Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP).

PubMed

Liu, Albert Y; Yang, Qiyun; Huang, Yong; Bacchetti, Peter; Anderson, Peter L; Jin, Chengshi; Goggin, Kathy; Stojanovski, Kristefer; Grant, Robert; Buchbinder, Susan P; Greenblatt, Ruth M; Gandhi, Monica

2014-01-01

Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. ClinicalTrials.gov NCT00903084.

Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP)

PubMed Central

Liu, Albert Y.; Yang, Qiyun; Huang, Yong; Bacchetti, Peter; Anderson, Peter L.; Jin, Chengshi; Goggin, Kathy; Stojanovski, Kristefer; Grant, Robert; Buchbinder, Susan P.; Greenblatt, Ruth M.; Gandhi, Monica

2014-01-01

Background Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. Methods A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Results Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. Conclusions This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. Trial Registration ClinicalTrials.gov +NCT00903084. PMID:24421901

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors.

PubMed

Wang-Gillam, Andrea; Arnold, Susanne M; Bukowski, Ronald M; Rothenberg, Mace L; Cooper, Wendy; Wang, Kenneth K; Gauthier, Eric; Lockhart, A Craig

2012-02-01

This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels. Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL. A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.

Adequacy of Fixed-Dose Heparin Infusions for Venous Thromboembolism Prevention after Microsurgical Procedures.

PubMed

Bertolaccini, Corinne M; Prazak, Ann Marie B; Agarwal, Jayant; Goodwin, Isak A; Rockwell, W Bradford; Pannucci, Christopher J

2018-05-22

 In microvascular surgery, patients often receive unfractionated heparin infusions to minimize risk for microvascular thrombosis. Patients who receive intravenous (IV) heparin are believed to have adequate prophylaxis against venous thromboembolism (VTE). Whether a fixed dose of IV heparin provides detectable levels of anticoagulation, or whether the "one size fits all" approach provides adequate prophylaxis against VTE remains unknown. This study examined the pharmacodynamics of fixed-dose heparin infusions and the effects of real-time, anti-factor Xa (aFXa) level driven heparin dose adjustments.  This prospective clinical trial recruited adult microvascular surgery patients placed on a fixed-dose (500 units/h) unfractionated heparin infusion during their initial microsurgical procedure. Steady-state aFXa levels, a marker of unfractionated heparin efficacy and safety, were monitored. Patients with out-of-range aFXa levels received protocol-driven real-time dose adjustments. Outcomes of interest included aFXa levels in response to heparin 500 units/h, number of dose adjustments required to achieve goal aFXa levels, time to reach goal aFXa level, and 90-day clinically relevant bleeding and VTE.  Twenty patients were recruited prospectively. None of 20 patients had any detectable level of anticoagulation in response to heparin infusions at 500 units/h. The median number of dose adjustments required to reach goal level was five, and median weight-based dose to reach goal level was 11.8 units/kg/h. Real-time dose adjustments significantly increased the proportion of patients with in-range levels (60 vs. 0%, p  = 0.0001). The 90-day VTE rate was 5% and 90-day clinically relevant bleeding rate was 5%.  Fixed-dose heparin infusions at a rate of 500 units/h do not provide a detectable level of anticoagulation after microsurgical procedures and are insufficient for the majority of patients who require VTE prophylaxis. Weight-based heparin infusions at 10 to 12 units/kg/h deserve future study in patients undergoing microsurgical procedures to increase the proportion of patients receiving adequate VTE prophylaxis. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Phase I Study of Preoperative Chemoradiation With S-1 and Oxaliplatin in Patients With Locally Advanced Resectable Rectal Cancer

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

Hong, Yong Sang; Lee, Jae-Lyun; Park, Jin Hong

Purpose: To perform a Phase I study of preoperative chemoradiation (CRT) with S-1, a novel oral fluoropyrimidine, plus oxaliplatin in patients with locally advanced rectal cancer, to determine the maximum tolerated dose and the recommended dose. Methods and Materials: Radiotherapy was delivered to a total of 45 Gy in 25 fractions and followed by a coned-down boost of 5.4 Gy in 3 fractions. Concurrent chemotherapy consisted of a fixed dose of oxaliplatin (50 mg/m{sup 2}/week) on Days 1, 8, 22, and 29 and escalated doses of S-1 on Days 1-14 and 22-35. The initial dose of S-1 was 50 mg/m{supmore » 2}/day, gradually increasing to 60, 70, and 80 mg/m{sup 2}/day. Surgery was performed within 6 {+-} 2 weeks. Results: Twelve patients were enrolled and tolerated up to Dose Level 4 (3 patients at each dose level) without dose-limiting toxicity. An additional 3 patients were enrolled at Dose Level 4, with 1 experiencing a dose-limiting toxicity of Grade 3 diarrhea. Although maximum tolerated dose was not attained, Dose Level 4 (S-1 80 mg/m{sup 2}/day) was chosen as the recommended dose for further Phase II studies. No Grade 4 toxicity was observed, and Grade 3 toxicities of leukopenia and diarrhea occurred in the same patient (1 of 15, 6.7%). Pathologic complete responses were observed in 2 of 15 patients (13.3%). Conclusions: The recommended dose of S-1 was determined to be 80 mg/m{sup 2}/day when combined with oxaliplatin in preoperative CRT, and a Phase II trial is now ongoing.« less

Serum tocopherol levels in very preterm infants after a single dose of vitamin E at birth.

PubMed

Bell, Edward F; Hansen, Nellie I; Brion, Luc P; Ehrenkranz, Richard A; Kennedy, Kathleen A; Walsh, Michele C; Shankaran, Seetha; Acarregui, Michael J; Johnson, Karen J; Hale, Ellen C; Messina, Lynn A; Crawford, Margaret M; Laptook, Abbot R; Goldberg, Ronald N; Van Meurs, Krisa P; Carlo, Waldemar A; Poindexter, Brenda B; Faix, Roger G; Carlton, David P; Watterberg, Kristi L; Ellsbury, Dan L; Das, Abhik; Higgins, Rosemary D

2013-12-01

Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage. Ninety-three infants <27 weeks' gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-α-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing. Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs. 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels <0.5 mg/dL. A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

A pharmacokinetic comparison of choline magnesium trisalicylate and soluble aspirin.

PubMed

Helliwell, M; Gibson, T; Berry, D; Volans, G

1984-11-01

Claims that twice-daily dosage of choline magnesium trisalicylate (CMT) may alter salicylate disposal kinetics and result in sustained plasma levels were examined. Plasma levels, urine excretion and pharmacokinetics of salicylate were estimated in six men following the recommended twice-daily dose of CMT and a smaller dose of soluble aspirin. The plasma salicylate levels achieved with CMT were lower than those seen in previous studies but this probably reflected differences of methodology. Salicylate levels were not sustained between doses and elimination rates and half-life were similar for both preparations. No major alteration of disposal kinetics could be demonstrated for CMT with the dose used in the present study.

Risk equivalent of exposure versus dose of radiation

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

Bond, V.P.

This report describes a risk analysis study of low-dose irradiation and the resulting biological effects on a cell. The author describes fundamental differences between the effects of high-level exposure (HLE) and low-level exposure (LLE). He stresses that the concept of absorbed dose to an organ is not a dose but a level of effect produced by a particular number of particles. He discusses the confusion between a linear-proportional representation of dose limits and a threshold-curvilinear representation, suggesting that a LLE is a composite of both systems. (TEM)

Dose reduction potential of iterative reconstruction algorithms in neck CTA-a simulation study.

PubMed

Ellmann, Stephan; Kammerer, Ferdinand; Allmendinger, Thomas; Brand, Michael; Janka, Rolf; Hammon, Matthias; Lell, Michael M; Uder, Michael; Kramer, Manuel

2016-10-01

This study aimed to determine the degree of radiation dose reduction in neck CT angiography (CTA) achievable with Sinogram-affirmed iterative reconstruction (SAFIRE) algorithms. 10 consecutive patients scheduled for neck CTA were included in this study. CTA images of the external carotid arteries either were reconstructed with filtered back projection (FBP) at full radiation dose level or underwent simulated dose reduction by proprietary reconstruction software. The dose-reduced images were reconstructed using either SAFIRE 3 or SAFIRE 5 and compared with full-dose FBP images in terms of vessel definition. 5 observers performed a total of 3000 pairwise comparisons. SAFIRE allowed substantial radiation dose reductions in neck CTA while maintaining vessel definition. The possible levels of radiation dose reduction ranged from approximately 34 to approximately 90% and depended on the SAFIRE algorithm strength and the size of the vessel of interest. In general, larger vessels permitted higher degrees of radiation dose reduction, especially with higher SAFIRE strength levels. With small vessels, the superiority of SAFIRE 5 over SAFIRE 3 was lost. Neck CTA can be performed with substantially less radiation dose when SAFIRE is applied. The exact degree of radiation dose reduction should be adapted to the clinical question, in particular to the smallest vessel needing excellent definition.

Icosapent ethyl: Eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies.

PubMed

Bays, Harold E; Ballantyne, Christie M; Doyle, Ralph T; Juliano, Rebecca A; Philip, Sephy

2016-09-01

Icosapent ethyl is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved at a dose of 4g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500mg/dL) hypertriglyceridemia. This post-hoc exploratory analysis examined the relationship of icosapent ethyl dose with EPA concentrations in plasma and red blood cells (RBCs) across 3 clinical studies-a phase 1 pharmacokinetic study in healthy adult volunteers and 2 pivotal phase 3 studies (MARINE and ANCHOR) in adult patients with hypertriglyceridemia-and examined the relationship between EPA levels and TG-lowering effects in MARINE and ANCHOR. In all 3 studies, icosapent ethyl produced dose-dependent increases in the concentrations of EPA in plasma and RBCs. In both MARINE and ANCHOR, these dose-dependent EPA increases correlated with the degree of TG level lowering (all P<0.01). In patients with high TG levels (≥200mg/dL) and treated with icosapent ethyl 4g/day, the end-of-treatment plasma and RBC EPA concentrations were >170μg/mL and>70μg/mL, respectively. These studies support icosapent ethyl as producing predictable dose-dependent pharmacokinetics/pharmacodynamics, with TG level lowering dependent upon icosapent ethyl dose and EPA concentrations in plasma and RBCs. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Rates of Change in Naturalistic Psychotherapy: Contrasting Dose-Effect and Good-Enough Level Models of Change

ERIC Educational Resources Information Center

Baldwin, Scott A.; Berkeljon, Arjan; Atkins, David C.; Olsen, Joseph A.; Nielsen, Stevan L.

2009-01-01

Most research on the dose-effect model of change has combined data across patients who vary in their total dose of treatment and has implicitly assumed that the rate of change during therapy is constant across doses. In contrast, the good-enough level model predicts that rate of change will be related to total dose of therapy. In this study, the…

Dose-response study of sajabalssuk ethanol extract from Artemisia princeps Pampanini on blood glucose in subjects with impaired fasting glucose or mild type 2 diabetes.

PubMed

Choi, Ji-Young; Shin, Su-Kyung; Jeon, Seon-Min; Baek, Nam-In; Chung, Hae-Gon; Jeong, Tae-Sook; Lee, Kyung Tae; Lee, Mi-Kyung; Choi, Myung-Sook

2011-01-01

Previously we reported that an ethanol extract from Artemisia princeps Pampanini lowered blood glucose in db/db mice. Here we report a preliminary study in which the blood glucose-lowering effects of two different doses of sajabalssuk ethanol extract (SBE), containing eupatilin and jaseocidin, were examined in hyperglycemic subjects with fasting blood glucose (FBG) levels of 100-150 mg/dL. Subjects were randomized into four groups: negative control (2,000 mg of lactose /day), positive control (1,140 mg of pinitol/day), low-dose SBE (2,000 mg of SBE/day), and high-dose SBE (4,000 mg of SBE/day). After 8 weeks of supplementation, FBG and glycosylated hemoglobin levels were significantly lowered in low-and high-dose SBE groups compared to the baseline values; high-dose SBE also resulted in significantly lower plasma free fatty acid levels and systolic blood pressure. This study demonstrated that supplementation of 2 g or 4 g of SBE daily can significantly reduce blood glucose in hyperglycemic subjects, although high-dose SBE seemed to be more effective than low-dose SBE for lowering plasma free fatty acid level and systolic blood pressure.

Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis.

PubMed

Shiue, Harn J; Taylor, Maria; Sands, Kara A

2017-10-01

Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. To compare two LEV dosing regimens, daily versus twice-daily (BID), in ESRD patients undergoing HD. Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 ± 6.3, 19.4 ± 5.2, 34.9 ± 4.3 vs 21.1 ± 3.9, 6.9 ± 1.5, 11.9 ± 1.7 µg/mL; P < 0.05). BID post-HD levels were 41.9 ± 4.6% of predialysis levels versus 36.9 ± 7.3% with daily dosing ( P = 0.275). Post-HD dose levels were 81.4±4.3% of predialysis on LEV BID versus 65.7 ± 8.8% on LEV daily ( P = 0.045). No seizures were reported during hospital admission in either group. Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected.

Positron Emission Tomography-Guided, Focal-Dose Escalation Using Intensity-Modulated Radiotherapy for Head and Neck Cancer

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

Madani, Indira; Duthoy, Wim; Derie, Cristina R.N.

2007-05-01

Purpose: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. Methods and Materials: A Phase I clinical trial was designed to escalate the dose limited to the [{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography ({sup 18}F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was appliedmore » for the remaining 22 fractions of 2.16 Gy. Results: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted {sup 18}F-FDG-PET-delineated region. Conclusions: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.« less

Isotretinoin kinetics after 80 to 320 mg oral doses.

PubMed

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.

Determination of cytokine protein levels in oral secretions in patients undergoing radiotherapy for head and neck malignancies

PubMed Central

2012-01-01

Background Cytokines may be elevated in tumor and normal tissues following irradiation. Cytokine expression in these tissues may predict for toxicity or tumor control. The purpose of this pilot study was to determine the feasibility of measuring local salivary cytokine levels using buccal sponges in patients receiving chemo-radiation for head and neck malignancies. Patients and methods 11 patients with epithelial malignancies of the head and neck were recruiting to this study. All patients received radiotherapy to the head and neck region with doses ranging between 60 – 67.5 Gy. Chemotherapy was delivered concurrently with radiation in all patients. Salivary samples were obtained from high dose and low dose regions prior to treatment and at three intervals during treatment for assessment of cytokine levels (IL-4, IL-6, IL-8, IL-10, EGF, MCP-1, TNF-α, and VEGF). Results Cytokine levels were detectable in the salivary samples. Salivary cytokine levels of IL-4, IL-6, IL-8, EGF, MCP-1, TNF- α , and VEGF were higher in the high dose region compared to the low dose region at all time points (p < 0.05). A trend toward an increase in cytokine levels as radiation dose increased was observed for IL-6, IL-8, MCP-1, and TNF-α. Conclusion Assessment of salivary cytokine levels may provide a novel method to follow local cytokine levels during radiotherapy and may provide a mechanism to study cytokine levels in a regional manner. PMID:22537315

Comparing probabilistic and descriptive analyses of time–dose–toxicity relationship for determining no-observed-adverse-effect level in drug development

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

A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer.

PubMed

Fakih, Marwan G; Pendyala, Lakshmi; Fetterly, Gerald; Toth, Karoli; Zwiebel, James A; Espinoza-Delgado, Igor; Litwin, Alan; Rustum, Youcef M; Ross, Mary Ellen; Holleran, Julianne L; Egorin, Merrill J

2009-05-01

We conducted a phase I study to determine the maximum tolerated dose of vorinostat in combination with fixed doses of 5-fluorouracil (FU), leucovorin, and oxaliplatin (FOLFOX). Vorinostat was given orally twice daily for 1 week every 2 weeks. FOLFOX was given on days 4 and 5 of vorinostat. The vorinostat starting dose was 100 mg twice daily. Escalation occurred in cohorts of three to six patients. Pharmacokinetics of vorinostat, FU, and oxaliplatin were studied. Twenty-one patients were enrolled. Thrombocytopenia, neutropenia, gastrointestinal toxicities, and fatigue increased in frequency and severity at higher dose levels of vorinostat. Two of 4 evaluable patients at dose level 4 (vorinostat 400 mg orally twice daily) developed dose-limiting fatigue. One of 10 evaluable patients at dose level 3 (vorinostat 300 mg orally twice daily) had dose-limiting fatigue, anorexia, and dehydration. There were significant relationships between vorinostat dose and the area under the curve on days 1 and 5 (Pearson, < 0.001). The vorinostat area under the curve increased (P = 0.005) and clearance decreased (P = 0.003) on day 5 compared with day 1. The median C(max) of FU at each dose level increased significantly with increasing doses of vorinostat, suggesting a pharmacokinetic interaction between FU and vorinostat. Vorinostat-induced thymidylate synthase (TS) modulation was not consistent; only two of six patients had a decrease in intratumoral TS expression by reverse transcription-PCR. The maximum tolerated dose of vorinostat in combination with FOLFOX is 300 mg orally twice daily x 1 week every 2 weeks. Alternative vorinostat dosing schedules may be needed for optimal down-regulation of TS expression.

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

PubMed

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

2018-01-20

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

Dose validation of PhIP hair level as a biomarker of heterocyclic aromatic amines exposure: a feeding study.

PubMed

Le Marchand, Loïc; Yonemori, Kim; White, Kami K; Franke, Adrian A; Wilkens, Lynne R; Turesky, Robert J

2016-07-01

Hair measurement of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a promising biomarker of exposure to this carcinogen formed in cooked meats. However, the dose relationship between normal range intake and hair levels and the modulating effects of CYP1A2 metabolism and hair melanin need to be evaluated. We conducted a randomized, cross-over feeding study among 41 non-smokers using ground beef cooked to two different levels of doneness, 5 days a week for 1 month. PhIP was measured by liquid chromatography/mass spectrometry in food (mean low dose = 0.72 µg/serving; mean high dose = 2.99 µg/serving), and change in PhIP hair level was evaluated. CYP1A2 activity was assessed in urine with the caffeine challenge test and head hair melanin was estimated by UV spectrophotometry. We observed a strong dose-dependent increase in hair PhIP levels. This increase was highly correlated with dose received (ρ = 0.68, P < 0.0001). CYP1A2 activity and normalizing for hair melanin did not modify the response to the intervention. Consumption of PhIP at doses similar to those in the American diet results in a marked dose-dependent accumulation of PhIP in hair. Hair PhIP levels may be used as a biomarker of dietary exposure in studies investigating disease risk. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Pulmonary Nodule Volumetry at Different Low Computed Tomography Radiation Dose Levels With Hybrid and Model-Based Iterative Reconstruction: A Within Patient Analysis.

PubMed

den Harder, Annemarie M; Willemink, Martin J; van Hamersvelt, Robbert W; Vonken, Evertjan P A; Schilham, Arnold M R; Lammers, Jan-Willem J; Luijk, Bart; Budde, Ricardo P J; Leiner, Tim; de Jong, Pim A

2016-01-01

The aim of the study was to determine the effects of dose reduction and iterative reconstruction (IR) on pulmonary nodule volumetry. In this prospective study, 25 patients scheduled for follow-up of pulmonary nodules were included. Computed tomography acquisitions were acquired at 4 dose levels with a median of 2.1, 1.2, 0.8, and 0.6 mSv. Data were reconstructed with filtered back projection (FBP), hybrid IR, and model-based IR. Volumetry was performed using semiautomatic software. At the highest dose level, more than 91% (34/37) of the nodules could be segmented, and at the lowest dose level, this was more than 83%. Thirty-three nodules were included for further analysis. Filtered back projection and hybrid IR did not lead to significant differences, whereas model-based IR resulted in lower volume measurements with a maximum difference of -11% compared with FBP at routine dose. Pulmonary nodule volumetry can be accurately performed at a submillisievert dose with both FBP and hybrid IR.

Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study.

PubMed

Dellinger, Ryan W; Santos, Santiago Roel; Morris, Mark; Evans, Mal; Alminana, Dan; Guarente, Leonard; Marcotulli, Eric

2017-01-01

NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD +) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD + in whole blood demonstrated that NRPT significantly increases the concentration of NAD + in a dose-dependent manner. NAD + levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD + levels was sustained throughout the entire 8-week trial. NAD + levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD + levels sustainably.

Effect of ketoconazole on cyclosporine dose in healthy dogs.

PubMed

Dahlinger, J; Gregory, C; Bea, J

1998-01-01

To determine the degree to which the dose of oral cyclosporine (CyA), in healthy dogs, can be decreased by concurrent oral administration of ketoconazole. Dogs in this study were observed for physical or biochemical side effects that might have been caused by the administration of CyA and ketoconazole. Prospective research study. Five healthy, intact female Beagle dogs. CyA was administered orally twice daily to achieve stable whole blood trough levels of 400 to 600 ng/mL. Ketoconazole was added at a low therapeutic dose (average dose: 13.6 mg/kg/d) then at a subtherapeutic dose (average dose: 4.7 mg/kg/d). CyA whole blood trough levels were monitored every 3 to 4 days and maintained at 400 to 600 ng/mL by adjusting CyA doses accordingly. Physical examination, CBC, biochemical profile, and urinalysis were performed at 2-week intervals throughout the study period. The initial mean dose of CyA required to achieve target blood levels was 14.5 mg/ kg/d. With concurrent ketoconazole (low therapeutic dose, average dose: 13.6 mg/kg/d) and CyA administration, the CyA dose declined to 3.4 mg/kg/day (range: 1.2 to 5.2 mg/kg/d), representing a 75% reduction in CyA dose and monetary savings of 57.8%. At a subtherapeutic dose of ketoconazole (average dose: 4.7 mg/kg/d), combination therapy resulted in a CyA dose of 10.1 mg/kg/day (4.9 to 10.6 mg/kg/d), representing a 38% reduction in CyA dose and monetary savings of 23.8%. Weight loss and transient hypoalbuminemia of unknown clinical significance were observed. Other physical and biochemical evaluations were unremarkable over the 12-week study period. The oral administration of ketoconazole can be used to reduce substantially the oral CyA dose needed to maintain selected blood levels in healthy dogs. The oral administration of ketoconazole can result in substantial cost savings to owners of dogs receiving CyA after renal allograft transplantation or for the treatment of autoimmune disease.

Nonclinical pharmacokinetic and pharmacodynamic characterisation of somapacitan: A reversible non-covalent albumin-binding growth hormone.

PubMed

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.

Phase I/II study of erlotinib, carboplatin, pemetrexed, and bevacizumab in chemotherapy-naïve patients with advanced non-squamous non-small cell lung cancer harboring epidermal growth factor receptor mutation

PubMed Central

Kurata, Takayasu; Nakaya, Aya; Yokoi, Takashi; Niki, Maiko; Kibata, Kayoko; Takeyasu, Yuki; Torii, Yoshitaro; Katashiba, Yuichi; Ogata, Makoto; Miyara, Takayuki; Nomura, Shosaku

2017-01-01

Background Epidermal growth factor receptor tyrosine kinase inhibitors significantly prolong the progression-free survival of patients with non-squamous non-small cell lung cancer (NSCLC). However, most patients develop tumor regrowth and their prognosis remains poor. A new treatment strategy for NSCLC harboring EGFR mutation is therefore necessary. Methods In phase I, eligible patients were administered oral erlotinib daily and intravenous pemetrexed, carboplatin, and bevacizumab every 3 weeks for four cycles with maintenance of pemetrexed and bevacizumab until progressive disease was observed. The dose of erlotinib was 100 mg for dose level 1 and 150 mg for dose level 2. The doses of pemetrexed, carboplatin, and bevacizumab were fixed at 500 mg/m2, area under the concentration–time curve of 6 mg/mL · min, and 15 mg/kg, respectively. The dose-limiting toxicities were grade 3/4 neutropenia with fever or infection, grade 4 leukopenia lasting for ≥7 days, grade 4 thrombocytopenia, grade 3/4 uncontrollable nonhematological toxicity, and delayed administration of the subsequent cycle by >2 weeks because of adverse events. Results Six patients were enrolled in phase I (dose level 1, n = 3; dose level 2, n = 3). During the induction phase, grade 3 neutropenia without fever was observed in one patient at dose level 1 and two patients at dose level 2. Grade 3 anemia was reported in one patient at dose level 1 and grade 3 thrombocytopenia was reported in two patients at dose level 1 and dose level 2, respectively. Conclusion Four-drug combination therapy is a feasible and promising. PMID:28740574

The maximum single dose of resistant maltodextrin that does not cause diarrhea in humans.

