed measurements in plant primary tissue cultures (stem pith explants of kale and tobacco) exposed to varying doses of sucrose, cytokinins (BA or kinetin) or auxins (IAA or NAA) revealed that growth and several biochemical parameters exhibit multiple reproducible, statistically significant maxima over a wide range of exogenous substance concentrations. This results in complex, non-monotonic dose-response curves, reminiscent of previous reports of analogous observations in both metazoan and plant systems responding to diverse pharmacological treatments. These findings suggest the existence of a hitherto neglected class of biological phenomena resulting in dose-response curves exhibiting periodic patterns of maxima and minima, whose causes remain so far uncharacterized, partly due to insufficient sampling frequency used in many studies.
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Saber, Anne T; Jacobsen, Nicklas R; Bornholdt, Jette; Kjær, Sanna L; Dybdahl, Marianne; Risom, Lotte; Loft, Steffen; Vogel, Ulla; Wallin, Håkan
2006-01-01
Background Particulate air pollution has been associated with lung and cardiovascular disease, for which lung inflammation may be a driving mechanism. The pro-inflammatory cytokine, tumor necrosis factor (TNF) has been suggested to have a key-role in particle-induced inflammation. We studied the time course of gene expression of inflammatory markers in the lungs of wild type mice and Tnf-/- mice after exposure to diesel exhaust particles (DEPs). Mice were exposed to either a single or multiple doses of DEP by inhalation. We measured the mRNA level of the cytokines Tnf and interleukin-6 (Il-6) and the chemokines, monocyte chemoattractant protein (Mcp-1), macrophage inflammatory protein-2 (Mip-2) and keratinocyte derived chemokine (Kc) in the lung tissue at different time points after exposure. Results Tnf mRNA expression levels increased late after DEP-inhalation, whereas the expression levels of Il-6, Mcp-1 and Kc increased early. The expression of Mip-2 was independent of TNF if the dose was above a certain level. The expression levels of the cytokines Kc, Mcp-1 and Il-6, were increased in the absence of TNF. Conclusion Our data demonstrate that Tnf is not important in early DEP induced inflammation and rather exerts negative influence on Mcp-1 and Kc mRNA levels. This suggests that other signalling pathways are important, a candidate being one involving Mcp-1. PMID:16504008
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Duska, Frantisek; Fric, Michal; Pazout, Jaroslav; Waldauf, Petr; Tůma, Petr; Pachl, Jan
2008-02-01
We aim to demonstrate that low dose growth hormone (GH) administered in i.v. pulses every 3h is able to normalize IGF-I levels in subjects with prolonged critical illness, after multiple trauma. We also ask whether it is possible to control glycaemia during such a treatment and how alanylglutamine (AG) supplementation influences plasma glutamine concentration. We used a prospective double-blind (group 1 vs. 2), randomized trial with an open-label control arm (group 3). Thirty multiple trauma patients (median age: 36, 42, 46 years) were randomized on day 4 after trauma to receive (group 1, n=10) i.v. AG supplementation (0.3 g/kg day from day 4 till 17) and i.v. GH (0.05 mg/kg day divided into 8 boluses, maximum dose at 3 AM, administered on days 7-17) or AG and placebo (group 2, n=10). Group 3 (n=10) received isocaloric isonitrogenous (proteins 1.5 g/kg day) nutrition without AG. Glycaemia was controlled by i.v. insulin infusion according to a routine protocol. GH treatment caused an increase of IGF-I (from median 169 on day 4 to 493 ng/ml on day 17), IGFBP-3 (from 2.4 to 3.2 microg/ml) and a fall in IGFBP-1 (from 11.5 to 3.1 microg/ml), whilst in both groups 2 and 3 these indices remained unchanged. At the end of the study (day 17) IGF-I and IGFBP-1 differed significantly among groups (p=0.008 resp. p=0.010, Kruskal-Wallis). Plasma glutamine remained below the normal range through the study in all groups (median: 0.18-0.30 mM), but had a tendency to rise in group 2 in contrast with a fall in groups 1 and 3 (NS). Group 1 required more insulin (p<0.01) than did the control group but median glycaemia was only 0.4-0.5 mM higher in group 1 (6.5 mM) than in groups 2 and 3 (6.1 resp. 6.0 mM). GH (0.05 g/kg day) administered in i.v. pulses is able to normalize IGF-I levels in subjects with prolonged critical illness after trauma. During this treatment, the standard dose of AG prevents worsening of plasma glutamine deficiency and glucose control is possible using routine algorithms, but it requires higher insulin doses.
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Williams, Brent A.; Law, Arjun Datt; Routy, Bertrand; denHollander, Neal; Gupta, Vikas; Wang, Xing-Hua; Chaboureau, Amélie; Viswanathan, Sowmya; Keating, Armand
2017-01-01
Background Autologous NK cell therapy can treat a variety of malignancies, but is limited by patient-specific variations in potency and cell number expansion. In contrast, allogeneic NK cell lines can overcome many of these limitations. Cells from the permanent NK-92 line are constitutively activated, lack inhibitory receptors and appear to be safe based on two prior phase I trials. Materials and Methods We conducted a single-center, non-randomized, non-blinded, open-label, Phase I dose-escalation trial of irradiated NK-92 cells in adults with refractory hematological malignancies who relapsed after autologous hematopoietic cell transplantation (AHCT). The objectives were to determine safety, feasibility and evidence of activity. Patients were treated at one of three dose levels (1 × 109 cells/m2, 3 × 109 cells/m2 and 5 × 109 cells/m2), given on day 1, 3 and 5 for a planned total of six monthly cycles. Results Twelve patients with lymphoma or multiple myeloma who relapsed after AHCT for relapsed/refractory disease were enrolled in this trial. The treatment was well tolerated, with minor toxicities restricted to acute infusional events, including fever, chills, nausea and fatigue. Two patients achieved a complete response (Hodgkin lymphoma and multiple myeloma), two patients had minor responses and one had clinical improvement on the trial. Conclusions Irradiated NK-92 cells can be administered at very high doses with minimal toxicity in patients with refractory blood cancers, who had relapsed after AHCT. We conclude that high dose NK-92 therapy is safe, shows some evidence of efficacy in patients with refractory blood cancers and warrants further clinical investigation. PMID:29179517
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Karkhanis, Anushree N; Beveridge, Thomas J R; Blough, Bruce E; Jones, Sara R; Ferris, Mark J
2016-09-01
The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly due in part to the fact that repeated cocaine use results in dysregulation of multiple neurotransmitter systems, including glutamate and dopamine, and an emergence of increased negative affective states and heightening motivation to take cocaine despite negative consequences. We used a combination therapy approach to assess whether modulation of both glutamate and dopamine transmission would reduce the motivation to self- administer cocaine compared to modulation of either system alone. The metabotropic glutamate 2/3 receptor agonist, LY379268, and the monoamine releaser, phenmetrazine, were used to assess their individual and combined ability to decrease the reinforcing efficacy of cocaine because they modulate glutamate and dopamine levels, respectively. Cocaine breakpoints and cocaine intake was assessed, using a progressive ratio schedule, at baseline in three groups based on dose of cocaine (0.19, 0.38, 0.75mg/kg/infusion), and following LY379268 (0.03 or 0.30mg/kg; i.p.), phenmetrazine (25mg/kg/day; osmotic minipump), and a combination of the two drugs. LY379268 and phenmetrazine alone reduced breakpoints for all doses of cocaine. The combination of the two drugs showed a concerted effect in reducing breakpoints for all doses of cocaine, with the lowest dose of cocaine reduced by as much as 70%. These data support combination therapy of dopamine and glutamate systems as an effective means to reduce the motivation to take cocaine since a combination of drugs can address neurobiological dysfunction in multiple neurotransmitter systems compared to therapies using single drugs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
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Soffritti, Morando; Belpoggi, Fiorella; Manservigi, Marco; Tibaldi, Eva; Lauriola, Michelina; Falcioni, Laura; Bua, Luciano
2010-12-01
Aspartame (APM) is a well-known intense artificial sweetener used in more than 6,000 products. Among the major users of aspartame are children and women of childbearing age. In previous lifespan experiments conducted on Sprague-Dawley rats we have shown that APM is a carcinogenic agent in multiple sites and that its effects are increased when exposure starts from prenatal life. The aim of this study is to evaluate the potential of APM to induce carcinogenic effects in mice. Six groups of 62-122 male and female Swiss mice were treated with APM in feed at doses of 32,000, 16,000, 8,000, 2,000, or 0 ppm from prenatal life (12 days of gestation) until death. At death each animal underwent complete necropsy and all tissues and organs of all animals in the experiment were microscopically examined. APM in our experimental conditions induces in males a significant dose-related increased incidence of hepatocellular carcinomas (P < 0.01), and a significant increase at the dose levels of 32,000 ppm (P < 0.01) and 16,000 ppm (P < 0.05). Moreover, the results show a significant dose-related increased incidence of alveolar/bronchiolar carcinomas in males (P < 0.05), and a significant increase at 32,000 ppm (P < 0.05). The results of the present study confirm that APM is a carcinogenic agent in multiple sites in rodents, and that this effect is induced in two species, rats (males and females) and mice (males). No carcinogenic effects were observed in female mice. Am. J. Ind. Med. 53:1197-1206, 2010. © 2010 Wiley-Liss, Inc.
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An, Guohua; Liu, Wei; Duan, W Rachel; Nothaft, Wolfram; Awni, Walid; Dutta, Sandeep
2015-03-01
ABT-639 is a selective T-type calcium channel blocker with efficacy in a wide range of preclinical models of nociceptive and neuropathic pain. In the current first-in-human (FIH) study, the pharmacokinetics, tolerability, and safety of ABT-639 after single- (up to 170 mg) and multiple doses (up to 160 mg BID) were evaluated in healthy volunteers in a randomized, double-blinded, placebo-controlled manner. ABT-639 demonstrated acceptable safety and pharmacokinetic profiles in human. Results from assessment of the routine laboratory variables showed an unexpected statistically significant and clinically relevant decrease in blood uric acid with the increase in ABT-639 dose, which is possibly due to inhibition in URAT1 transporter. Pharmacokinetic/pharmacodynamic models were constructed to characterize the relationship between ABT-639 exposure and uric acid response. The final model was a mechanism-based indirect response pharmacodynamic model with the stimulation of uric acid elimination by ABT-639. The model estimated K in values in males and females were 10.2 and 7.13 μmol/h, respectively. The model estimated K out was 0.033 1/h. ABT-639 concentration that can produce 50% stimulation in uric acid elimination was estimated to be 8,070 ng/mL. Based on the final model, further simulations were conducted to predict the effect of ABT-639 on uric acid in gout patients. The simulation results indicated that, if the urate-lowering response to ABT-639 in gout patients is similar to that in healthy subjects, ABT-639 BID doses of 140 mg or higher would be expected to provide clinically meaningful lowering of blood uric acid levels below the 380 μmol/L solubility limit of monosodium urate.
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Geometrical correction of the e-beam proximity effect for raster scan systems
NASA Astrophysics Data System (ADS)
Belic, Nikola; Eisenmann, Hans; Hartmann, Hans; Waas, Thomas
1999-06-01
Increasing demands on pattern fidelity and CD accuracy in e- beam lithography require a correction of the e-beam proximity effect. The new needs are mainly coming from OPC at mask level and x-ray lithography. The e-beam proximity limits the achievable resolution and affects neighboring structures causing under- or over-exposion depending on the local pattern densities and process settings. Methods to compensate for this unequilibrated does distribution usually use a dose modulation or multiple passes. In general raster scan systems are not able to apply variable doses in order to compensate for the proximity effect. For system of this kind a geometrical modulation of the original pattern offers a solution for compensation of line edge deviations due to the proximity effect. In this paper a new method for the fast correction of the e-beam proximity effect via geometrical pattern optimization is described. The method consists of two steps. In a first step the pattern dependent dose distribution caused by back scattering is calculated by convolution of the pattern with the long range part of the proximity function. The restriction to the long range part result in a quadratic sped gain in computing time for the transformation. The influence of the short range part coming from forward scattering is not pattern dependent and can therefore be determined separately in a second step. The second calculation yields the dose curve at the border of a written structure. The finite gradient of this curve leads to an edge displacement depending on the amount of underground dosage at the observed position which was previously determined in the pattern dependent step. This unintended edge displacement is corrected by splitting the line into segments and shifting them by multiples of the writers address grid to the opposite direction.
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NASA Astrophysics Data System (ADS)
Montillo, Albert; Song, Qi; Das, Bipul; Yin, Zhye
2015-03-01
Parsing volumetric computed tomography (CT) into 10 or more salient organs simultaneously is a challenging task with many applications such as personalized scan planning and dose reporting. In the clinic, pre-scan data can come in the form of very low dose volumes acquired just prior to the primary scan or from an existing primary scan. To localize organs in such diverse data, we propose a new learning based framework that we call hierarchical pictorial structures (HPS) which builds multiple levels of models in a tree-like hierarchy that mirrors the natural decomposition of human anatomy from gross structures to finer structures. Each node of our hierarchical model learns (1) the local appearance and shape of structures, and (2) a generative global model that learns probabilistic, structural arrangement. Our main contribution is twofold. First we embed the pictorial structures approach in a hierarchical framework which reduces test time image interpretation and allows for the incorporation of additional geometric constraints that robustly guide model fitting in the presence of noise. Second we guide our HPS framework with the probabilistic cost maps extracted using random decision forests using volumetric 3D HOG features which makes our model fast to train and fast to apply to novel test data and posses a high degree of invariance to shape distortion and imaging artifacts. All steps require approximate 3 mins to compute and all organs are located with suitably high accuracy for our clinical applications such as personalized scan planning for radiation dose reduction. We assess our method using a database of volumetric CT scans from 81 subjects with widely varying age and pathology and with simulated ultra-low dose cadaver pre-scan data.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Dance-Barnes, Stephanie T.; Kock, Nancy D.; Floyd, Heather S.
2008-08-15
Studies in cell culture have suggested that the level of RAS expression can influence the transformation of cells and the signaling pathways stimulated by mutant RAS expression. However, the levels of RAS expression in vivo appear to be subject to feedback regulation, limiting the total amount of RAS protein that can be expressed. We utilized a bitransgenic mouse lung tumor model that expressed the human Ki-ras{sup G12C} allele in a tetracycline-inducible, lung-specific manner. Treatment for 12 months with 500 {mu}g/ml of doxycycline (DOX) allowed for maximal expression of the human Ki-ras{sup G12C} allele in the lung, and resulted in themore » development of focal hyperplasia and adenomas. We determined if different levels of mutant RAS expression would influence the phenotype of the lung lesions. Treatment with 25, 100 and 500 {mu}g/ml of DOX resulted in dose-dependent increases in transgene expression and tumor multiplicity. Microscopic analysis of the lungs of mice treated with the 25 {mu}g/ml dose of DOX revealed infrequent foci of hyperplasia, whereas mice treated with the 100 and 500 {mu}g/ml doses exhibited numerous hyperplastic foci and also adenomas. Immunohistochemical and RNA analysis of the downstream effector pathways demonstrated that different levels of mutant RAS transgene expression resulted in differences in the expression and/or phosphorylation of specific signaling molecules. Our results suggest that the molecular alterations driving tumorigenesis may differ at different levels of mutant Ki-ras{sup G12C} expression, and this should be taken into consideration when inducible transgene systems are utilized to promote tumorigenesis in mouse models.« less
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SU-F-J-173: Online Replanning for Dose Painting Based On Changing ADC Map of Pancreas Cancer
DOE Office of Scientific and Technical Information (OSTI.GOV)
Ates, O; Ahunbay, E; Erickson, B
Purpose: The introduction of MR-guided radiation therapy (RT), e.g., MR-Linac, would allow dose painting to adapt spatial RT response revealed from MRI data during the RT delivery. The purpose of this study is to investigate the use of an online replanning method to adapt dose painting from the MRI Apparent Diffusion Coefficient (ADC) map acquired during the delivery of RT for pancreatic cancers. Methods: Original dose painting plans were created based on multi-parametric simulation MRI including T1, T2 and ADC, using a treatment planning system (MONACO, Elekta) equipped with an online replanning algorithm (WSO, warm start optimization). Multiple GTVs, identifiedmore » based on various ADC levels were prescribed to different doses ranging from 50–70 Gy with simultaneous integrated boost in 28 fractions. The MRI acquired after RT were used to mimic weekly MRI, on which the changing GTVs, pancreatic head and other organs-at-risk (OAR) (duodenum, stomach, small bowel) were delineated. The adaptive plan was generated by applying WSO algorithm starting from the deformed original plan based on the weekly MRI using a deformable image registration (DIR) software (ADMIRE, Elekta). The online replanning method takes <10 min. including DIR, target delineation, WSO execution and final dose calculation. Standard IGRT repositioning and full-blown reoptimization plans were also generated to compare with the adaptive plans. Results: The online replanning method significantly improved the multiple target coverages and OAR sparing for pancreatic cancers. For example, for a case with two GTVs with prescriptions of 60 and 70 Gy in pancreatic head, V100-GTV70 (the volume covered by 100% of prescription dose for GTV with 70 Gy)/V100-GTV60/V100-CTV50/V45-duodenum were (95.1/22.2/69.5/85.7), (95.0/97.0/98.6/34.3), and (95.0/98.1/100.0/38.7) for the IGRT, adaptive and reoptimization plans, respectively. Conclusion: The introduced online adaptive replanning method can effectively account for interfractional changes including tumor spatial response during MR-guided RT delivery, allowing precise delivery of dose painting. This study was partially supported by Elekta Inc.« less
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Yang, Jia-Ming; Ip, Siu-Po; Xian, Yanfang; Zhao, Ming; Lin, Zhi-Xiu; Yeung, John Hok Keung; Chan, Raphael Chiu Yeung; Lee, Shui-Shan; Che, Chun-Tao
2012-01-01
Sophora flavescens is a Chinese medicinal herb used for the treatment of gastrointestinal hemorrhage, skin diseases, pyretic stranguria and viral hepatitis. In this study the herb-drug interactions between S. flavescens and indinavir, a protease inhibitor for HIV treatment, were evaluated in rats. Concomitant oral administration of Sophora extract (0.158 g/kg or 0.63 g/kg, p.o.) and indinavir (40 mg/kg, p.o.) in rats twice a day for 7 days resulted in a dose-dependent decrease of plasma indinavir concentrations, with 55%–83% decrease in AUC0-∞ and 38%–78% reduction in Cmax. The CL (Clearance)/F (fraction of dose available in the systemic circulation) increased up to 7.4-fold in Sophora-treated rats. Oxymatrine treatment (45 mg/kg, p.o.) also decreased indinavir concentrations, while the ethyl acetate fraction of Sophora extract had no effect. Urinary indinavir (24-h) was reduced, while the fraction of indinavir in faeces was increased after Sophora treatment. Compared to the controls, multiple dosing of Sophora extract elevated both mRNA and protein levels of P-gp in the small intestine and liver. In addition, Sophora treatment increased intestinal and hepatic mRNA expression of CYP3A1, but had less effect on CYP3A2 expression. Although protein levels of CYP3A1 and CYP3A2 were not altered by Sophora treatment, hepatic CYP3A activity increased in the Sophora-treated rats. All available data demonstrated that Sophora flavescens reduced plasma indinavir concentration after multiple concomitant doses, possibly through hepatic CYP3A activity and induction of intestinal and hepatic P-gp. The animal study would be useful for predicting potential interactions between natural products and oral pharmaceutics and understanding the mechanisms prior to human studies. Results in the current study suggest that patients using indinavir might be cautioned in the use of S. flavescens extract or Sophora-derived products. PMID:22359586
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Yang, Jia-Ming; Ip, Siu-Po; Xian, Yanfang; Zhao, Ming; Lin, Zhi-Xiu; Yeung, John Hok Keung; Chan, Raphael Chiu Yeung; Lee, Shui-Shan; Che, Chun-Tao
2012-01-01
Sophora flavescens is a Chinese medicinal herb used for the treatment of gastrointestinal hemorrhage, skin diseases, pyretic stranguria and viral hepatitis. In this study the herb-drug interactions between S. flavescens and indinavir, a protease inhibitor for HIV treatment, were evaluated in rats. Concomitant oral administration of Sophora extract (0.158 g/kg or 0.63 g/kg, p.o.) and indinavir (40 mg/kg, p.o.) in rats twice a day for 7 days resulted in a dose-dependent decrease of plasma indinavir concentrations, with 55%-83% decrease in AUC(0-∞) and 38%-78% reduction in C(max). The CL (Clearance)/F (fraction of dose available in the systemic circulation) increased up to 7.4-fold in Sophora-treated rats. Oxymatrine treatment (45 mg/kg, p.o.) also decreased indinavir concentrations, while the ethyl acetate fraction of Sophora extract had no effect. Urinary indinavir (24-h) was reduced, while the fraction of indinavir in faeces was increased after Sophora treatment. Compared to the controls, multiple dosing of Sophora extract elevated both mRNA and protein levels of P-gp in the small intestine and liver. In addition, Sophora treatment increased intestinal and hepatic mRNA expression of CYP3A1, but had less effect on CYP3A2 expression. Although protein levels of CYP3A1 and CYP3A2 were not altered by Sophora treatment, hepatic CYP3A activity increased in the Sophora-treated rats. All available data demonstrated that Sophora flavescens reduced plasma indinavir concentration after multiple concomitant doses, possibly through hepatic CYP3A activity and induction of intestinal and hepatic P-gp. The animal study would be useful for predicting potential interactions between natural products and oral pharmaceutics and understanding the mechanisms prior to human studies. Results in the current study suggest that patients using indinavir might be cautioned in the use of S. flavescens extract or Sophora-derived products.