PubMed

Kishimoto, Yuka; Kanahori, Sumiko; Sakano, Katsuhisa; Ebihara, Shukuko

2013-01-01

The objective of the present study was to determine the maximum dose of resistant maltodextrin (Fibersol)-2, a non-viscous water-soluble dietary fiber), that does not induce transitory diarrhea. Ten healthy adult subjects (5 men and 5 women) ingested Fibersol-2 at increasing dose levels of 0.7, 0.8, 0.9, 1.0, and 1.1 g/kg body weight (bw). Each administration was separated from the previous dose by an interval of 1 wk. The highest dose level that did not cause diarrhea in any subject was regarded as the maximum non-effective level for a single dose. The results showed that no subject of either sex experienced diarrhea at dose levels of 0.7, 0.8, 0.9, or 1.0 g/kg bw. At the highest dose level of 1.1 g/kg bw, no female subject experienced diarrhea, whereas 1 male subject developed diarrhea with muddy stools 2 h after ingestion of the test substance. Consequently, the maximum non-effective level for a single dose of the resistant maltodextrin Fibersol-2 is 1.0 g/kg bw for men and >1.1 g/kg bw for women. Gastrointestinal symptoms were gurgling sounds in 4 subjects (7 events) and flatus in 5 subjects (9 events), although no association with dose level was observed. These symptoms were mild and transient and resolved without treatment.

A Phase I Study of Triapine® in Combination with Doxorubicin in Patients with Advanced Solid Tumors

PubMed Central

Schelman, William R.; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M.; Ivy, Percy; Wilding, George; Traynor, Anne M.

2011-01-01

Purpose To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine® administered in combination with doxorubicin. Study Design Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine® IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m2 and Triapine® 25 mg/m2. PK analysis was performed at various time-points before and after treatment. Results Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m2, Triapine® 45 mg/m2), 2 patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional 3 patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m2) with Triapine® 45 mg/m2. The 2 patients enrolled on this level had 2 DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine® were reduced to 45 mg/m2 and 25 mg/m2, respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Conclusions Pretreated patients with advanced malignancies can tolerate the combination of Triapine® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m2 on day 1 and Triapine® 25 mg/m2 on days 1-4 of a 21 day cycle. PMID:19082825

A comprehensive study on the relationship between the image quality and imaging dose in low-dose cone beam CT

NASA Astrophysics Data System (ADS)

Yan, Hao; Cervino, Laura; Jia, Xun; Jiang, Steve B.

2012-04-01

While compressed sensing (CS)-based algorithms have been developed for the low-dose cone beam CT (CBCT) reconstruction, a clear understanding of the relationship between the image quality and imaging dose at low-dose levels is needed. In this paper, we qualitatively investigate this subject in a comprehensive manner with extensive experimental and simulation studies. The basic idea is to plot both the image quality and imaging dose together as functions of the number of projections and mAs per projection over the whole clinically relevant range. On this basis, a clear understanding of the tradeoff between the image quality and imaging dose can be achieved and optimal low-dose CBCT scan protocols can be developed to maximize the dose reduction while minimizing the image quality loss for various imaging tasks in image-guided radiation therapy (IGRT). Main findings of this work include (1) under the CS-based reconstruction framework, image quality has little degradation over a large range of dose variation. Image quality degradation becomes evident when the imaging dose (approximated with the x-ray tube load) is decreased below 100 total mAs. An imaging dose lower than 40 total mAs leads to a dramatic image degradation, and thus should be used cautiously. Optimal low-dose CBCT scan protocols likely fall in the dose range of 40-100 total mAs, depending on the specific IGRT applications. (2) Among different scan protocols at a constant low-dose level, the super sparse-view reconstruction with the projection number less than 50 is the most challenging case, even with strong regularization. Better image quality can be acquired with low mAs protocols. (3) The optimal scan protocol is the combination of a medium number of projections and a medium level of mAs/view. This is more evident when the dose is around 72.8 total mAs or below and when the ROI is a low-contrast or high-resolution object. Based on our results, the optimal number of projections is around 90 to 120. (4) The clinically acceptable lowest imaging dose level is task dependent. In our study, 72.8 mAs is a safe dose level for visualizing low-contrast objects, while 12.2 total mAs is sufficient for detecting high-contrast objects of diameter greater than 3 mm.

Reference Levels for Patient Radiation Doses in Interventional Radiology: Proposed Initial Values for U.S. Practice1

PubMed Central

Miller, Donald L.; Kwon, Deukwoo; Bonavia, Grant H.

2009-01-01

Purpose: To propose initial values for patient reference levels for fluoroscopically guided procedures in the United States. Materials and Methods: This secondary analysis of data from the Radiation Doses in Interventional Radiology Procedures (RAD-IR) study was conducted under a protocol approved by the institutional review board and was HIPAA compliant. Dose distributions (percentiles) were calculated for each type of procedure in the RAD-IR study where there were data from at least 30 cases. Confidence intervals for the dose distributions were determined by using bootstrap resampling. Weight banding and size correction methods for normalizing dose to patient body habitus were tested. Results: The different methods for normalizing patient radiation dose according to patient weight gave results that were not significantly different (P > .05). The 75th percentile patient radiation doses normalized with weight banding were not significantly different from those that were uncorrected for body habitus. Proposed initial reference levels for various interventional procedures are provided for reference air kerma, kerma-area product, fluoroscopy time, and number of images. Conclusion: Sufficient data exist to permit an initial proposal of values for reference levels for interventional radiologic procedures in the United States. For ease of use, reference levels without correction for body habitus are recommended. A national registry of radiation-dose data for interventional radiologic procedures is a necessary next step to refine these reference levels. © RSNA, 2009 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.2533090354/-/DC1 PMID:19789226

Phase 1 study of ombrabulin in combination with cisplatin (CDDP) in Japanese patients with advanced solid tumors.

PubMed

Takahashi, Shunji; Nakano, Kenji; Yokota, Tomoya; Shitara, Kohei; Muro, Kei; Sunaga, Yoshinori; Ecstein-Fraisse, Evelyne; Ura, Takashi

2016-08-27

In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m 2 ombrabulin with 75 mg/m 2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors. This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m 2 combined with cisplatin 75 mg/m 2 . The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities. Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m 2 with cisplatin 75 mg/m 2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients. Ombrabulin 25 mg/m 2 with cisplatin 75 mg/m 2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Prolactin is a peripheral marker of manganese neurotoxicity

PubMed Central

Marreilha dos Santos, AP; Lopes Santos, M; BatorÉu, Maria C; Aschner, M

2011-01-01

Excessive exposure to Mn induces neurotoxicity, referred to as manganism. Exposure assessment relies on Mn blood and urine analyses, both of which show poor correlation to exposure. Accordingly, there is a critical need for better surrogate biomarkers of Mn exposure. The aim of this study was to examine the relationship between Mn exposure and early indicators of neurotoxicity, with particular emphasis on peripheral biomarkers. Male Wistar rats (180–200 g) were injected intraperitoneally with 4 or 8 doses of Mn (10 mg/kg). Mn exposure was evaluated by analysis of Mn levels in brain and blood along with biochemical end-points (see below). Results Brain Mn levels were significantly increased both after 4 and 8 doses of Mn compared with controls (p<0.001). Blood levels failed to reflect a dose-dependent increase in brain Mn, with only the 8-dose treated group showing significant differences (p<0.001). Brain glutathione (GSH) levels were significantly decreased in the 8-dose-treated animals (p<0.001). A significant and dose-dependent increase in prolactin levels was found for both treated groups (p<0.001) compared to controls. In addition, a decrease in motor activity was observed in the 8-dose-treated group compared to controls. Conclusions 1) The present study demonstrates that peripheral blood level is a poor indicator of Mn brain accumulation and exposure; 2) Mn reduces GSH brain levels, likely reflecting oxidative stress; 3) Mn increases blood prolactin levels, indicating changes in the integrity of the dopaminergic system. Taken together these results suggest that peripheral prolactin levels may serve as reliable predictive biomarkers of Mn neurotoxicity. PMID:21262206

Final report of the 70.2-Gy and 75.6-Gy dose levels of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non-small cell lung cancer.

PubMed

Rosenzweig, K E; Mychalczak, B; Fuks, Z; Hanley, J; Burman, C; Ling, C C; Armstrong, J; Ginsberg, R; Kris, M G; Raben, A; Leibel, S

2000-01-01

Three-dimensional conformal radiotherapy (3D-CRT) is a mode of high-precision radiotherapy designed to increase the tumor dose and decrease the dose to normal tissues. This study reports the final results of the first two dose levels (70.2 Gy and 75.6 Gy) of a phase I dose-escalation study using 3D-CRT for the treatment of non-small cell lung cancer. Fifty-two patients were treated with 3D-CRT without chemotherapy. The median age was 67 years (range, 39-82 years). The majority of patients had locally advanced cancer. Tumor was staged as I/II in 10%, IIIA in 40%, and IIIB in 50%. Radiation was delivered in daily fractions of 1.8 Gy, 5 days a week. A radiation dose level was considered complete when 10 patients received the intended dose without unacceptable acute morbidity. Toxicity was scored according to the Radiation Therapy Oncology Group grading scheme. Twenty patients were initially assigned to the 70.2-Gy level; 14 of them received the intended dose. Three patients experienced severe acute toxicity, two with grade 3 (requiring steroids or oxygen) and a third with grade 5 (fatal) acute radiation pneumonitis. Because of the grade 5 pulmonary toxicity, the protocol was modified, and only patients with a calculated risk of normal tissue complication of less than 25% were eligible for dose escalation. Patients who had a normal tissue complication probability (NTCP) of greater than 25% received a lower dose of radiation. An additional 18 patients were entered on the modified study; 11 of them received 70.2 Gy. One patient experienced grade 3 acute pneumonitis. Despite dose reduction in four patients because of an unacceptably high NTCP, two additional patients developed grade 3 pulmonary toxicity. Fourteen patients were accrued to the 75.6-Gy dose level, and 10 received the intended dose. One of the 10 patients experienced grade 3 pulmonary toxicity and one developed grade 3 esophageal toxicity. Three patients were treated to lower doses as a result of their calculated NTCP without toxicity, and one patient refused treatment. The 2-year local control, disease-free survival, and overall survival rates were 37%, 12%, and 24%, respectively. The median survival time was 11 months. Treatment to 70.2 Gy and 75.6 Gy using 3D-CRT was delivered with acceptable morbidity when NTCP constraints were observed. Local control was encouraging in these patients with locally advanced disease. Patients are currently being accrued to the 81-Gy level of the study.

Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma.

PubMed

Hohloch, Karin; Zeynalova, Samira; Chapuy, Björn; Pfreundschuh, Michael; Loeffler, Markus; Ziepert, Marita; Feller, Alfred C; Trümper, Lorenz; Hasenclever, Dirk; Wulf, Gerald; Schmitz, Norbert

2016-06-01

Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3 %) stopped treatment early. Infections (27 %) and stomatitis (13 %) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33 %, respectively. Overall survival (OS) after 1 and 3 years was 50 and 38 %. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.

Efficacy of two once-daily methylphenidate formulations compared across dose levels at different times of the day: preliminary indications from a secondary analysis of the COMACS study data.