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Nakashima, A K; Highsmith, A K; Martone, W J
1987-01-01
In an epidemic of septic arthritis due to Serratia marcescens, the intra-articular injection of contaminated methylprednisolone may have played a key role. The epidemic strain was found in used multiple-dose vials of methylprednisolone and in a canister of cotton balls soaked in benzalkonium chloride. The cotton balls had been used for antisepsis and disinfection. Growth characteristics of the epidemic strain of S. marcescens were compared with those of control strains of S. marcescens which had been obtained from unrelated nosocomial outbreaks. The epidemic strain was able to survive in 1:100 dilutions of benzalkonium chloride and was able to grow to greater than 10(5) CFU/ml in multiple-dose vials of methylprednisoline; control strains could not be recovered after 24 h in the same solutions. The preservative in methylprednisolone is gamma-myristyl picolinium chloride, a compound chemically related to benzalkonium chloride. We speculate that the epidemic strain of S. marcescens, which was resistant to benzalkonium chloride, had cross-resistance to gamma-myristyl picolinium chloride. If the cotton balls were used to disinfect the tops of the multiple-dose vials of methylprednisolone, small numbers of organisms subsequently introduced into the solution could have grown to high concentrations. PMID:3298309
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Georgescu, Walter; Osseiran, Alma; Rojec, Maria; Liu, Yueyong; Bombrun, Maxime; Tang, Jonathan; Costes, Sylvain V.
2015-01-01
Traditionally, the kinetics of DNA repair have been estimated using immunocytochemistry by labeling proteins involved in the DNA damage response (DDR) with fluorescent markers in a fixed cell assay. However, detailed knowledge of DDR dynamics across multiple cell generations cannot be obtained using a limited number of fixed cell time-points. Here we report on the dynamics of 53BP1 radiation induced foci (RIF) across multiple cell generations using live cell imaging of non-malignant human mammary epithelial cells (MCF10A) expressing histone H2B-GFP and the DNA repair protein 53BP1-mCherry. Using automatic extraction of RIF imaging features and linear programming techniques, we were able to characterize detailed RIF kinetics for 24 hours before and 24 hours after exposure to low and high doses of ionizing radiation. High-content-analysis at the single cell level over hundreds of cells allows us to quantify precisely the dose dependence of 53BP1 protein production, RIF nuclear localization and RIF movement after exposure to X-ray. Using elastic registration techniques based on the nuclear pattern of individual cells, we could describe the motion of individual RIF precisely within the nucleus. We show that DNA repair occurs in a limited number of large domains, within which multiple small RIFs form, merge and/or resolve with random motion following normal diffusion law. Large foci formation is shown to be mainly happening through the merging of smaller RIF rather than through growth of an individual focus. We estimate repair domain sizes of 7.5 to 11 µm2 with a maximum number of ~15 domains per MCF10A cell. This work also highlights DDR which are specific to doses larger than 1 Gy such as rapid 53BP1 protein increase in the nucleus and foci diffusion rates that are significantly faster than for spontaneous foci movement. We hypothesize that RIF merging reflects a "stressed" DNA repair process that has been taken outside physiological conditions when too many DSB occur at once. High doses of ionizing radiation lead to RIF merging into repair domains which in turn increases DSB proximity and misrepair. Such finding may therefore be critical to explain the supralinear dose dependence for chromosomal rearrangement and cell death measured after exposure to ionizing radiation. PMID:26107175
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Georgescu, Walter; Osseiran, Alma; Rojec, Maria; ...
2015-06-24
Traditionally, the kinetics of DNA repair have been estimated using immunocytochemistry by labeling proteins involved in the DNA damage response (DDR) with fluorescent markers in a fixed cell assay. However, detailed knowledge of DDR dynamics across multiple cell generations cannot be obtained using a limited number of fixed cell time-points. Here we report on the dynamics of 53BP1 radiation induced foci (RIF) across multiple cell generations using live cell imaging of non-malignant human mammary epithelial cells (MCF10A) expressing histone H2B-GFP and the DNA repair protein 53BP1-mCherry. Using automatic extraction of RIF imaging features and linear programming techniques, we were ablemore » to characterize detailed RIF kinetics for 24 hours before and 24 hours after exposure to low and high doses of ionizing radiation. High-content-analysis at the single cell level over hundreds of cells allows us to quantify precisely the dose dependence of 53BP1 protein production, RIF nuclear localization and RIF movement after exposure to X-ray. Using elastic registration techniques based on the nuclear pattern of individual cells, we could describe the motion of individual RIF precisely within the nucleus. We show that DNA repair occurs in a limited number of large domains, within which multiple small RIFs form, merge and/or resolve with random motion following normal diffusion law. Large foci formation is shown to be mainly happening through the merging of smaller RIF rather than through growth of an individual focus. We estimate repair domain sizes of 7.5 to 11 µm 2 with a maximum number of ~15 domains per MCF10A cell. This work also highlights DDR which are specific to doses larger than 1 Gy such as rapid 53BP1 protein increase in the nucleus and foci diffusion rates that are significantly faster than for spontaneous foci movement. We hypothesize that RIF merging reflects a "stressed" DNA repair process that has been taken outside physiological conditions when too many DSB occur at once. High doses of ionizing radiation lead to RIF merging into repair domains which in turn increases DSB proximity and misrepair. Furthermore, such finding may therefore be critical to explain the supralinear dose dependence for chromosomal rearrangement and cell death measured after exposure to ionizing radiation.« less
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Definitions and outlook targeting x-ray exposure of patients in diagnostic imaging
NASA Astrophysics Data System (ADS)
Regulla, Dieter F.
2011-03-01
Computer tomography (CT) is vital and currently irreplaceable in diagnostic radiology. But CT operates with ionizing radiation which may cause cancer or non-cancer diseases in humans. The degree of radiation impact depends on the dose administered by an investigation. And this is the core issue: Even CT exams executed lege artis, administer doses to patients which by magnitude are far beyond the level of hitherto known doses of conventional film-screen techniques. Patients undergoing one or multiple CT examinations, digital angiographies or interventions will be exposed to effective doses between roughly several mSv and several 100 mSv depending on type and frequency of the diagnostic investigations. From the radiation protection point of view, there is therefore the worldwide problem of formulating firm rules for the control of these high-dose investigations, as dose limits can not be established for reasons of the medical benefit. This makes the difference compared with radiation protection for occupationally exposed persons. What remains is "software", namely "justification" and "optimization". Justification requires balancing the interests between the health benefit and the potential harm of an exam which has to be responsibly executed by the physician himself; therefore the radiologists' associations are in the duty to prepare practicable rules for justification. Optimization again needs a cooperative solution, and that is the establishment of reference doses for diagnostic examinations, to be checked by the technical service of the producers' companies. Experts and authorities have been aware of the high-dose dilemma in diagnostic imaging since long. It is time for the reflection of active solutions and their implementation into practice.
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Chou, Ting-Chao
2006-09-01
The median-effect equation derived from the mass-action law principle at equilibrium-steady state via mathematical induction and deduction for different reaction sequences and mechanisms and different types of inhibition has been shown to be the unified theory for the Michaelis-Menten equation, Hill equation, Henderson-Hasselbalch equation, and Scatchard equation. It is shown that dose and effect are interchangeable via defined parameters. This general equation for the single drug effect has been extended to the multiple drug effect equation for n drugs. These equations provide the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI < 1, = 1, and > 1 indicate synergism, additive effect, and antagonism, respectively. Based on these algorithms, computer software has been developed to allow automated simulation of synergism and antagonism at all dose or effect levels. It displays the dose-effect curve, median-effect plot, combination index plot, isobologram, dose-reduction index plot, and polygonogram for in vitro or in vivo studies. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation or carcinogen and radiation risk assessment, as well as for drug or other entity combinations in a vast field of disciplines of biomedical sciences. In this review, selected examples of applications are given, and step-by-step examples of experimental designs and real data analysis are also illustrated. The merging of the mass-action law principle with mathematical induction-deduction has been proven to be a unique and effective scientific method for general theory development. The median-effect principle and its mass-action law based computer software are gaining increased applications in biomedical sciences, from how to effectively evaluate a single compound or entity to how to beneficially use multiple drugs or modalities in combination therapies.
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Global Gene Expression Profiling in Lung Tissues of Rat Exposed to Lunar Dust Particles
NASA Technical Reports Server (NTRS)
Yeshitla, Samrawit A.; Lam, Chiu-Wing; Kidane, Yared H.; Feiveson, Alan H.; Ploutz-Snyder, Robert; Wu, Honglu; James, John T.; Meyers, Valerie E.; Zhang, Ye
2014-01-01
The Moon's surface is covered by a layer of fine, potential reactive dust. Lunar dust contain about 1-2% respirable very fine dust (less than 3 micrometers). The habitable area of any lunar landing vehicle and outpost would inevitably be contaminated with lunar dust that could pose a health risk. The purpose of the study is to analyze the dynamics of global gene expression changes in lung tissues of rats exposed to lunar dust particles. F344 rats were exposed for 4 weeks (6h/d; 5d/wk) in nose-only inhalation chambers to concentrations of 0 (control air), 2.1, 6.8, 21, and 61 mg/m3 of lunar dust. Animals were euthanized at 1 day and 13 weeks after the last inhalation exposure. After being lavaged, lung tissue from each animal was collected and total RNA was isolated. Four samples of each dose group were analyzed using Agilent Rat GE v3 microarray to profile global gene expression of 44K transcripts. After background subtraction, normalization, and log transformation, t tests were used to compare the mean expression levels of each exposed group to the control group. Correction for multiple testing was made using the method of Benjamini, Krieger, and Yekuteli (1) to control the false discovery rate. Genes with significant changes of at least 1.75 fold were identified as genes of interest. Both low and high doses of lunar dust caused dramatic, dose-dependent global gene expression changes in the lung tissues. However, the responses of lung tissue to low dose lunar dust are distinguished from those of high doses, especially those associated with 61mg/m3 dust exposure. The data were further integrated into the Ingenuity system to analyze the gene ontology (GO), pathway distribution and putative upstream regulators and gene targets. Multiple pathways, functions, and upstream regulators have been identified in response to lunar dust induced damage in the lung tissue.
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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
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Stochastic simulation of radium-223 dichloride therapy at the sub-cellular level
NASA Astrophysics Data System (ADS)
Gholami, Y.; Zhu, X.; Fulton, R.; Meikle, S.; El-Fakhri, G.; Kuncic, Z.
2015-08-01
Radium-223 dichloride (223Ra) is an alpha particle emitter and a natural bone-seeking radionuclide that is currently used for treating osteoblastic bone metastases associated with prostate cancer. The stochastic nature of alpha emission, hits and energy deposition poses some challenges for estimating radiation damage. In this paper we investigate the distribution of hits to cells by multiple alpha particles corresponding to a typical clinically delivered dose using a Monte Carlo model to simulate the stochastic effects. The number of hits and dose deposition were recorded in the cytoplasm and nucleus of each cell. Alpha particle tracks were also visualized. We found that the stochastic variation in dose deposited in cell nuclei (≃ 40%) can be attributed in part to the variation in LET with pathlength. We also found that ≃ 18% of cell nuclei receive less than one sigma below the average dose per cell (≃ 15.4 Gy). One possible implication of this is that the efficacy of cell kill in alpha particle therapy need not rely solely on ionization clustering on DNA but possibly also on indirect DNA damage through the production of free radicals and ensuing intracellular signaling.
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Intrathecal Baclofen Dosing Regimens: A Retrospective Chart Review.
Clearfield, Jacob S; Nelson, Mary Elizabeth S; McGuire, John; Rein, Lisa E; Tarima, Sergey
2016-08-01
To examine dosing patterns in patients receiving baclofen via intrathecal baclofen pumps to assess for common patterns by diagnosis, ambulation ability, and affected limbs distribution. This trial study included 25 patients with baclofen pumps selected from the 356 patients enrolled in our center's baclofen pump program. Selection was done by splitting all patients into diagnostic categories of stroke, multiple sclerosis, traumatic/anoxic brain injury, cerebral palsy, and spinal cord injury, and then, five patients were randomly selected from each diagnosis.A systematic chart review was then conducted for each patient from Jan 1, 2008, through September 16, 2013, to look at factors including mean daily dose at end of study, and among those implanted during the study mean initial stable dose and time to initial stable dose. Analysis of mean daily dose across diagnoses found significant differences, with brain injury, cerebral palsy, and spinal cord injury patients having higher doses while multiple sclerosis and stroke patients required lower doses. Nonambulatory patients strongly trended to have higher daily doses than ambulatory patients. Similar trends of mean initial stable dose being higher in a similar pattern as that of end mean daily dose were seen according to diagnoses and ambulatory status, although statistical significance could not be achieved with the small sample size. Significant differences in dosing were found between diagnoses and trended to differ by ambulatory status at the end of the study, and similar trends could be observed in achieving initial stable dose. © 2015 International Neuromodulation Society.
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Boone, M.D.; Bridges, C.M.; Rothermel, B.B.
2001-01-01
Our objective was to determine how green frogs (Rana clamitans) are affected by multiple exposures to a sublethal level of the carbamate insecticide, carbaryl, in outdoor ponds. Tadpoles were added to 1,000-1 ponds at a low or high density which were exposed to carbaryl 0, 1, 2, or 3 times. Length of the larval period, mass, developmental stage, tadpole survival, and proportion metamorphosed were used to determine treatment effects. The frequency of dosing affected the proportion of green frogs that reached metamorphosis and the developmental stage of tadpoles. Generally, exposure to carbaryl increased rates of metamorphosis and development. The effect of the frequency of carbaryl exposure on development varied with the density treatment; the majority of metamorphs and the most developed tadpoles came from high-density ponds exposed to carbaryl 3 times. This interaction suggests that exposure to carbaryl later in the larval period stimulated metamorphosis, directly or indirectly, under high-density conditions. Our study indicates that exposure to a contaminant can lead to early initiation of metamorphosis and that natural biotic factors can mediate the effects of a contaminant in the environment.
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Tai, Kuo-Feng; Chen, Ding-Shinn; Hwang, Lih-Hwa
2004-01-01
In preclinical studies, tumor cells genetically engineered to secrete cytokines, hereafter referred to as tumor cell vaccines, can often generate systemic antitumor immunity. This study investigated the therapeutic effects of live or irradiated tumor cell vaccines that secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) on established orthotopic liver tumors. Experimental results indicated that two doses (3 x 10(7) cells per dose) of irradiated tumor cell vaccines were therapeutically ineffective, whereas one dose (3 x 10(6) cells) of live tumor cell vaccines caused complete tumor regression. In vivo depletion of CD8+ T cells, but not natural killer cells, restored tumor formation in the live vaccine-treated animals. Additionally, the treatment of cells with live vaccine induced markedly higher levels of cytotoxic T lymphocyte activity than the irradiated vaccines in the draining lymph nodes. The higher levels of cytokine and antigen loads could partly explain the superior antitumor activity of live tumor cell vaccines, but other unidentified mechanisms could also play a role in the early T cell activation in the lymph nodes. A protocol using multiple and higher dosages of irradiated tumor cell vaccines also caused significant regression of liver tumors. These results suggest that the GM-CSF-secreting tumor cell vaccines are highly promising for orthotopic liver tumors if higher levels of immune responses are elicited during early tumor development. Copyright 2004 National Science Council, ROC and S. Karger AG, Basel
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Quercetin does not alter the oral bioavailability of Atorvastatin in rats.
Koritala, Rekha; Challa, Siva Reddy; Ragam, Satheesh Kumar; Geddam, Lal Babu; Venkatesh Reddy Challa, Venkatesh Reddy; Devi, Renuka; Sattenapalli, Srinu; Babu, Narendra
2015-09-01
The study was undertaken to evaluate the effect of Quercetin on the pharmacokinetics of Atorvastatin Calcium. In-vivo Pharmacokinetic studies were performed on rats in a single dose study and multiple dose study. Rats were treated with Quercetin (10 mg/kg) and Atorvastatin Calcium (20 mg/kg) orally and blood samples were collected at (0) pretreatment and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24 hours post treatment. Plasma concentrations of Atorvastatin were estimated by HPLC method. Quercetin treatment did not significantly alter the pharmacokinetic parameters of atorvastatin like AUC(0-24), AUC(0-α) , T(max), C(max) and T(½) in both single dose and multiple dose studies of Atorvastatin Calcium. Quercetin does not alter the oral bioavailability of Atorvastatin Calcium in rats.
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Identifying a maximum tolerated contour in two-dimensional dose-finding
Wages, Nolan A.
2016-01-01
The majority of Phase I methods for multi-agent trials have focused on identifying a single maximum tolerated dose combination (MTDC) among those being investigated. Some published methods in the area have been based on the notion that there is no unique MTDC, and that the set of dose combinations with acceptable toxicity forms an equivalence contour in two dimensions. Therefore, it may be of interest to find multiple MTDC's for further testing for efficacy in a Phase II setting. In this paper, we present a new dose-finding method that extends the continual reassessment method to account for the location of multiple MTDC's. Operating characteristics are demonstrated through simulation studies, and are compared to existing methodology. Some brief discussion of implementation and available software is also provided. PMID:26910586
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Evaluation of the sterility of single-dose medications used in a multiple-dose fashion
Martin, Elizabeth P.; Mukherjee, Jean; Sharp, Claire R.; Sinnott-Stutzman, Virginia B.
2017-01-01
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
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Choi, Yewon; Yoon, Seonghae; Matsumoto, Kyoko; Ohta, Yoshiyasu; Lee, SeungHwan; Yu, Kyung-Sang; Jang, In-Jin
2018-01-01
Telaprevir, a reversible selective inhibitor of viral protease and a potential blocker of viral replication, is indicated for the treatment of hepatitis C virus genotype 1 infection. In this study, the pharmacokinetic profile, safety, and tolerability of telaprevir and the effect of food on telaprevir exposure were evaluated in healthy Korean subjects, and compared with data from a previous study in Japanese male subjects. The single ascending dose study was conducted in 3 dose-based groups (500, 750, and 1,250 mg, six subjects each) in a fasted state. In the multiple dose study, eight subjects in the fed state received 750 mg of telaprevir once on Day 1 and every 8 hours from Day 2 until the morning of Day 6. Serial blood samples for pharmacokinetic analysis were collected for up to 24 hours in the single ascending dose study and for 6 days in the multiple dose study. Individual pharmacokinetic parameters were calculated using a non-compartmental analysis method. Safety and tolerability profiles were evaluated throughout the study. Following multiple administrations of telaprevir, maximum plasma concentrations (C max ), area under the concentration-time curve (AUC 0-8 ), and C trough (concentration at 8 h after drug administration) increased by ~2.41-fold. Compared to fasted state values, mean C max and AUC 0-24 increased by 4.92- and 4.81-fold, respectively, after food intake. The C max and AUC inf of Korean subjects were 26%-34% higher than those of Japanese subjects; however, these differences were not clinically significant. All observed adverse events were mild and there was no discontinuation due to AEs. In conclusion, the telaprevir's pharmacokinetic characteristics were similar in Korean and Japanese subjects. Telaprevir was well tolerated in a single dose of up to 1,250 mg and in multiple doses of 750 mg.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Muralidhar, K Raja; Pangam, S; Kolla, J
2015-06-15
Purpose: To develop a method for verification of dose distribution in a patient during treatment using multiple isocentric Intensity modulated and volumetric modulated arc therapy techniques with portal dosimetry. Methods: Varian True Beam accelerator, equipped with an aS1000 megavoltage electronic portal imaging device (EPID) has an integrated image mode for portal dosimetry (PD). The source-to-imager distance was taken at 150 cm to avoid collision to the table. Fourteen fractions were analyzed for this study. During shift in a single plan from one isocenter to another isocenter, EPID also shifted longitudinally for each field by taking the extent of divergence ofmore » beam into the consideration for EPID distance of 150cm. Patients were given treatment everyday with EPID placed in proper position for each field. Several parameters were obtained by comparing the dose distribution between fractions to fraction. The impact of the intra-fraction and inter-fraction of the patient in combination with isocenter shift of the beams were observed. Results: During treatment, measurements were performed by EPID and were evaluated by the gamma method. Analysis was done between fractions for multiple isocenter treatments. The pass rates of the gamma analysis with a criterion of 3% and 3 mm for the 14 fractions were over 97.8% with good consistency. Whereas maximum gamma exceeded the criteria in few fractions (in<1 cc vol). Average gamma was observed in the criteria of 0.5%. Maximum dose difference and average dose differences were less than 0.22 CU and 0.01 CU for maximum tolerance of 1.0 CU and 0.2 CU respectively. Conclusion: EPID with extended distance is ideal method to verify the multiple isocentric dose distribution in patient during treatment, especially cold and hot spots in junction dose. Verification of shifts as well as the dose differences between each fraction due to inter-fraction and intra-fraction of the patient can be derived.« less
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Hampton, Caryn; Rosa, Raymond; Szeto, Daphne; Forrest, Gail; Campbell, Barry; Kennan, Richard; Wang, Shubing; Huang, Chin-Hu; Gichuru, Loise; Ping, Xiaoli; Shen, Xiaolan; Small, Kersten; Madwed, Jeffrey; Lynch, Joseph J
2017-01-01
Despite the widespread use of the mouse transverse aortic constriction heart failure model, there are no reports on the characterization of the standard-of-care agent carvedilol in this model. Left ventricular pressure overload was produced in mice by transverse aortic constriction between the innominate and left common carotid arteries. Carvedilol was administered at multiple dose levels (3, 10 and 30 mg/kg/day per os ; yielding end-study mean plasma concentrations of 0.002, 0.015 and 0.044 µM, respectively) in a therapeutic design protocol with treatment initiated after the manifestation of left ventricular remodeling at 3 weeks post transverse aortic constriction and continued for 10 weeks. Carvedilol treatment in transverse aortic constriction mice significantly decreased heart rate and left ventricular dP/dt (max) at all dose levels consistent with β-adrenoceptor blockade. The middle dose of carvedilol significantly decreased left ventricular weight, whereas the higher dose decreased total heart, left and right ventricular weight and wet lung weight compared to untreated transverse aortic constriction mice. The higher dose of carvedilol significantly increased cardiac performance as measured by ejection fraction and fractional shortening and decreased left ventricular end systolic volume consistent with the beneficial effect on cardiac function. End-study plasma sST-2 and Gal-3 levels did not differ among sham, transverse aortic constriction control and transverse aortic constriction carvedilol groups. Plasma b rain natriuretic peptide concentrations were elevated significantly in transverse aortic constriction control animals (~150%) compared to shams in association with changes in ejection fraction and heart weight and tended to decrease (~30%, p = 0.10-0.12) with the mid- and high-dose carvedilol treatment. A comparison of carvedilol hemodynamic and structural effects in the mouse transverse aortic constriction model versus clinical use indicates a strong agreement in effect profiles preclinical versus clinical, providing important translational validation for this widely used animal model. The present plasma brain natriuretic peptide biomarker findings support the measurement of plasma natriuretic peptides in the mouse transverse aortic constriction model to extend the translational utility of the model.