PubMed

Sonuga-Barke, Edmund J S; Swanson, James M; Coghill, David; DeCory, Heleen H; Hatch, Simon J

2004-09-30

Methylphenidate (MPH) is commonly prescribed in the treatment of Attention-Deficit/Hyperactivity Disorder or ADHD. Concerta and Metadate CD are once-daily formulations of MPH using different delivery mechanisms resulting in different pharmacokinetic profiles. A recent study (COMACS) showed that for near-milligram (mg) equivalent daily doses, Metadate CD provides greater symptom control in the morning (1.5 through 4.5 hours post-dose), while Concerta provides greater control in the early evening (12 hours post-dose). Non-inferential comparison of effects for different dose levels of the two formulations suggested that equivalent levels of morning symptom control could be obtained with lower daily doses of Metadate CD than Concerta; the situation being reversed in the evening. The current paper presents a secondary analysis that provides a statistical test of these observations. The COMACS study was a multi-center, double-blind crossover study of Metadate CD, Concerta and placebo with each treatment administered for 1 week. Children were assigned on the basis of their pre-trial dosage to either high (Metadate CD 60 mg; Concerta 54 mg), medium (Metadate CD 40 mg; Concerta 36 mg) or low doses (Metadate CD 20 mg; Concerta 18 mg) of MPH, and attended a laboratory school on the 7th day for assessment at 7 sessions across the day. For the post-hoc comparisons across dose levels presented here, total SKAMP scores with the active treatments (adjusted for placebo response) were analyzed using an analysis of covariance, with a combined measure modeling placebo response across all time period as the covariate. Symptom control from 1.5 through 6.0 hours post-dose was as good with lower doses of Metadate CD (20 and 40 mg) as with higher doses of Concerta (36 and 54 mg, respectively). Lower daily doses of Concerta (18 and 36 mg) and higher doses of Metadate CD (40 and 60 mg, respectively) gave equivalent control at 7.5 and 12 hours with Metadate CD giving better control from1.5 through 6.0 hours post-dose. Different delivery profiles of Metadate CD and Concerta can be exploited to limit total daily exposure to MPH while at the same targeting a specific, especially clinically significant, period of the day. These results need to be confirmed in a study in which children are randomly allocated to different dose levels of the two formulations and plasma MPH concentrations are assessed simultaneously.

First-in-human Phase I study of Pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors

PubMed Central

Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A.; Raynaud, Florence I.; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S.; Kaye, Stan B.; Derynck, Mika K.; Workman, Paul; de Bono, Johann S.

2014-01-01

Purpose This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal tolerated dose (MTD), dose limiting toxicities (DLTs), pharmacokinetics, pharmacodynamics and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent and selective inhibitor of the Class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450mg once-daily, initially on days 1-21 every 28 days and later, utilizing continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma and tumor tissue. Results Pictilisib was well-tolerated. The most common toxicities were grade 1-2 nausea, rash and fatigue while the DLT was grade 3 maculopapular rash (450mg, 2 of 3 patients; 330mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in platelet rich plasma at 3 hours post-dose at the MTD and in tumor at pictilisib doses associated with AUC >20uM.hr. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100mg and signs of antitumor activity. The recommended Phase II dose was continuous dosing at 330mg once-daily. PMID:25370471

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

PubMed

Sarker, Debashis; Ang, Joo Ern; Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A; Raynaud, Florence I; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S; Kaye, Stan B; Derynck, Mika K; Workman, Paul; de Bono, Johann S

2015-01-01

This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. ©2014 American Association for Cancer Research.

Adaptive Dose Painting by Numbers for Head-and-Neck Cancer

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

Duprez, Frederic, E-mail: frederic.duprez@ugent.be; De Neve, Wilfried; De Gersem, Werner

Purpose: To investigate the feasibility of adaptive intensity-modulated radiation therapy (IMRT) using dose painting by numbers (DPBN) for head-and-neck cancer. Methods and Materials: Each patient's treatment used three separate treatment plans: fractions 1-10 used a DPBN ([{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography [{sup 18}F-FDG-PET]) voxel intensity-based IMRT plan based on a pretreatment {sup 18}F-FDG-PET/computed tomography (CT) scan; fractions 11-20 used a DPBN plan based on a {sup 18}F-FDG-PET/CT scan acquired after the eighth fraction; and fractions 21-32 used a conventional (uniform dose) IMRT plan. In a Phase I trial, two dose prescription levels were tested: a median dose of 80.9 Gymore » to the high-dose clinical target volume (CTV{sub highdose}) (dose level I) and a median dose of 85.9 Gy to the gross tumor volume (GTV) (dose level II). Between February 2007 and August 2009, 7 patients at dose level I and 14 patients at dose level II were enrolled. Results: All patients finished treatment without a break, and no Grade 4 acute toxicity was observed. Treatment adaptation (i.e., plans based on the second {sup 18}F-FDG-PET/CT scan) reduced the volumes for the GTV (41%, p = 0.01), CTV{sub highdose} (18%, p = 0.01), high-dose planning target volume (14%, p = 0.02), and parotids (9-12%, p < 0.05). Because the GTV was much smaller than the CTV{sub highdose} and target adaptation, further dose escalation at dose level II resulted in less severe toxicity than that observed at dose level I. Conclusion: To our knowledge, this represents the first clinical study that combines adaptive treatments with dose painting by numbers. Treatment as described above is feasible.« less

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

PubMed Central

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

2004-01-01

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

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs

PubMed Central

Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-01-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day. PMID:25874036

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs.

PubMed

Nam, Chunja; Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-03-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

Experimental study of radiation dose rate at different strategic points of the BAEC TRIGA Research Reactor.

PubMed

Ajijul Hoq, M; Malek Soner, M A; Salam, M A; Haque, M M; Khanom, Salma; Fahad, S M

2017-12-01

The 3MW TRIGA Mark-II Research Reactor of Bangladesh Atomic Energy Commission (BAEC) has been under operation for about thirty years since its commissioning at 1986. In accordance with the demand of fundamental nuclear research works, the reactor has to operate at different power levels by utilizing a number of experimental facilities. Regarding the enquiry for safety of reactor operating personnel and radiation workers, it is necessary to know the radiation level at different strategic points of the reactor where they are often worked. In the present study, neutron, beta and gamma radiation dose rate at different strategic points of the reactor facility with reactor power level of 2.4MW was measured to estimate the rising level of radiation due to its operational activities. From the obtained results high radiation dose is observed at the measurement position of the piercing beam port which is caused by neutron leakage and accordingly, dose rate at the stated position with different reactor power levels was measured. This study also deals with the gamma dose rate measurements at a fixed position of the reactor pool top surface for different reactor power levels under both Natural Convection Cooling Mode (NCCM) and Forced Convection Cooling Mode (FCCM). Results show that, radiation dose rate is higher for NCCM in compared with FCCM and increasing with the increase of reactor power. Thus, concerning the radiological safety issues for working personnel and the general public, the radiation dose level monitoring and the experimental analysis performed within this paper is so much effective and the result of this work can be utilized for base line data and code verification of the nuclear reactor. Copyright © 2017 Elsevier Ltd. All rights reserved.

Characteristics and Dose Levels for Spent Reactor Fuels

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

Coates, Cameron W

2007-01-01

Current guidance considers highly radioactive special nuclear materials to be those materials that, unshielded, emit a radiation dose [rate] measured at 1 m which exceeds 100 rem/h. Smaller, less massive fuel assemblies from research reactors can present a challenge from the point of view of self protection because of their size (lower dose, easier to handle) and the desirability of higher enrichments; however, a follow-on study to cross-compare dose trends of research reactors and power reactors was deemed useful to confirm/verify these trends. This paper summarizes the characteristics and dose levels of spent reactor fuels for both research reactors andmore » power reactors and extends previous studies aimed at quantifying expected dose rates from research reactor fuels worldwide.« less

Hypovitaminosis D in Bariatric Surgery: A Systematic Review of Observational Studies

PubMed Central

Chakhtoura, M; Nakhoul, N; Shawwa, K; Mantzoros, C; El Hajj Fuleihan, G

2016-01-01

Background Obesity is a public health problem that carries global and substantial social and economic burden. Relative to non-surgical interventions, bariatric surgery has the most substantial and lasting impact on weight loss. However, it leads to a number of nutritional deficiencies requiring long term supplementation. Objectives The aims of this paper are to review 25-hydroxyvitamin D [25(OH)D] status pre and post - bariatric surgery, describe the dose response of vitamin D supplementation, and assess the effect of the surgical procedure on 25(OH)D level following supplementation. Methods We searched Medline, PubMed, the Cochrane Library and EMBASE, for relevant observational studies published in English, from 2000–April 2015. The identified references were reviewed, in duplicate and independently, by two reviewers. Results We identified 51 eligible observational studies assessing 25(OH)D status pre and/or post bariatric surgery. Mean pre-surgery 25(OH)D level was below 30 ng/ml in 29 studies and 17 of these studies showed mean 25(OH)D levels ≤ 20 ng/ml. Mean 25(OH)D levels remained below 30 ng/ml following bariatric surgery despite various vitamin D replacement regimens, with only few exceptions. The increase in postoperative 25(OH)D levels tended to parallel increments in vitamin D supplementation dose but varied widely across studies. An increase in 25(OH)D level by 9–13 ng/ml was achieved when vitamin D deficiency was corrected using vitamin D replacement doses of 1,100–7,100 IU/day, in addition to the usual maintenance equivalent daily dose of 400 – 2,000 IU (total equivalent daily dose 1,500–9,150 IU). There was no difference in mean 25(OH)D level following supplementation between malabsorptive/ combination procedures and restrictive procedures. Conclusion Hypovitaminosisis D persists in obese patients undergoing bariatric surgery, despite various vitamin D supplementation regimens. Further research is needed to determine the optimal vitamin D dose to reach desirable 25(OH)D levels in this population, and to demonstrate whether this dose varies according to the surgical procedure. PMID:26805016

Radiation dose distributions due to sudden ejection of cobalt device.

PubMed

Abdelhady, Amr

2016-09-01

The evaluation of the radiation dose during accident in a nuclear reactor is of great concern from the viewpoint of safety. One of important accident must be analyzed and may be occurred in open pool type reactor is the rejection of cobalt device. The study is evaluating the dose rate levels resulting from upset withdrawal of co device especially the radiation dose received by the operator in the control room. Study of indirect radiation exposure to the environment due to skyshine effect is also taken into consideration in order to evaluate the radiation dose levels around the reactor during the ejection trip. Microshield, SHLDUTIL, and MCSky codes were used in this study to calculate the radiation dose profiles during cobalt device ejection trip inside and outside the reactor building. Copyright © 2016 Elsevier Ltd. All rights reserved.

Use of a hybrid iterative reconstruction technique to reduce image noise and improve image quality in obese patients undergoing computed tomographic pulmonary angiography.

PubMed

Kligerman, Seth; Mehta, Dhruv; Farnadesh, Mahmmoudreza; Jeudy, Jean; Olsen, Kathryn; White, Charles

2013-01-01

To determine whether an iterative reconstruction (IR) technique (iDose, Philips Healthcare) can reduce image noise and improve image quality in obese patients undergoing computed tomographic pulmonary angiography (CTPA). The study was Health Insurance Portability and Accountability Act compliant and approved by our institutional review board. A total of 33 obese patients (average body mass index: 42.7) underwent CTPA studies following standard departmental protocols. The data were reconstructed with filtered back projection (FBP) and 3 iDose strengths (iDoseL1, iDoseL3, and iDoseL5) for a total of 132 studies. FBP data were collected from 33 controls (average body mass index: 22) undergoing CTPA. Regions of interest were drawn at 6 identical levels in the pulmonary artery (PA), from the main PA to a subsegmental branch, in both the control group and study groups using each algorithm. Noise and attenuation were measured at all PA levels. Three thoracic radiologists graded each study on a scale of 1 (very poor) to 5 (ideal) by 4 categories: image quality, noise, PA enhancement, and "plastic" appearance. Statistical analysis was performed using an unpaired t test, 1-way analysis of variance, and linear weighted κ. Compared with the control group, there was significantly higher noise with FBP, iDoseL1, and iDoseL3 algorithms (P<0.001) in the study group. There was no significant difference between the noise in the control group and iDoseL5 algorithm in the study group. Analysis within the study group showed a significant and progressive decrease in noise and increase in the contrast-to-noise ratio as the level of IR was increased (P<0.001). Compared with FBP, readers graded overall image quality as being higher using iDoseL1 (P=0.0018), iDoseL3 (P<0.001), and iDoseL5 (P<0.001). Compared with FBP, there was subjective improvement in image noise and PA enhancement with increasing levels of iDose. The use of an IR technique leads to qualitative and quantitative improvements in image noise and image quality in obese patients undergoing CTPA.

Alternative dosing of prophylactic enoxaparin in the trauma patient: is more the answer?

PubMed

Kopelman, Tammy R; O'Neill, Patrick J; Pieri, Paola G; Salomone, Jeffrey P; Hall, Scott T; Quan, Asia; Wells, Jordan R; Pressman, Melissa S

2013-12-01

Inadequate anti-factor Xa levels and increased venous thromboembolic events occur in trauma patients receiving standard prophylactic enoxaparin dosing. The aim of this study was to test the hypothesis that higher dosing (40 mg twice daily) would improve peak anti-Xa levels and decrease venous thromboembolism. A retrospective review was performed of trauma patients who received prophylactic enoxaparin and peak anti-Xa levels over 27 months. Patients were divided on the basis of dose: group A received 30 mg twice daily, and group B received 40 mg twice daily. Demographics and rates of venous thromboembolism were compared between dose groups and patients with inadequate or adequate anti-Xa levels. One hundred twenty-four patients were included, 90 in group A and 34 in group B. Demographics were similar, except that patients in group B had a higher mean body weight. Despite this, only 9% of group B patients had inadequate anti-Xa levels, compared with 33% of those in group A (P = .01). Imaging studies were available in 69 patients and revealed 8 venous thromboembolic events (P = NS, group A vs group B) with significantly more venous thromboembolic events occurring in patients with low anti-Xa levels (P = .02). Although higher dosing of enoxaparin led to improved anti-Xa levels, this did not equate to a statistical decrease in venous thromboembolism. Copyright © 2013 Elsevier Inc. All rights reserved.

Phase I dose escalation study of capecitabine and erlotinib concurrent with radiation in locally advanced pancreatic cancer.

PubMed

Jiang, Yixing; Mackley, Heath B; Kimchi, Eric T; Zhu, Junjia; Gusani, Niraj; Kaifi, Jussuf; Staveley-O'Carroll, Kevin F; Belani, Chandra P

2014-07-01

Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. The median survival of locally advanced nonoperable disease is approximately 9 months. 5-FU-based chemoradiotherapy has been the standard treatment. However, the survival benefit of this approach is modest. To improve the efficacy of 5-FU-based chemoradiation therapy, we evaluated the safety and feasibility of the combination of capecitabine and erlotinib with radiotherapy in this group of patients. A traditional "3 + 3" dose escalation design was adopted in the study. A total of four dose levels were designed. For safety purpose, a minus I dose level (-I) was also planned. The -I level consisted of capecitabine 600 mg/m² and erlotinib 50 mg daily, and the remaining four dose levels were as follows: level I: capecitabine 600 mg/m² bid (twice daily); level II: 700 mg/m² bid; level III: 825 mg/m² bid; and level IV: 925 mg/m² bid. Erlotinib was administered at 100 mg daily at all dose levels. Erlotinib and capceitabine were given continuously Monday through Friday concurrent with radiotherapy (50.4 Gy in 28 fractions). A total of 18 patients were consented. Fifteen patients were enrolled and completed therapy. No dose-limiting toxicity was observed. The most frequent side effects were lymphopenia, nausea, vomiting, diarrhea, electrolyte imbalances, and skin rashes. The majority of the toxicities were grade 1 and 2. No objective response was observed. The median progression-free survival was 0.59 years (95 % CI 0.31-1.1), and the median overall survival was 1.1 years (95 % CI 0.62-1.59). The combination of capecitabine and erlotinib with radiotherapy in locally advanced pancreatic cancer is well tolerated and feasible at the dose level of capecitabine 925 mg/m² bid and erlotinib 100 mg daily.

Dose escalation in permanent brachytherapy for prostate cancer: dosimetric and biological considerations

NASA Astrophysics Data System (ADS)

Li, X. Allen; Wang, Jian Z.; Stewart, Robert D.; Di Biase, Steven J.

2003-09-01

No prospective dose escalation study for prostate brachytherapy (PB) with permanent implants has been reported. In this work, we have performed a dosimetric and biological analysis to explore the implications of dose escalation in PB using 125I and 103Pd implants. The concept of equivalent uniform dose (EUD), proposed originally for external-beam radiotherapy (EBRT), is applied to low dose rate brachytherapy. For a given 125I or 103Pd PB, the EUD for tumour that corresponds to a dose distribution delivered by EBRT is calculated based on the linear quadratic model. The EUD calculation is based on the dose volume histogram (DVH) obtained retrospectively from representative actual patient data. Tumour control probabilities (TCPs) are also determined in order to compare the relative effectiveness of different dose levels. The EUD for normal tissue is computed using the Lyman model. A commercial inverse treatment planning algorithm is used to investigate the feasibility of escalating the dose to prostate with acceptable dose increases in the rectum and urethra. The dosimetric calculation is performed for five representative patients with different prostate sizes. A series of PB dose levels are considered for each patient using 125I and 103Pd seeds. It is found that the PB prescribed doses (minimum peripheral dose) that give an equivalent EBRT dose of 64.8, 70.2, 75.6 and 81 Gy with a fraction size of 1.8 Gy are 129, 139, 150 and 161 Gy for 125I and 103, 112, 122 and 132 Gy for 103Pd implants, respectively. Estimates of the EUD and TCP for a series of possible prescribed dose levels (e.g., 145, 160, 170 and 180 Gy for 125I and 125, 135, 145 and 155 for 103Pd implants) are tabulated. The EUD calculation was found to depend strongly on DVHs and radiobiological parameters. The dosimetric calculations suggest that the dose to prostate can be escalated without a substantial increase in both rectal and urethral dose. For example, increasing the PB prescribed dose from 145 to 180 Gy increases EUD for the rectum by only 3%. Our studies indicate that the dose to urethra can be kept within 100-120% of the prescription dose for all the dose levels studied. In conclusion, dose escalation in permanent implant for localized prostate cancer may be advantageous. It is dosimetrically possible to increase dose to prostate without a substantial increase in the dose to the rectum and urethra. Based on the results of our studies, a prospective dose escalation trial for prostate permanent implants has been initiated at our institution.

Errors and Uncertainties in Dose Reconstruction for Radiation Effects Research

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

Strom, Daniel J.

Dose reconstruction for studies of the health effects of ionizing radiation have been carried out for many decades. Major studies have included Japanese bomb survivors, atomic veterans, downwinders of the Nevada Test Site and Hanford, underground uranium miners, and populations of nuclear workers. For such studies to be credible, significant effort must be put into applying the best science to reconstructing unbiased absorbed doses to tissues and organs as a function of time. In many cases, more and more sophisticated dose reconstruction methods have been developed as studies progressed. For the example of the Japanese bomb survivors, the dose surrogatemore » “distance from the hypocenter” was replaced by slant range, and then by TD65 doses, DS86 doses, and more recently DS02 doses. Over the years, it has become increasingly clear that an equal level of effort must be expended on the quantitative assessment of uncertainty in such doses, and to reducing and managing uncertainty. In this context, this paper reviews difficulties in terminology, explores the nature of Berkson and classical uncertainties in dose reconstruction through examples, and proposes a path forward for Joint Coordinating Committee for Radiation Effects Research (JCCRER) Project 2.4 that requires a reasonably small level of effort for DOSES-2008.« less

Effects of Epoetin Alfa Titration Practices, Implemented After Changes to Product Labeling, on Hemoglobin Levels, Transfusion Use, and Hospitalization Rates.

PubMed

Molony, Julia T; Monda, Keri L; Li, Suying; Beaubrun, Anne C; Gilbertson, David T; Bradbury, Brian D; Collins, Allan J

2016-08-01

Little is known about epoetin alfa (EPO) dosing at dialysis centers after implementation of the US Medicare prospective payment system and revision of the EPO label in 2011. Retrospective cohort study. Approximately 412,000 adult hemodialysis patients with Medicare Parts A and B as primary payer in 2009 to 2012 to describe EPO dosing and hemoglobin patterns; of these, about 70,000 patients clustered in about 1,300 dialysis facilities to evaluate facility-level EPO titration practices and patient-level outcomes in 2012. Facility EPO titration practices when hemoglobin levels were <10 and >11g/dL (grouped treatment variable) determined from monthly EPO dosing and hemoglobin level patterns. Patient mean hemoglobin levels, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates using a facility-based analysis. Monthly EPO dose and hemoglobin level, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates. Monthly EPO doses declined across all hemoglobin levels, with the greatest decline in patients with hemoglobin levels < 10g/dL (July-October 2011). In 2012, nine distinct facility titration practices were identified. Across groups, mean hemoglobin levels differed slightly (10.5-10.8g/dL) but within-patient hemoglobin standard deviations were similar (∼0.68g/dL). Patients at facilities implementing greater dose reductions and smaller dose escalations had lower hemoglobin levels and higher transfusion rates. In contrast, patients at facilities that implemented greater dose escalations (and large or small dose reductions) had higher hemoglobin levels and lower transfusion rates. There were no clinically meaningful differences in all-cause or cause-specific hospitalization events across groups. Possibly incomplete claims data; excluded small facilities and those without consistent titration patterns; hemoglobin levels reported monthly; inferred facility practice from observed dosing. Following prospective payment system implementation and labeling revisions, EPO doses declined significantly. Under the new label, facility EPO titration practices were associated with mean hemoglobin levels (but not standard deviations) and transfusion use, but not hospitalization rates. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Study design and early result of a phase I study of SABR for early-stage glottic cancer.

PubMed

Yu, Tosol; Wee, Chan Woo; Choi, Noorie; Wu, Hong-Gyun; Kang, Hyun-Cheol; Park, Jong Min; Kim, Jung-In; Kim, Jin Ho; Kwon, Tack-Kyun; Chung, Eun-Jae

2018-05-14

Avoidance of organs at risk has become possible with advances in image-guided volumetric-modulated arc therapy (VMAT) techniques. This study was designed to evaluate the safety and feasibility of stereotactic ablative radiotherapy (SABR) for early stage glottic cancer. This report presents the preliminary result of the first and second dose level. Fraction size was increased from 3.5 gray (Gy) (total dose 59.5 Gy) to 9 Gy (total dose 45 Gy). Dose-limiting toxicities were defined as grade 3 or higher treatment-related toxicities. Voice outcome was assessed with electroglottography, and quality of life (QoL) was measured with the Head and Neck Cancer Inventory (HNCI). Seven patients received 59.5 Gy at 3.5 Gy per fraction as the first dose level, and five patients received 55 Gy at 5 Gy per fraction as the second dose level. None of the patients developed grade 3+ toxicity throughout a median follow-up of 17.5 months (range, 1.7-30.6 months). One patient in the second dose level recurred in the primary site at 4 months after radiotherapy (RT) and received total laryngectomy. The rest of participants were disease-free at locoregional and distant sites. Jitter, shimmer, mean phonation time, and noise-to-harmony ratio did not change significantly at 6 months after RT. HNCI scores between pretreatment and posttreatment were not significantly different (P = 0.221). This study revealed acceptable toxicity, voice outcome, and QoL in patients treated with hypofractionated VMAT of 3.5 Gy and 5 Gy per fraction. This phase I study is currently ongoing with a dose of 55 Gy in 11 fractions and 45 Gy in five fractions. 2b. Laryngoscope, 2018. © 2018 The American Laryngological, Rhinological and Otological Society, Inc.

Efficacy and safety of weight-based insulin glargine dose titration regimen compared with glucose level- and current dose-based regimens in hospitalized patients with type 2 diabetes: a randomized, controlled study.