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Hampton, Caryn; Rosa, Raymond; Szeto, Daphne; Forrest, Gail; Campbell, Barry; Kennan, Richard; Wang, Shubing; Huang, Chin-Hu; Gichuru, Loise; Ping, Xiaoli; Shen, Xiaolan; Small, Kersten; Madwed, Jeffrey; Lynch, Joseph J
2017-01-01
Introduction: Despite the widespread use of the mouse transverse aortic constriction heart failure model, there are no reports on the characterization of the standard-of-care agent carvedilol in this model. Methods: Left ventricular pressure overload was produced in mice by transverse aortic constriction between the innominate and left common carotid arteries. Carvedilol was administered at multiple dose levels (3, 10 and 30 mg/kg/day per os; yielding end-study mean plasma concentrations of 0.002, 0.015 and 0.044 µM, respectively) in a therapeutic design protocol with treatment initiated after the manifestation of left ventricular remodeling at 3 weeks post transverse aortic constriction and continued for 10 weeks. Results: Carvedilol treatment in transverse aortic constriction mice significantly decreased heart rate and left ventricular dP/dt (max) at all dose levels consistent with β-adrenoceptor blockade. The middle dose of carvedilol significantly decreased left ventricular weight, whereas the higher dose decreased total heart, left and right ventricular weight and wet lung weight compared to untreated transverse aortic constriction mice. The higher dose of carvedilol significantly increased cardiac performance as measured by ejection fraction and fractional shortening and decreased left ventricular end systolic volume consistent with the beneficial effect on cardiac function. End-study plasma sST-2 and Gal-3 levels did not differ among sham, transverse aortic constriction control and transverse aortic constriction carvedilol groups. Plasma brain natriuretic peptide concentrations were elevated significantly in transverse aortic constriction control animals (~150%) compared to shams in association with changes in ejection fraction and heart weight and tended to decrease (~30%, p = 0.10–0.12) with the mid- and high-dose carvedilol treatment. Conclusion: A comparison of carvedilol hemodynamic and structural effects in the mouse transverse aortic constriction model versus clinical use indicates a strong agreement in effect profiles preclinical versus clinical, providing important translational validation for this widely used animal model. The present plasma brain natriuretic peptide biomarker findings support the measurement of plasma natriuretic peptides in the mouse transverse aortic constriction model to extend the translational utility of the model. PMID:28491305
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Dose response relationship in anti-stress gene regulatory networks.
Zhang, Qiang; Andersen, Melvin E
2007-03-02
To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.
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Perumal, P Saravana; Anaswara, P V; Muthuraman, A; Krishan, S
2014-04-01
Diabetes mellitus is major metabolic disorders of carbohydrate metabolism. This leads to alter the multiple organ system. To investigate the antidiabetic and antioxidant effects of the saponin rich aqueous extract of Scoparia dulcis (SRE-SD) using alloxan-induced hyperglycemic rat model. The single dose of alloxan was injected for the induction of diabetes in rats. The SRE-SD and glibenclamide were administered for 15 consecutive days from the 3(rd) day of alloxan administration. Quantity of food and water intake was measured at day 0, and 18. Further, body weight was recorded and blood samples were collected at different time intervals that is, day 0, 3, 8, 13, and 18. The oxidative biomarkers (i.e. thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and nitrite (NO(2-)) levels were also estimated in the serum sample. The SRE-SD showed a remarkable dose and time-dependent changes in alloxan-induced rise in the level of food consumption and water intake, serum glucose level, TBARS, NO(2-) and fall in the level of GSH. Further, significant attenuation was observed at 20 and 30 mg/kg of SRE-SD treated group. These findings demonstrate that SRE-SD has both antidiabetic and antioxidant effects on the experimental model of diabetes in rat.
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BMI levels with MS Bone mineral density levels in adults with multiple sclerosis: a meta-analysis.
Huang, Zhongming; Qi, Yiying; Du, Shaohua; Chen, Guangnan; Yan, Weiqi
2015-01-01
Multiple sclerosis (MS) and osteoporosis (OP) affect a substantial proportion of the population. Accumulating evidence suggests that MS patients are at high risk for OP. We performed a meta-analysis to identify risk factors for lowered bone mineral density (BMD) in MS patients. We searched for articles within the Medline, Embase and Cochrane Library databases, published up to March 2014, pertaining to associations between MS and BMD. A total of 11 studies was included in the meta-analysis. The analysis indicated that MS patients have reduced lumbar spine, femur neck, and hip BMD compared with healthy controls (lumbar spine, standardized mean difference (SMD) = -0.76, 95% CI: -1.07, -0.45; femur neck, SMD = -0.56, 95% CI: -0.84, -0.29; and hip, SMD = -0.62, 95% CI: -0.96, -0.29). Further subgroup analysis revealed that a disease duration of >7 years, total steroid dose during the disease of >15 g, and an Expanded Disability Status Scale (EDSS) score of > 3, increased the risk of reduced BMD in the lumbar spine and femoral neck, but not in the hip. Meta-regression analysis did not explain the heterogeneity in the clinical characteristics or outcome definitions. Our meta-analysis suggests that MS patients have reduced overall BMD compared with healthy controls. Furthermore, disease duration (>7 years), total steroid dose (>15 g), and EDSS score (>3) are risk factors for reduced BMD in MS patients.
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A standalone perfusion platform for drug testing and target validation in micro-vessel networks
Zhang, Boyang; Peticone, Carlotta; Murthy, Shashi K.; Radisic, Milica
2013-01-01
Studying the effects of pharmacological agents on human endothelium includes the routine use of cell monolayers cultivated in multi-well plates. This configuration fails to recapitulate the complex architecture of vascular networks in vivo and does not capture the relationship between shear stress (i.e. flow) experienced by the cells and dose of the applied pharmacological agents. Microfluidic platforms have been applied extensively to create vascular systems in vitro; however, they rely on bulky external hardware to operate, which hinders the wide application of microfluidic chips by non-microfluidic experts. Here, we have developed a standalone perfusion platform where multiple devices were perfused at a time with a single miniaturized peristaltic pump. Using the platform, multiple micro-vessel networks, that contained three levels of branching structures, were created by culturing endothelial cells within circular micro-channel networks mimicking the geometrical configuration of natural blood vessels. To demonstrate the feasibility of our platform for drug testing and validation assays, a drug induced nitric oxide assay was performed on the engineered micro-vessel network using a panel of vaso-active drugs (acetylcholine, phenylephrine, atorvastatin, and sildenafil), showing both flow and drug dose dependent responses. The interactive effects between flow and drug dose for sildenafil could not be captured by a simple straight rectangular channel coated with endothelial cells, but it was captured in a more physiological branching circular network. A monocyte adhesion assay was also demonstrated with and without stimulation by an inflammatory cytokine, tumor necrosis factor-α. PMID:24404058
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Lo, P; Young, S; Kim, H J; Brown, M S; McNitt-Gray, M F
2016-08-01
To investigate the effects of dose level and reconstruction method on density and texture based features computed from CT lung nodules. This study had two major components. In the first component, a uniform water phantom was scanned at three dose levels and images were reconstructed using four conventional filtered backprojection (FBP) and four iterative reconstruction (IR) methods for a total of 24 different combinations of acquisition and reconstruction conditions. In the second component, raw projection (sinogram) data were obtained for 33 lung nodules from patients scanned as a part of their clinical practice, where low dose acquisitions were simulated by adding noise to sinograms acquired at clinical dose levels (a total of four dose levels) and reconstructed using one FBP kernel and two IR kernels for a total of 12 conditions. For the water phantom, spherical regions of interest (ROIs) were created at multiple locations within the water phantom on one reference image obtained at a reference condition. For the lung nodule cases, the ROI of each nodule was contoured semiautomatically (with manual editing) from images obtained at a reference condition. All ROIs were applied to their corresponding images reconstructed at different conditions. For 17 of the nodule cases, repeat contours were performed to assess repeatability. Histogram (eight features) and gray level co-occurrence matrix (GLCM) based texture features (34 features) were computed for all ROIs. For the lung nodule cases, the reference condition was selected to be 100% of clinical dose with FBP reconstruction using the B45f kernel; feature values calculated from other conditions were compared to this reference condition. A measure was introduced, which the authors refer to as Q, to assess the stability of features across different conditions, which is defined as the ratio of reproducibility (across conditions) to repeatability (across repeat contours) of each feature. The water phantom results demonstrated substantial variability among feature values calculated across conditions, with the exception of histogram mean. Features calculated from lung nodules demonstrated similar results with histogram mean as the most robust feature (Q ≤ 1), having a mean and standard deviation Q of 0.37 and 0.22, respectively. Surprisingly, histogram standard deviation and variance features were also quite robust. Some GLCM features were also quite robust across conditions, namely, diff. variance, sum variance, sum average, variance, and mean. Except for histogram mean, all features have a Q of larger than one in at least one of the 3% dose level conditions. As expected, the histogram mean is the most robust feature in their study. The effects of acquisition and reconstruction conditions on GLCM features vary widely, though trending toward features involving summation of product between intensities and probabilities being more robust, barring a few exceptions. Overall, care should be taken into account for variation in density and texture features if a variety of dose and reconstruction conditions are used for the quantification of lung nodules in CT, otherwise changes in quantification results may be more reflective of changes due to acquisition and reconstruction conditions than in the nodule itself.