PubMed

Li, Xiaowei; Du, Tao; Li, Wangen; Zhang, Tong; Liu, Haiyan; Xiong, Yifeng

2014-09-01

Insulin glargine is widely used as basal insulin. However, published dose titration regimens for insulin glargine are complex. This study aimed to compare the efficacy and safety profile of a user-friendly, weight-based insulin glargine dose titration regimen with 2 published regimens. A total of 160 hospitalized patients with hyperglycemia in 3 medical centers were screened. Our inclusion criteria included age 18 to 80 years and being conscious. Exclusion criteria included pregnancy or breast-feeding and hepatic or renal dysfunction. A total of 149 patients were randomly assigned to receive weight-based, glucose level-based, or dose-based insulin glargine dose titration regimen between January 2011 and February 2013. The initial dose of insulin glargine was 0.2 U/kg. In the weight-based regimen (n = 49), the dose was titrated by increments of 0.1 U/kg daily. In the glucose level-based regimen (n = 51), the dose was titrated by 2, 4, 6, or 8 U daily when fasting blood glucose (FBG) was, respectively, between 7.0 and 7.9, 8.0 and 8.9, 9.0 and 9.9, or ≥10 mmol/L. In the current dose-based regimen (n = 49), titration was by daily increments of 20% of the current dose. The target FBG in all groups was ≤7.0 mmol/L. The incidence of hypoglycemia was recorded. One-way ANOVA and χ(2) test were used to compare data between the 3 groups. All but 1 patient who required additional oral antidiabetic medication completed the study. The mean (SD) time to achieve target FBG was 3.2 (1.2) days with the weight-based regimen and 3.7 (1.5) days with the glucose level-based regimen (P = 0.266). These times were both shorter than that achieved with the current dose-based regimen (4.8 [2.8] days; P = 0.0001 and P = 0.005, respectively). The daily doses of insulin glargine at the study end point were 0.43 (0.13) U/kg with the weight-based regimen, 0.50 (0.20) U/kg with the glucose level-based regimen, and 0.47 (0.23) U/kg with the current dose-based regimen (P = 0.184). The incidence of hypoglycemia was 4.1%, 2.0%, and 6.3%, respectively (P = 0.557). The currently proposed weight-based insulin glargine dose titration regimen is effective, tolerable, and user-friendly at achieving FBG target levels in hospitalized patients with hyperglycemia. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Alternative chitosan-based EPR dosimeter applicable for a relatively wide range of gamma radiation doses

NASA Astrophysics Data System (ADS)

Piroonpan, Thananchai; Katemake, Pichayada; Panritdam, Eagkapong; Pasanphan, Wanvimol

2017-12-01

Chitosan biopolymer is proposed as an alternative EPR dosimeter. Its ability to be EPR dosimeter was studied in comparison with the conventional alanine, sugars (i.e., glucose and sucrose), formate derivatives (i.e., lithium (Li), magnesium (Mg), and calcium (Ca) formate). Ethylene vinyl acetate (EVA) and paraffin were used as binder for the preparation of composite EPR dosimeter. Dose responses of all materials were investigated in a wide dose range of radiation doses, i.e., low-level (0-1 kGy), medium-level (1-10 kGy) and high-level (10-100 kGy). The EPR dosimeter properties were studied under different parameters, i.e., microwave power, materials contents, absorbed doses, storage conditions and post-irradiation effects. Li-formate showed a simple EPR spectrum and exhibited superior radiation response for low-dose range; whereas chitosan and sucrose exhibited linear dose response in all studied dose ranges. The EPR signals of chitosan exhibited similar stability as glucose, Li-formate and alanine at ambient temperature after irradiation as long as a year. All EPR signals of the studied materials were affected post-irradiation temperature and humidity after gamma irradiation. The EPR signal of chitosan exhibited long-term stability and it was not sensitive to high storage temperatures and humidity values after irradiation. Chitosan has a good merit as the alternative bio-based material for a stable EPR dosimeter in a wide range of radiation-absorbed doses.

Neuroprotection of dietary virgin olive oil on brain lipidomics during stroke.

PubMed

Rabiei, Zahra; Bigdeli, Mohammad Reza; Rasoulian, Bahram

2013-08-01

Recent studies suggest that dietary virgin olive oil reduces hypoxia-reoxygenation injury in rat brain. This study investigated the effect of pretreatment with different doses of dietary virgin olive oil on brain lipidomics during stroke. In this experimental trial, 60 male Wistar rats were studied in 5 groups of 12 each. The control group received distilled water while three treatment groups received oral virgin olive oil for 30 days (0.25, 0.5 and 0.75 ml/kg/day respectively). Also the sham group received distilled water. Two hours after the last dose, the animals divided two groups. The middle cerebral artery occlusion (MCAO) group subjected to 60 min of middle cerebral artery occlusion (MCAO) and intact groups for brain lipids analysis. The brain phosphatidylcholine, cholesterol ester and cholesterol levels increased significantly in doses of 0.5 and 0.75 ml/kg/day compare with control group. VOO in all three doses increased the brain triglyceride levels. VOO with dose 0.75 ml/kg increased the brain cerebroside levels when compared with control group. VOO pretreatment for 30 days decreased the brain ceramide levels in doses of 0.5 and 0.75 ml/kg/day (p<0.05). Although further studies are needed, the results indicate that the VOO pretreatment improved the injury of ischemia and reperfusion and might be beneficial in patients with these disorders and seems to partly exert their effects via change in brain lipid levels in rat.

Effects of irradiation source and dose level on quality characteristics of processed meat products

NASA Astrophysics Data System (ADS)

Ham, Youn-Kyung; Kim, Hyun-Wook; Hwang, Ko-Eun; Song, Dong-Heon; Kim, Yong-Jae; Choi, Yun-Sang; Song, Beom-Seok; Park, Jong-Heum; Kim, Cheon-Jei

2017-01-01

The effect of irradiation source (gamma-ray, electron-beam, and X-ray) and dose levels on the physicochemical, organoleptic and microbial properties of cooked beef patties and pork sausages was studied, during 10 days of storage at 30±1 °C. The processed meat products were irradiated at 0, 2.5, 5, 7.5, and 10 kGy by three different irradiation sources. The pH of cooked beef patties and pork sausages was unaffected by irradiation sources or their doses. The redness of beef patties linearly decreased with increasing dose level (P<0.05), obviously by e-beam irradiation compared to gamma-ray and X-ray (P<0.05). The redness of pork sausages was increased by gamma-ray irradiation, whereas it decreased by e-beam irradiation depending on absorbed dose level. No significant changes in overall acceptability were observed for pork sausages regardless of irradiation source (P>0.05), while gamma-ray irradiated beef patties showed significantly decreased overall acceptability in a dose-dependent manner (P<0.05). Lipid oxidation of samples was accelerated by irradiation depending on irradiation sources and dose levels during storage at 30 °C. E-beam reduced total aerobic bacteria of beef patties more effectively, while gamma-ray considerably decreased microbes in pork sausages as irradiation dose increased. The results of this study indicate that quality attributes of meat products, in particular color, lipid oxidation, and microbial properties are significantly influenced by the irradiation sources.

A phase I study of docetaxel as a radio-sensitizer for locally advanced squamous cell cervical cancer.

PubMed

Alvarez, Edwin A; Wolfson, Aaron H; Pearson, J Matt; Crisp, Meredith P; Mendez, Luis E; Lambrou, Nicholas C; Lucci, Joseph A

2009-05-01

This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel with concurrent radiotherapy (RT) for the primary treatment of locally advanced squamous cell carcinoma of the cervix. Eligible patients included those with locally advanced squamous cell cervical cancer without para-aortic lymph node involvement. Docetaxel dose levels were 20 mg/m(2), 30 mg/m(2) and 40 mg/m(2) given intravenously weekly for 6 cycles. Three patients were to be treated at each dose level and 6 to receive the MTD. Fifteen patients completed 4-6 cycles of chemotherapy. One of three patients experienced 2 delayed grade 3 severe adverse events (SAE) at the 20 mg/m(2) dose level consisting of colonic and ureteral obstruction. At the 30 mg/m(2) dose level, 1/4 patients had a probable treatment-related celiotomy due to obstipation and a necrotic tumor. Of the 8 patients treated at the 40 mg/m(2) dose level, 1 experienced grade 3 pneumonitis, likely treatment related. Overall, 10/15 (67%) experienced grade 1 or 2 diarrhea, 6 had grade 2 hematologic toxicity, and 2 had grade 2 hypersensitivity. 10 of 16 patients (67%) had no evidence of disease with follow-up ranging from 10-33 months (average 23 months). The recommended phase II dose of docetaxel administered weekly with concurrent radiotherapy for locally advanced squamous cell carcinoma of the cervix is 40 mg/m(2).

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2013-01-01

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

Effect of metronidazole use on tacrolimus concentrations in transplant patients treated for Clostridium difficile.

PubMed

Early, C R; Park, J M; Dorsch, M P; Pogue, K T; Hanigan, S M

2016-10-01

Two case reports suggest that metronidazole treatment for Clostridium difficile infections (CDI) increases tacrolimus (TAC) trough levels. The primary objective of this study was to determine the clinical significance of this potential interaction in transplant patients receiving CDI treatment. Currently, no robust literature exists to estimate a magnitude of pharmacokinetic interaction between metronidazole and TAC. In this retrospective study, the effects of CDI and metronidazole treatment on TAC levels in 52 adult solid organ transplant patients were investigated. The primary outcome was to determine the difference in dose-normalized TAC levels between baseline and symptom resolution in patients treated with metronidazole or vancomycin. The secondary outcome was to determine the difference in dose-normalized TAC levels at baseline and CDI diagnosis. The average change in log-transformed dose-normalized TAC levels from baseline to symptom resolution was 0.99 for metronidazole (n = 35) and 1.04 for vancomycin (n = 17) treatment. The mean difference between the groups was 0.96 (95% confidence interval: 0.74-1.24). No significant difference was found between dose-normalized TAC levels at CDI diagnosis and baseline (P = 0.37). CDI treatment with metronidazole was not associated with a >30% increase in TAC levels compared with vancomycin. Both treatment groups required TAC dose adjustments to maintain goal TAC levels and those treated with metronidazole did not require a significantly greater dose adjustment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Phase I Study of Chemoradiotherapy With Use of Involved-Field Conformal Radiotherapy and Accelerated Hyperfractionation for Stage III Non-Small Cell Lung Cancer: WJTOG 3305

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

Tada, Takuhito, E-mail: tada@msic.med.osaka-cu.ac.jp; Department of Radiology, Izumi Municipal Hospital, Izumi; Chiba, Yasutaka

2012-05-01

Purpose: A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small-cell lung cancer was conducted. Methods and Materials: Patients with unresectable Stage III non-small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m{sup 2}) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m{sup 2}). Total doses were 54 Gy in 36 fractions, 60 Gymore » in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade {>=}4 esophagitis and neutropenic fever and Grade {>=}3 other nonhematologic toxicities, was monitored for 90 days. Results: Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. Conclusions: The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient.« less

EYE LENS EXPOSURE TO MEDICAL STAFF PERFORMING ELECTROPHYSIOLOGY PROCEDURES: DOSE ASSESSMENT AND CORRELATION TO PATIENT DOSE.

PubMed

Ciraj-Bjelac, Olivera; Antic, Vojislav; Selakovic, Jovana; Bozovic, Predrag; Arandjic, Danijela; Pavlovic, Sinisa

2016-12-01

The purpose of this study was to assess the patient exposure and staff eye dose levels during implantation procedures for all types of pacemaker therapy devices performed under fluoroscopic guidance and to investigate potential correlation between patients and staff dose levels. The mean eye dose during pacemaker/defibrillator implementation was 12 µSv for the first operator, 8.7 µSv for the second operator/nurse and 0.50 µSv for radiographer. Corresponding values for cardiac resynchronisation therapy procedures were 30, 26 and 2.0 µSv, respectively. Significant (p < 0.01) correlation between the eye dose and the kerma-area product was found for the first operator and radiographers, but not for other staff categories. The study revealed eye dose per procedure and eye dose normalised to patient dose indices for different staff categories and provided an input for radiation protection in electrophysiology procedures. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Synthesis, Characterization, Antioxidant Status, and Toxicity Study of Vanadium-Rutin Complex in Balb/c Mice.