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Optimized image acquisition for breast tomosynthesis in projection and reconstruction space.
Chawla, Amarpreet S; Lo, Joseph Y; Baker, Jay A; Samei, Ehsan
2009-11-01
Breast tomosynthesis has been an exciting new development in the field of breast imaging. While the diagnostic improvement via tomosynthesis is notable, the full potential of tomosynthesis has not yet been realized. This may be attributed to the dependency of the diagnostic quality of tomosynthesis on multiple variables, each of which needs to be optimized. Those include dose, number of angular projections, and the total angular span of those projections. In this study, the authors investigated the effects of these acquisition parameters on the overall diagnostic image quality of breast tomosynthesis in both the projection and reconstruction space. Five mastectomy specimens were imaged using a prototype tomosynthesis system. 25 angular projections of each specimen were acquired at 6.2 times typical single-view clinical dose level. Images at lower dose levels were then simulated using a noise modification routine. Each projection image was supplemented with 84 simulated 3 mm 3D lesions embedded at the center of 84 nonoverlapping ROIs. The projection images were then reconstructed using a filtered backprojection algorithm at different combinations of acquisition parameters to investigate which of the many possible combinations maximizes the performance. Performance was evaluated in terms of a Laguerre-Gauss channelized Hotelling observer model-based measure of lesion detectability. The analysis was also performed without reconstruction by combining the model results from projection images using Bayesian decision fusion algorithm. The effect of acquisition parameters on projection images and reconstructed slices were then compared to derive an optimization rule for tomosynthesis. The results indicated that projection images yield comparable but higher performance than reconstructed images. Both modes, however, offered similar trends: Performance improved with an increase in the total acquisition dose level and the angular span. Using a constant dose level and angular span, the performance rolled off beyond a certain number of projections, indicating that simply increasing the number of projections in tomosynthesis may not necessarily improve its performance. The best performance for both projection images and tomosynthesis slices was obtained for 15-17 projections spanning an angular are of approximately 45 degrees--the maximum tested in our study, and for an acquisition dose equal to single-view mammography. The optimization framework developed in this framework is applicable to other reconstruction techniques and other multiprojection systems.
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Statistical considerations in the analysis of data from replicated bioassays
USDA-ARS?s Scientific Manuscript database
Multiple-dose bioassay is generally the preferred method for characterizing virulence of insect pathogens. Linear regression of probit mortality on log dose enables estimation of LD50/LC50 and slope, the latter having substantial effect on LD90/95s (doses of considerable interest in pest management)...
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Prado, C; MacVittie, T J; Bennett, A W; Kazi, A; Farese, A M; Prado, K
2017-12-01
A partial-body irradiation model with approximately 2.5% bone marrow sparing (PBI/BM2.5) was established to determine the radiation dose-response relationships for the prolonged and delayed multi-organ effects of acute radiation exposure. Historically, doses reported to the entire body were assumed to be equal to the prescribed dose at some defined calculation point, and the dose-response relationship for multi-organ injury has been defined relative to the prescribed dose being delivered at this point, e.g., to a point at mid-depth at the level of the xiphoid of the non-human primate (NHP). In this retrospective-dose study, the true distribution of dose within the major organs of the NHP was evaluated, and these doses were related to that at the traditional dose-prescription point. Male rhesus macaques were exposed using the PBI/BM2.5 protocol to a prescribed dose of 10 Gy using 6-MV linear accelerator photons at a rate of 0.80 Gy/min. Point and organ doses were calculated for each NHP from computed tomography (CT) scans using heterogeneous density data. The prescribed dose of 10.0 Gy to a point at midline tissue assuming homogeneous media resulted in 10.28 Gy delivered to the prescription point when calculated using the heterogeneous CT volume of the NHP. Respective mean organ doses to the volumes of nine organs, including the heart, lung, bowel and kidney, were computed. With modern treatment planning systems, utilizing a three-dimensional reconstruction of the NHP's CT images to account for the variations in body shape and size, and using density corrections for each of the tissue types, bone, water, muscle and air, accurate determination of the differences in dose to the NHP can be achieved. Dose and volume statistics can be ascertained for any body structure or organ that has been defined using contouring tools in the planning system. Analysis of the dose delivered to critical organs relative to the total-body target dose will permit a more definitive analysis of organ-specific effects and their respective influence in multiple organ injury.
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Söderman, Christina; Johnsson, Åse Allansdotter; Vikgren, Jenny; Norrlund, Rauni Rossi; Molnar, David; Svalkvist, Angelica; Månsson, Lars Gunnar; Båth, Magnus
2016-01-01
The aim of the present study was to investigate the dependency of the accuracy and precision of nodule diameter measurements on the radiation dose level in chest tomosynthesis. Artificial ellipsoid-shaped nodules with known dimensions were inserted in clinical chest tomosynthesis images. Noise was added to the images in order to simulate radiation dose levels corresponding to effective doses for a standard-sized patient of 0.06 and 0.04 mSv. These levels were compared with the original dose level, corresponding to an effective dose of 0.12 mSv for a standard-sized patient. Four thoracic radiologists measured the longest diameter of the nodules. The study was restricted to nodules located in high-dose areas of the tomosynthesis projection radiographs. A significant decrease of the measurement accuracy and intraobserver variability was seen for the lowest dose level for a subset of the observers. No significant effect of dose level on the interobserver variability was found. The number of non-measurable small nodules (≤5 mm) was higher for the two lowest dose levels compared with the original dose level. In conclusion, for pulmonary nodules at positions in the lung corresponding to locations in high-dose areas of the projection radiographs, using a radiation dose level resulting in an effective dose of 0.06 mSv to a standard-sized patient may be possible in chest tomosynthesis without affecting the accuracy and precision of nodule diameter measurements to any large extent. However, an increasing number of non-measurable small nodules (≤5 mm) with decreasing radiation dose may raise some concerns regarding an applied general dose reduction for chest tomosynthesis examinations in the clinical praxis. PMID:26994093
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Söderman, Christina; Johnsson, Åse Allansdotter; Vikgren, Jenny; Norrlund, Rauni Rossi; Molnar, David; Svalkvist, Angelica; Månsson, Lars Gunnar; Båth, Magnus
2016-06-01
The aim of the present study was to investigate the dependency of the accuracy and precision of nodule diameter measurements on the radiation dose level in chest tomosynthesis. Artificial ellipsoid-shaped nodules with known dimensions were inserted in clinical chest tomosynthesis images. Noise was added to the images in order to simulate radiation dose levels corresponding to effective doses for a standard-sized patient of 0.06 and 0.04 mSv. These levels were compared with the original dose level, corresponding to an effective dose of 0.12 mSv for a standard-sized patient. Four thoracic radiologists measured the longest diameter of the nodules. The study was restricted to nodules located in high-dose areas of the tomosynthesis projection radiographs. A significant decrease of the measurement accuracy and intraobserver variability was seen for the lowest dose level for a subset of the observers. No significant effect of dose level on the interobserver variability was found. The number of non-measurable small nodules (≤5 mm) was higher for the two lowest dose levels compared with the original dose level. In conclusion, for pulmonary nodules at positions in the lung corresponding to locations in high-dose areas of the projection radiographs, using a radiation dose level resulting in an effective dose of 0.06 mSv to a standard-sized patient may be possible in chest tomosynthesis without affecting the accuracy and precision of nodule diameter measurements to any large extent. However, an increasing number of non-measurable small nodules (≤5 mm) with decreasing radiation dose may raise some concerns regarding an applied general dose reduction for chest tomosynthesis examinations in the clinical praxis. © The Author 2016. Published by Oxford University Press.
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Reliability of Current Biokinetic and Dosimetric Models for Radionuclides: A Pilot Study
DOE Office of Scientific and Technical Information (OSTI.GOV)
Leggett, Richard Wayne; Eckerman, Keith F; Meck, Robert A.
2008-10-01
This report describes the results of a pilot study of the reliability of the biokinetic and dosimetric models currently used by the U.S. Nuclear Regulatory Commission (NRC) as predictors of dose per unit internal or external exposure to radionuclides. The study examines the feasibility of critically evaluating the accuracy of these models for a comprehensive set of radionuclides of concern to the NRC. Each critical evaluation would include: identification of discrepancies between the models and current databases; characterization of uncertainties in model predictions of dose per unit intake or unit external exposure; characterization of variability in dose per unit intakemore » or unit external exposure; and evaluation of prospects for development of more accurate models. Uncertainty refers here to the level of knowledge of a central value for a population, and variability refers to quantitative differences between different members of a population. This pilot study provides a critical assessment of models for selected radionuclides representing different levels of knowledge of dose per unit exposure. The main conclusions of this study are as follows: (1) To optimize the use of available NRC resources, the full study should focus on radionuclides most frequently encountered in the workplace or environment. A list of 50 radionuclides is proposed. (2) The reliability of a dose coefficient for inhalation or ingestion of a radionuclide (i.e., an estimate of dose per unit intake) may depend strongly on the specific application. Multiple characterizations of the uncertainty in a dose coefficient for inhalation or ingestion of a radionuclide may be needed for different forms of the radionuclide and different levels of information of that form available to the dose analyst. (3) A meaningful characterization of variability in dose per unit intake of a radionuclide requires detailed information on the biokinetics of the radionuclide and hence is not feasible for many infrequently studied radionuclides. (4) The biokinetics of a radionuclide in the human body typically represents the greatest source of uncertainty or variability in dose per unit intake. (5) Characterization of uncertainty in dose per unit exposure is generally a more straightforward problem for external exposure than for intake of a radionuclide. (6) For many radionuclides the most important outcome of a large-scale critical evaluation of databases and biokinetic models for radionuclides is expected to be the improvement of current models. Many of the current models do not fully or accurately reflect available radiobiological or physiological information, either because the models are outdated or because they were based on selective or uncritical use of data or inadequate model structures. In such cases the models should be replaced with physiologically realistic models that incorporate a wider spectrum of information.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Prokic, Vesna, E-mail: vesna.prokic@uniklinik-freiburg.de; Wiedenmann, Nicole; Fels, Franziska
2013-01-01
Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individualmore » brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 {+-} 0.62 Gy and 6.29 {+-} 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 {+-} 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 {+-} 0.7 Gy and 32.7 {+-} 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 {+-} 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.« less
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Bercu, Joel P; Jolly, Robert A; Flagella, Kelly M; Baker, Thomas K; Romero, Pedro; Stevens, James L
2010-12-01
In order to determine a threshold for nongenotoxic carcinogens, the traditional risk assessment approach has been to identify a mode of action (MOA) with a nonlinear dose-response. The dose-response for one or more key event(s) linked to the MOA for carcinogenicity allows a point of departure (POD) to be selected from the most sensitive effect dose or no-effect dose. However, this can be challenging because multiple MOAs and key events may exist for carcinogenicity and oftentimes extensive research is required to elucidate the MOA. In the present study, a microarray analysis was conducted to determine if a POD could be identified following short-term oral rat exposure with two nongenotoxic rodent carcinogens, fenofibrate and methapyrilene, using a benchmark dose analysis of genes aggregated in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) biological processes, which likely encompass key event(s) for carcinogenicity. The gene expression response for fenofibrate given to rats for 2days was consistent with its MOA and known key events linked to PPARα activation. The temporal response from daily dosing with methapyrilene demonstrated biological complexity with waves of pathways/biological processes occurring over 1, 3, and 7days; nonetheless, the benchmark dose values were consistent over time. When comparing the dose-response of toxicogenomic data to tumorigenesis or precursor events, the toxicogenomics POD was slightly below any effect level. Our results suggest that toxicogenomic analysis using short-term studies can be used to identify a threshold for nongenotoxic carcinogens based on evaluation of potential key event(s) which then can be used within a risk assessment framework. Copyright © 2010 Elsevier Inc. All rights reserved.
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Bantseev, Vladimir; Erickson, Rebecca; Leipold, Douglas; Amaya, Caroline; Miller, Paul E; Booler, Helen; Thackaberry, Evan A
The nonclinical toxicology program described here was designed to characterize the safety profile of anti-factor D (AFD; FCFD4514S, lampalizumab) to support intravitreal (ITV) administration in patients with geographic atrophy (GA). The toxicity of AFD was assessed in a single-dose and 6-month repeat-dose study in monkeys at doses up to 10 mg/eye. Toxicity was assessed by clinical ophthalmic examinations, intraocular pressure measurements, ocular photography, electroretinography, fluorescein angiography, optical coherence tomography, and anatomic pathology. Systemic exposure to AFD generally increased with the increase in dose level. The increases in mean maximal concentration and area under the curve values were roughly dose proportional. No accumulation of AFD was observed following 10 doses, and drug exposures were not affected by anti-drug antibodies. AFD was locally and systemically well tolerated in monkeys following ITV doses of up to 10 mg/eye. Ocular effects associated with AFD were limited to transient, reversible, dose-related, aqueous cell responses and injection-related, mild, vitreal cell responses. In the 6-month repeat-dose study, 2 monkeys had a nonspecific immune response to AFD that resulted in severe ocular inflammation, attributed to administration of a heterologous (humanized) protein. The comprehensive toxicology program in monkeys described here was designed to evaluate the safety profile of AFD and to support multiple ITV injections in the clinic. Administration of a heterologous (humanized) protein presents a challenge, and immunogenicity in nonclinical species is not predictive of immunogenicity in humans. Taken together, the results of the nonclinical program described here support the use of AFD in patients with GA.
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Rumpler, M J; Colahan, P; Sams, R A
2014-02-01
A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration. © 2013 John Wiley & Sons Ltd.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Buckley, L; Lambert, C; Nyiri, B
Purpose: To standardize the tube calibration for Elekta XVI cone beam CT (CBCT) systems in order to provide a meaningful estimate of the daily imaging dose and reduce the variation between units in a large centre with multiple treatment units. Methods: Initial measurements of the output from the CBCT systems were made using a Farmer chamber and standard CTDI phantom. The correlation between the measured CTDI and the tube current was confirmed using an Unfors Xi detector which was then used to perform a tube current calibration on each unit. Results: Initial measurements showed measured tube current variations of upmore » to 25% between units for scans with the same image settings. In order to reasonably estimate the imaging dose, a systematic approach to x-ray generator calibration was adopted to ensure that the imaging dose was consistent across all units at the centre and was adopted as part of the routine quality assurance program. Subsequent measurements show that the variation in measured dose across nine units is on the order of 5%. Conclusion: Increasingly, patients receiving radiation therapy have extended life expectancies and therefore the cumulative dose from daily imaging should not be ignored. In theory, an estimate of imaging dose can be made from the imaging parameters. However, measurements have shown that there are large differences in the x-ray generator calibration as installed at the clinic. Current protocols recommend routine checks of dose to ensure constancy. The present study suggests that in addition to constancy checks on a single machine, a tube current calibration should be performed on every unit to ensure agreement across multiple machines. This is crucial at a large centre with multiple units in order to provide physicians with a meaningful estimate of the daily imaging dose.« less
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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.
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Van Eldere, Johan; Mera, Robertino M; Miller, Linda A; Poupard, James A; Amrine-Madsen, Heather
2007-10-01
We investigated the impact of the usage of antibiotics in ambulatory patients in Belgium in 147 defined geographical circumscriptions and at the individual isolate level. The study included 14,448 Streptococcus pneumoniae strains collected by the Belgium national reference lab from 1994 to 2004. Additional risk factors for resistance, such as population density/structure and day care attendance, were investigated for the same time-space window. A statistical model that included resistance to two or more antimicrobial classes offered the best fit for measuring the changes in nonsusceptibility to penicillin, macrolides, and tetracycline over time and place in Belgium. Analysis at the geographic level identified antimicrobial consumption with a 1-year lag (0.5% increase per additional defined daily dose) and population density as independent predictors of multiple resistance. Independent risk factors at the isolate level were age (odds ratio [OR], 1.55 for children aged <5 years), population density (7% increase in multiple resistance per 100 inhabitants/km(2)), conjugate 7-valent vaccine serotype (OR, 14.3), location (OR, 1.55 for regions bordering high-resistance France), and isolate source (OR, 1.54 for ear isolates). The expansion of multiple-resistant strains explains most of the overall twofold increase and subsequent decrease in single antimicrobial resistance between 1994 and 2004. We conclude that factors in addition to antibiotic use, such as high population density and proximity to high-resistance regions, favor multiple resistance. Regional resistance rates are not linearly related to actual antibiotic use but are linked to past antibiotic use plus a combination of demographic and geographic factors.
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Zhao, Xia; Cui, Yimin; Zhao, Shuai; Lang, Benjamin; Broedl, Uli C; Salsali, Afshin; Pinnetti, Sabine; Macha, Sreeraj
2015-07-01
The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties and tolerability of the oral once-daily sodium glucose cotransporter 2 inhibitor empagliflozin, given in single and multiple 10 and 25 mg doses in Chinese patients with type 2 diabetes mellitus (T2DM). In a double-blind, placebo-controlled, parallel-group study, Chinese patients with T2DM were randomly assigned to receive a single dose of empagliflozin 10 or 25 mg or placebo on day 1 and once daily on days 3 to 9. A total of 24 patients were enrolled (14 men, 10 women; median age, 53.5 years; empagliflozin 10 mg, n = 9; empagliflozin 25 mg, n = 9; and placebo, n = 6). After both single- and multiple-dose administration, empagliflozin 10 and 25 mg were rapidly absorbed, reaching peak plasma concentrations within 1 to 1.5 hours (median), with plasma levels declining biphasically. Empagliflozin exposure increased roughly dose proportionally between 10 and 25 mg. Mean terminal elimination half-life values at steady state were 13.9 and 12.1 hours with empagliflozin 10 and 25 mg, respectively. Mean (SD) changes from baseline in 24-hour urinary glucose excretion (UGE) on day 1 were +87.7 (22.9) and +82.8 (18.8) g with empagliflozin 10 and 25 mg, respectively, compared with -1.0 (2.8) g with placebo, and on day 9 were +95.8 (24.1), +82.6 (34.8) g with empagliflozin 10 and 25 mg, respectively, compared with -4.1 (6.4) g with placebo. Mean (SD) changes from baseline in fasting plasma glucose (FPG) on day 2 were -18.7 (17.2) mg/dL and -25.8 (19.6) mg/dL with empagliflozin 10 and 25 mg, respectively, compared with -4.2 (15.2) mg/dL with placebo, and on day 9, were -25.6 (20.7) mg/dL and -31.4 (26.9) mg/dL with empagliflozin 10 and 25 mg, respectively, compared to -3.7 (7.5) mg/dL with placebo. On day 10, mean changes in weight were -1.1, -1.6, and +0.5 kg with empagliflozin 10 and 25 mg and placebo, respectively. Overall, empagliflozin 10 and 25 mg had safety profiles similar to that of placebo. There were no reports of hypoglycemia, urinary tract infections, or genital infections. Results with single and multiple doses of empagliflozin 10 and 25 mg suggest linear pharmacokinetic properties in Chinese patients with T2DM, with a safety profile similar to that of placebo. Empagliflozin treatment was associated with increases in UGE and reductions in FPG compared with placebo. ClinicalTrials.gov identifier: NCT01316341. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.