PubMed

Roy, Souvik; Majumdar, Sumana; Singh, Amit Kumar; Ghosh, Balaram; Ghosh, Nilanjan; Manna, Subhadip; Chakraborty, Tania; Mallick, Sougato

2015-08-01

A new trend was developed for the formation of a complex between vanadium and flavonoid derivatives in order to increase the intestinal absorption and to reduce the toxicity of vanadium compounds. The vanadium-rutin complex was characterized by several spectroscopic techniques like ultraviolet (UV)-visible, Fourier transform infrared (FTIR), NMR, mass spectrometry, and microscopic evaluation by scanning electron microscopy. The mononuclear complex was formed by the interaction between vanadium and rutin with 1:2 metal to ligand stoichiometry. Antioxidant activity of the complex was evaluated by 1,1-diphenyl-2 picrylhydrazyl, ferric-reducing power, and 2,2'-azin-obis 3-ethylbenzothiazoline-6-sulphonic acid methods. It was shown that radical scavenging activity and ferric-reducing potential of free rutin was lower as compared with vanadium-rutin complex. The study was also investigated for oral acute toxicity and 28 days repeated oral subacute toxicity study of vanadium-rutin complex in balb/c mice. The vanadium-rutin complex showed mortality at a dose of 120 mg/kg in the balb/c mice. In 28 days repeated oral toxicity study, vanadium-rutin complex was administered to both sex of balb/c mice at dose levels of 90, 45, and 20 ppm, respectively. In addition, subacute toxicity study of vanadium-rutin complex (at 90 ppm dose level) showed increase levels of white blood cell (WBC), total bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen and decrease level of total protein (TP) as compared with control group. Histopathological study of vanadium-rutin showed structural alteration in the liver, kidney, and stomach at 90 ppm dose level. No observed toxic level of vanadium-rutin complex at 20 ppm dose level could be good for further study.

Using Quality of Life Measures in a Phase I Clinical Trial of Noni in Patients with Advanced Cancer to Select a Phase II Dose

PubMed Central

Issell, Brian F.; Gotay, Carolyn C.; Pagano, Ian; Franke, A. Adrian

2015-01-01

Purpose We conducted a Phase I study of noni in patients with advanced cancer. Quality of life measures were examined as an alternate way to select a Phase II dose of this popular dietary supplement. Patients and Methods Starting at two capsules twice daily (2 grams), the dose suggested for marketed products, dose levels were escalated by 2 grams daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed QLQ-C30 Quality of Life, and the Brief Fatigue Inventory (BFI), questionnaires at baseline and at four week intervals. Scopoletin was measured in blood and urine collected at baseline and at approximately four week intervals. Results Fifty-one patients were enrolled at seven dose levels. Seven capsules four times daily (14 grams) was the maximum tolerated dose. No dose limiting toxicity was found but four of eight patients at this level withdrew from the study due to the challenges of ingesting so many capsules. There was a dose response for self reported physical functioning and the control of pain and fatigue. Patients taking four capsules four times daily experienced less fatigue than patients taking lower or higher doses. A relationship between noni dose and blood and urinary scopoletin concentrations was found. Conclusion Measuring quality of life to determine a dose for subsequent Phase II testing is feasible. A noni dose of four capsules four times daily (8 grams) is recommended for Phase II testing where controlling fatigue and maintaining physical function is the efficacy of interest. Scopoletin is a measurable noni ingredient for pharmacokinetic studies in patients with cancer. PMID:22435516

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

PubMed

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

2008-06-01

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

Estimation of 1945 to 1957 food consumption. Hanford Environmental Dose Reconstruction Project: Draft

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

Anderson, D.M.; Bates, D.J.; Marsh, T.L.

This report details the methods used and the results of the study on the estimated historic levels of food consumption by individuals in the Hanford Environmental Dose Reconstruction (HEDR) study area from 1945--1957. This period includes the time of highest releases from Hanford and is the period for which data are being collected in the Hanford Thyroid Disease Study. These estimates provide the food-consumption inputs for the HEDR database of individual diets. This database will be an input file in the Hanford Environmental Dose Reconstruction Integrated Code (HEDRIC) computer model that will be used to calculate the radiation dose. Themore » report focuses on fresh milk, eggs, lettuce, and spinach. These foods were chosen because they have been found to be significant contributors to radiation dose based on the Technical Steering Panel dose decision level.« less

Estimation of 1945 to 1957 food consumption. Hanford Environmental Dose Reconstruction Project

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

Anderson, D.M.; Bates, D.J.; Marsh, T.L.

This report details the methods used and the results of the study on the estimated historic levels of food consumption by individuals in the Hanford Environmental Dose Reconstruction (HEDR) study area from 1945--1957. This period includes the time of highest releases from Hanford and is the period for which data are being collected in the Hanford Thyroid Disease Study. These estimates provide the food-consumption inputs for the HEDR database of individual diets. This database will be an input file in the Hanford Environmental Dose Reconstruction Integrated Code (HEDRIC) computer model that will be used to calculate the radiation dose. Themore » report focuses on fresh milk, eggs, lettuce, and spinach. These foods were chosen because they have been found to be significant contributors to radiation dose based on the Technical Steering Panel dose decision level.« less

Evaluation of a new very low dose imaging protocol: feasibility and impact on X-ray dose levels in electrophysiology procedures

PubMed Central

Bourier, Felix; Reents, Tilko; Ammar-Busch, Sonia; Buiatti, Alessandra; Kottmaier, Marc; Semmler, Verena; Telishevska, Marta; Brkic, Amir; Grebmer, Christian; Lennerz, Carsten; Kolb, Christof; Hessling, Gabriele; Deisenhofer, Isabel

2016-01-01

Aims This study presents and evaluates the impact of a new lowest-dose fluoroscopy protocol (Siemens AG), especially designed for electrophysiology (EP) procedures, on X-ray dose levels. Methods and results From October 2014 to March 2015, 140 patients underwent an EP study on an Artis zee angiography system. The standard low-dose protocol was operated at 23 nGy (fluoroscopy) and at 120 nGy (cine-loop), the new lowest-dose protocol was operated at 8 nGy (fluoroscopy) and at 36 nGy (cine-loop). Procedural data, X-ray times, and doses were analysed in 100 complex left atrial and in 40 standard EP procedures. The resulting dose–area products were 877.9 ± 624.7 µGym² (n = 50 complex procedures, standard low dose), 199 ± 159.6 µGym² (n = 50 complex procedures, lowest dose), 387.7 ± 36.0 µGym² (n = 20 standard procedures, standard low dose), and 90.7 ± 62.3 µGym² (n = 20 standard procedures, lowest dose), P < 0.01. In the low-dose and lowest-dose groups, procedure times were 132.6 ± 35.7 vs. 126.7 ± 34.7 min (P = 0.40, complex procedures) and 72.3 ± 20.9 vs. 85.2 ± 44.1 min (P = 0.24, standard procedures), radiofrequency (RF) times were 53.8 ± 26.1 vs. 50.4 ± 29.4 min (P = 0.54, complex procedures) and 10.1 ± 9.9 vs. 12.2 ± 14.7 min (P = 0.60, standard procedures). One complication occurred in the standard low-dose and lowest-dose groups (P = 1.0). Conclusion The new lowest-dose imaging protocol reduces X-ray dose levels by 77% compared with the currently available standard low-dose protocol. From an operator standpoint, lowest X-ray dose levels create a different, reduced image quality. The new image quality did not significantly affect procedure or RF times and did not result in higher complication rates. Regarding radiological protection, operating at lowest-dose settings should become standard in EP procedures. PMID:26589627

The effects of slice thickness and radiation dose level variations on computer-aided diagnosis (CAD) nodule detection performance in pediatric chest CT scans

NASA Astrophysics Data System (ADS)

Emaminejad, Nastaran; Lo, Pechin; Ghahremani, Shahnaz; Kim, Grace H.; Brown, Matthew S.; McNitt-Gray, Michael F.

2017-03-01

For pediatric oncology patients, CT scans are performed to assess treatment response and disease progression. CAD may be used to detect lung nodules which would reflect metastatic disease. The purpose of this study was to investigate the effects of reducing radiation dose and varying slice thickness on CAD performance in the detection of solid lung nodules in pediatric patients. The dataset consisted of CT scans of 58 pediatric chest cases, from which 7 cases had lung nodules detected by radiologist, and a total of 28 nodules were marked. For each case, the original raw data (sinogram data) was collected and a noise addition model was used to simulate reduced-dose scans of 50%, 25% and 10% of the original dose. In addition, the original and reduced-dose raw data were reconstructed at slice thicknesses of 1.5 and 3 mm using a medium sharp (B45) kernel; the result was eight datasets (4 dose levels x 2 thicknesses) for each case An in-house CAD tool was applied on all reconstructed scans, and results were compared with the radiologist's markings. Patient level mean sensitivities at 3mm thickness were 24%, 26%, 25%, 27%, and at 1.5 mm thickness were 23%, 29%, 35%, 36% for 10%, 25%, 50%, and 100% dose level, respectively. Mean FP numbers were 1.5, 0.9, 0.8, 0.7 at 3 mm and 11.4, 3.5, 2.8, 2.8 at 1.5 mm thickness for 10%, 25%, 50%, and 100% dose level respectively. CAD sensitivity did not change with dose level for 3mm thickness, but did change with dose for 1.5 mm. False Positives increased at low dose levels where noise values were high.

76 FR 23898 - Mefenpyr-diethyl; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-29

... observed in the rabbit (abortions) at the same dose level producing maternal toxicity. Mefenpyr-diethyl did... (abortions) was observed in the rabbit at a dose level of 250 mg/kg/day. In the reproduction study, decreased...

A phase I study of Triapine in combination with doxorubicin in patients with advanced solid tumors.

PubMed

Schelman, William R; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M; Ivy, Percy; Wilding, George; Traynor, Anne M

2009-05-01

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine administered in combination with doxorubicin. Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m(2) and Triapine 25 mg/m(2). PK analysis was performed at various time-points before and after treatment. Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m(2), Triapine 45 mg/m(2)), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m(2)) with Triapine 45 mg/m(2). The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine were reduced to 45 and 25 mg/m(2), respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Pretreated patients with advanced malignancies can tolerate the combination of Triapine and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m(2) on day 1 and Triapine 25 mg/m(2) on days 1-4 of a 21-day cycle.

Patient dose, gray level and exposure index with a computed radiography system

NASA Astrophysics Data System (ADS)

Silva, T. R.; Yoshimura, E. M.

2014-02-01

Computed radiography (CR) is gradually replacing conventional screen-film system in Brazil. To assess image quality, manufactures provide the calculation of an exposure index through the acquisition software of the CR system. The objective of this study is to verify if the CR image can be used as an evaluator of patient absorbed dose too, through a relationship between the entrance skin dose and the exposure index or the gray level values obtained in the image. The CR system used for this study (Agfa model 30-X with NX acquisition software) calculates an exposure index called Log of the Median (lgM), related to the absorbed dose to the IP. The lgM value depends on the average gray level (called Scan Average Level (SAL)) of the segmented pixel value histogram of the whole image. A Rando male phantom was used to simulate a human body (chest and head), and was irradiated with an X-ray equipment, using usual radiologic techniques for chest exams. Thermoluminescent dosimeters (LiF, TLD100) were used to evaluate entrance skin dose and exit dose. The results showed a logarithm relation between entrance dose and SAL in the image center, regardless of the beam filtration. The exposure index varies linearly with the entrance dose, but the angular coefficient is beam quality dependent. We conclude that, with an adequate calibration, the CR system can be used to evaluate the patient absorbed dose.

Student's music exposure: Full-day personal dose measurements.