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Wu, Qixue; Snyder, Karen Chin; Liu, Chang; Huang, Yimei; Zhao, Bo; Chetty, Indrin J; Wen, Ning
2016-09-30
Treatment of patients with multiple brain metastases using a single-isocenter volumetric modulated arc therapy (VMAT) has been shown to decrease treatment time with the tradeoff of larger low dose to the normal brain tissue. We have developed an efficient Projection Summing Optimization Algorithm to optimize the treatment geometry in order to reduce dose to normal brain tissue for radiosurgery of multiple metastases with single-isocenter VMAT. The algorithm: (a) measures coordinates of outer boundary points of each lesion to be treated using the Eclipse Scripting Application Programming Interface, (b) determines the rotations of couch, collimator, and gantry using three matrices about the cardinal axes, (c) projects the outer boundary points of the lesion on to Beam Eye View projection plane, (d) optimizes couch and collimator angles by selecting the least total unblocked area for each specific treatment arc, and (e) generates a treatment plan with the optimized angles. The results showed significant reduction in the mean dose and low dose volume to normal brain, while maintaining the similar treatment plan qualities on the thirteen patients treated previously. The algorithm has the flexibility with regard to the beam arrangements and can be integrated in the treatment planning system for clinical application directly.
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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.
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Bødker, Julie Støve; Christensen, Heidi Søgaard; Johansen, Preben; Nielsen, Søren; Christiansen, Ilse; Bergmann, Olav Jonas; Bøgsted, Martin; Dybkær, Karen; Vyberg, Mogens; Johnsen, Hans Erik
2017-01-01
Background Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. Methods and Findings Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5–6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups. Conclusions Our results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity. PMID:28052121
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DOE Office of Scientific and Technical Information (OSTI.GOV)
McGill, Mitchell R.; Lebofsky, Margitta; Norris, Hye-Ryun K.
2013-06-15
At therapeutic doses, acetaminophen (APAP) is a safe and effective analgesic. However, overdose of APAP is the principal cause of acute liver failure in the West. Binding of the reactive metabolite of APAP (NAPQI) to proteins is thought to be the initiating event in the mechanism of hepatotoxicity. Early work suggested that APAP-protein binding could not occur without glutathione (GSH) depletion, and likely only at toxic doses. Moreover, it was found that protein-derived APAP-cysteine could only be detected in serum after the onset of liver injury. On this basis, it was recently proposed that serum APAP-cysteine could be used asmore » diagnostic marker of APAP overdose. However, comprehensive dose–response and time course studies have not yet been done. Furthermore, the effects of co-morbidities on this parameter have not been investigated. We treated groups of mice with APAP at multiple doses and measured liver GSH and both liver and plasma APAP-protein adducts at various timepoints. Our results show that protein binding can occur without much loss of GSH. Importantly, the data confirm earlier work that showed that protein-derived APAP-cysteine can appear in plasma without liver injury. Experiments performed in vitro suggest that this may involve multiple mechanisms, including secretion of adducted proteins and diffusion of NAPQI directly into plasma. Induction of liver necrosis through ischemia–reperfusion significantly increased the plasma concentration of protein-derived APAP-cysteine after a subtoxic dose of APAP. While our data generally support the measurement of serum APAP-protein adducts in the clinic, caution is suggested in the interpretation of this parameter. - Highlights: • Extensive GSH depletion is not required for APAP-protein binding in the liver. • APAP-protein adducts appear in plasma at subtoxic doses. • Proteins are adducted in the cell and secreted out. • Coincidental liver injury increases plasma APAP-protein adducts at subtoxic doses. • Plasma APAP-protein adducts are diagnostically useful, but interpret with care.« less
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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
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Lack of effect of drinking water barium on cardiovascular risk factors.
Wones, R G; Stadler, B L; Frohman, L A
1990-01-01
Higher cardiovascular mortality has been associated in a single epidemiological study with higher levels of barium in drinking water. The purpose of this study was to determine whether drinking water barium at levels found in some U.S. communities alters the known risk factors for cardiovascular disease. Eleven healthy men completed a 10-week dose-response protocol in which diet was controlled (600 mg cholesterol; 40% fat, 40% carbohydrate, 20% protein; sodium and potassium controlled at the subject's pre-protocol estimated intake). Other aspects of the subjects' lifestyles known to affect cardiac risk factors were controlled, and the barium content (as barium chloride) of the drinking water (1.5 L/day) was varied from 0 (first 2 weeks), to 5 ppm (next 4 weeks), to 10 ppm (last 4 weeks). Multiple blood and urine samples, morning and evening blood pressure measurements, and 48-hr electrocardiographic monitoring were performed at each dose of barium. There were no changes in morning or evening systolic or diastolic blood pressures, plasma cholesterol or lipoprotein or apolipoprotein levels, serum potassium or glucose levels, or urine catecholamine levels. There were no arrhythmias related to barium exposure detected on continuous electrocardiographic monitoring. A trend was seen toward increased total serum calcium levels with exposure to barium, which was of borderline statistical significance and of doubtful clinical significance. In summary, drinking water barium at levels of 5 and 10 ppm did not appear to affect any of the known modifiable cardiovascular risk factors. PMID:2384067
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Proof of concept and dose estimation with binary responses under model uncertainty.
Klingenberg, B
2009-01-30
This article suggests a unified framework for testing Proof of Concept (PoC) and estimating a target dose for the benefit of a more comprehensive, robust and powerful analysis in phase II or similar clinical trials. From a pre-specified set of candidate models, we choose the ones that best describe the observed dose-response. To decide which models, if any, significantly pick up a dose effect, we construct the permutation distribution of the minimum P-value over the candidate set. This allows us to find critical values and multiplicity adjusted P-values that control the familywise error rate of declaring any spurious effect in the candidate set as significant. Model averaging is then used to estimate a target dose. Popular single or multiple contrast tests for PoC, such as the Cochran-Armitage, Dunnett or Williams tests, are only optimal for specific dose-response shapes and do not provide target dose estimates with confidence limits. A thorough evaluation and comparison of our approach to these tests reveal that its power is as good or better in detecting a dose-response under various shapes with many more additional benefits: It incorporates model uncertainty in PoC decisions and target dose estimation, yields confidence intervals for target dose estimates and extends to more complicated data structures. We illustrate our method with the analysis of a Phase II clinical trial. Copyright (c) 2008 John Wiley & Sons, Ltd.
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OCCUPATIONAL RADIATION DOSES TO OPERATORS PERFORMING FLUOROSCOPICALLY-GUIDED PROCEDURES
Kim, Kwang Pyo; Miller, Donald L.; de Gonzalez, Amy Berrington; Balter, Stephen; Kleinerman, Ruth A.; Ostroumova, Evgenia; Simon, Steven L.; Linet, Martha S.
2012-01-01
In the past 30 years, the numbers and types of fluoroscopically-guided (FG) procedures have increased dramatically. The objective of the present study is to provide estimated radiation doses to physician specialists, other than cardiologists, who perform FG procedures. We searched Medline to identify English-language journal articles reporting radiation exposures to these physicians. We then identified several primarily therapeutic FG procedures that met specific criteria: well-defined procedures for which there were at least five published reports of estimated radiation doses to the operator, procedures performed frequently in current medical practice, and inclusion of physicians from multiple medical specialties. These procedures were percutaneous nephrolithotomy (PCNL), vertebroplasty, orthopedic extremity nailing for treatment of fractures, biliary tract procedures, transjugular intrahepatic portosystemic shunt creation (TIPS), head/neck endovascular therapeutic procedures, and endoscopic retrograde cholangiopancreatography (ERCP). We abstracted radiation doses and other associated data, and estimated effective dose to operators. Operators received estimated doses per patient procedure equivalent to doses received by interventional cardiologists. The estimated effective dose per case ranged from 1.7 – 56μSv for PCNL, 0.1 – 101 μSv for vertebroplasty, 2.5 – 88μSv for orthopedic extremity nailing, 2.0 – 46μSv for biliary tract procedures, 2.5 – 74μSv for TIPS, 1.8 – 53μSv for head/neck endovascular therapeutic procedures, and 0.2 – 49μSv for ERCP. Overall, mean operator radiation dose per case measured over personal protective devices at different anatomic sites on the head and body ranged from 19 – 800 (median = 113) μSv at eye level, 6 – 1180 (median = 75)μSv at the neck, and 2 – 1600 (median = 302) μSv at the trunk. Operators’ hands often received greater doses than the eyes, neck or trunk. Large variations in operator doses suggest that optimizing procedure protocols and proper use of protective devices and shields might reduce occupational radiation dose substantially. PMID:22647920
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Widmann, G; Juranek, D; Waldenberger, F; Schullian, P; Dennhardt, A; Hoermann, R; Steurer, M; Gassner, E-M; Puelacher, W
2017-08-01
Dose reduction on CT scans for surgical planning and postoperative evaluation of midface and orbital fractures is an important concern. The purpose of this study was to evaluate the variability of various low-dose and iterative reconstruction techniques on the visualization of orbital soft tissues. Contrast-to-noise ratios of the optic nerve and inferior rectus muscle and subjective scores of a human cadaver were calculated from CT with a reference dose protocol (CT dose index volume = 36.69 mGy) and a subsequent series of low-dose protocols (LDPs I-4: CT dose index volume = 4.18, 2.64, 0.99, and 0.53 mGy) with filtered back-projection (FBP) and adaptive statistical iterative reconstruction (ASIR)-50, ASIR-100, and model-based iterative reconstruction. The Dunn Multiple Comparison Test was used to compare each combination of protocols (α = .05). Compared with the reference dose protocol with FBP, the following statistically significant differences in contrast-to-noise ratios were shown (all, P ≤ .012) for the following: 1) optic nerve: LDP-I with FBP; LDP-II with FBP and ASIR-50; LDP-III with FBP, ASIR-50, and ASIR-100; and LDP-IV with FBP, ASIR-50, and ASIR-100; and 2) inferior rectus muscle: LDP-II with FBP, LDP-III with FBP and ASIR-50, and LDP-IV with FBP, ASIR-50, and ASIR-100. Model-based iterative reconstruction showed the best contrast-to-noise ratio in all images and provided similar subjective scores for LDP-II. ASIR-50 had no remarkable effect, and ASIR-100, a small effect on subjective scores. Compared with a reference dose protocol with FBP, model-based iterative reconstruction may show similar diagnostic visibility of orbital soft tissues at a CT dose index volume of 2.64 mGy. Low-dose technology and iterative reconstruction technology may redefine current reference dose levels in maxillofacial CT. © 2017 by American Journal of Neuroradiology.
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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.
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9 CFR 113.3 - Sampling of biological products.
Code of Federal Regulations, 2013 CFR
2013-01-01
... bacterial vaccines; (iii) Two samples of Coccidiosis Vaccine; (iv) Eighteen samples of Rabies Vaccine...) Twenty-two single-dose or 14 multiple-dose samples of Rabies Vaccine, Killed Virus; (viii) Sixteen single...