PubMed

Washnik, Nilesh Jeevandas; Phillips, Susan L; Teglas, Sandra

2016-01-01

Previous studies have shown that collegiate level music students are exposed to potentially hazardous sound levels. Compared to professional musicians, collegiate level music students typically do not perform as frequently, but they are exposed to intense sounds during practice and rehearsal sessions. The purpose of the study was to determine the full-day exposure dose including individual practice and ensemble rehearsals for collegiate student musicians. Sixty-seven college students of classical music were recruited representing 17 primary instruments. Of these students, 57 completed 2 days of noise dose measurements using Cirrus doseBadge programed according to the National Institute for Occupational Safety and Health criterion. Sound exposure was measured for 2 days from morning to evening, ranging from 7 to 9 h. Twenty-eight out of 57 (49%) student musicians exceeded a 100% daily noise dose on at least 1 day of the two measurement days. Eleven student musicians (19%) exceeded 100% daily noise dose on both days. Fourteen students exceeded 100% dose during large ensemble rehearsals and eight students exceeded 100% dose during individual practice sessions. Approximately, half of the student musicians exceeded 100% noise dose on a typical college schedule. This finding indicates that a large proportion of collegiate student musicians are at risk of developing noise-induced hearing loss due to hazardous sound levels. Considering the current finding, there is a need to conduct hearing conservation programs in all music schools, and to educate student musicians about the use and importance of hearing protection devices for their hearing.

Student's music exposure: Full-day personal dose measurements

PubMed Central

Washnik, Nilesh Jeevandas; Phillips, Susan L.; Teglas, Sandra

2016-01-01

Previous studies have shown that collegiate level music students are exposed to potentially hazardous sound levels. Compared to professional musicians, collegiate level music students typically do not perform as frequently, but they are exposed to intense sounds during practice and rehearsal sessions. The purpose of the study was to determine the full-day exposure dose including individual practice and ensemble rehearsals for collegiate student musicians. Sixty-seven college students of classical music were recruited representing 17 primary instruments. Of these students, 57 completed 2 days of noise dose measurements using Cirrus doseBadge programed according to the National Institute for Occupational Safety and Health criterion. Sound exposure was measured for 2 days from morning to evening, ranging from 7 to 9 h. Twenty-eight out of 57 (49%) student musicians exceeded a 100% daily noise dose on at least 1 day of the two measurement days. Eleven student musicians (19%) exceeded 100% daily noise dose on both days. Fourteen students exceeded 100% dose during large ensemble rehearsals and eight students exceeded 100% dose during individual practice sessions. Approximately, half of the student musicians exceeded 100% noise dose on a typical college schedule. This finding indicates that a large proportion of collegiate student musicians are at risk of developing noise-induced hearing loss due to hazardous sound levels. Considering the current finding, there is a need to conduct hearing conservation programs in all music schools, and to educate student musicians about the use and importance of hearing protection devices for their hearing. PMID:26960787

Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule

PubMed Central

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

Phase I Study of Oral S-1 Plus Cisplatin With Concurrent Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer

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

Kaira, Kyoichi; Sunaga, Noriaki; Yanagitani, Noriko

Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: S-1 was administered orally twice daily for 14 days and cisplatin on Days 1 and 8 of each cycle; this was repeated every 3 weeks. Doses of each drug were planned as follows: level 0, 50/40; level 1, 60/40; level 2, 70/40; level 3, 80/40 (S-1 [mg/m{sup -2}/day{sup -1}]/cisplatin [mg/m{sup -2}/day{sup -1}]). Thoracic radiation therapy was administered in 2 Gy fractions five times weekly to amore » total dose of 60 Gy. Results: Ten patients were enrolled in this study. All patients received 60 Gy of thoracic radiotherapy and 7 (70%) patients received four cycles of chemotherapy. At level 1, 2 of 3 patients experienced a delay exceeding 10 days in the cisplatin administration of Day 29. Grade 4 neutropenia and Grade 3 fever occurred in 1 and 1 patients, respectively. Nonhematologic toxicities were mild. None developed {>=}Grade 3 esophagitis or lung toxicity. At level 0, 2 of 7 patients developed dose-limiting toxicity. Thus, level 1 was considered the MTD and Level 0 was selected as the RD. Objective responses were seen in all patients. Conclusions: The RD is the level 0 dose, and this regimen is a feasible and well-tolerated regimen for the treatment of patients with Stage III NSCLC.« less

Method for inserting noise in digital mammography to simulate reduction in radiation dose

NASA Astrophysics Data System (ADS)

Borges, Lucas R.; de Oliveira, Helder C. R.; Nunes, Polyana F.; Vieira, Marcelo A. C.

2015-03-01

The quality of clinical x-ray images is closely related to the radiation dose used in the imaging study. The general principle for selecting the radiation is ALARA ("as low as reasonably achievable"). The practical optimization, however, remains challenging. It is well known that reducing the radiation dose increases the quantum noise, which could compromise the image quality. In order to conduct studies about dose reduction in mammography, it would be necessary to acquire repeated clinical images, from the same patient, with different dose levels. However, such practice would be unethical due to radiation related risks. One solution is to simulate the effects of dose reduction in clinical images. This work proposes a new method, based on the Anscombe transformation, which simulates dose reduction in digital mammography by inserting quantum noise into clinical mammograms acquired with the standard radiation dose. Thus, it is possible to simulate different levels of radiation doses without exposing the patient to new levels of radiation. Results showed that the achieved quality of simulated images generated with our method is the same as when using other methods found in the literature, with the novelty of using the Anscombe transformation for converting signal-independent Gaussian noise into signal-dependent quantum noise.

Cytogenetic effect of low dose gamma-radiation in Hordeum vulgare seedlings: non-linear dose-effect relationship.

PubMed

Geras'kin, Stanislav A; Oudalova, Alla A; Kim, Jin Kyu; Dikarev, Vladimir G; Dikareva, Nina S

2007-03-01

The induction of chromosome aberrations in Hordeum vulgare germinated seeds was studied after ionizing irradiation with doses in the range of 10-1,000 mGy. The relationship between the frequency of aberrant cells and the absorbed dose was found to be nonlinear. A dose-independent plateau in the dose range from about 50 to 500 mGy was observed, where the level of cytogenetic damage was significantly different from the spontaneous level. The comparison of the goodness of the experimental data fitting with mathematical models of different complexity, using the most common quantitative criteria, demonstrated the advantage of a piecewise linear model over linear and polynomial models in approximating the frequency of cytogenetical disturbances. The results of the study support the hypothesis of indirect mechanisms of mutagenesis induced by low doses. Fundamental and applied implications of these findings are discussed.

Oral vitamin C supplementation reduces erythropoietin requirement in hemodialysis patients with functional iron deficiency.

PubMed

Sultana, Tanjim; DeVita, Maria V; Michelis, Michael F

2016-09-01

Functional iron deficiency (FID) is a major cause of persistent anemia in dialysis patients and also contributes to a suboptimal response to erythropoietin (Epo) administration. Vitamin C acts as an enzyme cofactor and enhances mobilization of the ferrous form of iron to transferrin thus increasing its bioavailability. High-dose intravenous vitamin C has been shown to decrease the Epo requirement and improve hemoglobin levels in previous studies. This study assessed the effect of low-dose oral vitamin C on possible reduction in Epo dose requirements in stable hemodialysis patients with FID. This prospective study included 22 stable hemodialysis patients with FID defined as transferrin saturation (T sat) <30 % and ferritin levels of >100 mcg/L with Epo requirement of ≥4000 U/HD session. Patients received oral vitamin C 250 mg daily for 3 months. Hemoglobin, iron and T sat levels were recorded monthly. No one received iron supplementation during the study period. There was a significant reduction in median Epo dose requirement in the 15 patients who completed the study, from 203.1 U/kg/week (95 % CI 188.4-270.6) to 172.8 U/kg/week (95 % CI 160.2-214.8), (P = 0.01). In the seven responders, there was 33 % reduction in Epo dose from their baseline. Despite adjustment of Epo dose, the mean hemoglobin level was significantly increased from 10.1 ± 0.6 to 10.7 ± 0.6 mg/dL (P = 0.03). No adverse effects of oral vitamin C were observed. Daily low-dose oral vitamin C supplementation reduced Epo dose requirements in hemodialysis patients with FID. Limitations of this study include a small sample size and the lack of measurements of vitamin C and oxalate levels. Despite concerns regarding oral vitamin C absorption in dialysis patients, this study indicates vitamin C was well tolerated by all participants without reported adverse effect.

Evaluation of dose-area product of common radiographic examinations towards establishing a preliminary diagnostic reference levels (PDRLs) in Southwestern Nigeria.

PubMed

Jibiri, Nnamdi N; Olowookere, Christopher J

2016-11-08

In Nigeria, a large number of radiographic examinations are conducted yearly for various diagnostic purposes. However, most examinations carried out do not have records of doses received by the patients, and the employed exposure parameters used are not documented; therefore, adequate radiation dose management is hin-dered. The aim of the present study was to estimate the dose-area product (DAP) of patients examined in Nigeria, and to propose regional reference dose levels for nine common examinations (chest PA, abdomen AP, pelvis AP, lumbar AP, skull AP, leg AP, knee AP, hand AP, and thigh AP) undertaken in Nigeria. Measurement of entrance surface dose (ESD) was carried out using thermoluminescent dosimeter (TLD). Measured ESDS were converted into DAP using the beam area of patients in 12 purposely selected hospitals. Results of the study show that the maximum/ minimum ratio ranged from 3 for thigh AP to 57 in abdomen AP. The range of determined mean and 75th percentile DAPs were 0.18-17.16, and 0.25-28.59 Gy cm2, respectively. Data available for comparison show that 75th percentile DAPs in this study (in chest PA, abdomen AP, pelvis AP, lumbar AP) are higher than NRPB-HPE reference values. The DAP in this study is higher by factor of 31.4 (chest PA), 9.9 (abdomen AP), 2.2 (pelvis AP), and 2.1 (lumbar AP) than NRPB-HPE values. The relative higher dose found in this study shows nonoptimization of practice in Nigeria. It is expected that regular dose auditing and dose optimization implementation in Nigeria would lead to lower DAP value, especially in abdomen AP. The 75th percentile DAP distribution reported in this study could be taken as regional diagnostic reference level in the Southwestern Nigeria; however, a more extensive nationwide dose survey is required to establish national reference dose. © 2016 The Authors.

Treatment of subclinical hypothyroidism in pregnancy using fixed thyroxine daily doses of 75 μg.

PubMed

Penin, Manuel; Trigo, Cristina; López, Yolanda; Barragáns, María

2014-01-01

Treatment of hypothyroid pregnant women is usually calculated based on weight (1 μg/kg/day) and TSH levels. This study assessed the usefulness of treating these women with a fixed dose of 75 μg/day. All women with pregnancy diagnosed from January to August 2012 in the Vigo Health Area (Spain) without previous diagnosis of thyroid disease or thyroxine treatment and with TSH levels over 4,5 mUI/ml were enrolled by consecutive sampling. All 116 women in the sample were treated with a fixed daily dose of thyroxine 75 μg-thyroxine levels were measured at two, four, and six months, and thyroxine dose was modified if TSH level was lower than 0.3 or higher than 4.5 mUI/ml. A woman had a TSH level less than 0.3 mUI/ml in a test; reduction of thyroxine dose to 50 μg/day allowed for maintaining TSH level within the desired range until delivery. Six women had TSH levels over 4.5 mUI/ml in one test; in all of them, increase in thyroxine dose to 100 μg/day allowed for maintaining the level within the desired range until delivery. Fixed daily doses of thyroxine 75 μg allowed for achieving goal TSH levels in most of our pregnant women with subclinical hypothyroidism, irrespective of their weight and baseline TSH level. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

Dose-response study of spinal hyperbaric ropivacaine for cesarean section

PubMed Central

Chen, Xin-zhong; Chen, Hong; Lou, Ai-fei; Lü, Chang-cheng

2006-01-01

Background: Spinal hyperbaric ropivacaine may produce more predictable and reliable anesthesia than plain ropivacaine for cesarean section. The dose-response relation for spinal hyperbaric ropivacaine is undetermined. This double-blind, randomized, dose-response study determined the ED50 (50% effective dose) and ED95 (95% effective dose) of spinal hyperbaric ropivacaine for cesarean section anesthesia. Methods: Sixty parturients undergoing elective cesarean section delivery with use of combined spinal-epidural anesthesia were enrolled in this study. An epidural catheter was placed at the L1~L2 vertebral interspace, then lumbar puncture was performed at the L3~L4 vertebral interspace, and parturients were randomized to receive spinal hyperbaric ropivacaine in doses of 10.5 mg, 12 mg, 13.5 mg, or 15 mg in equal volumes of 3 ml. Sensory levels (pinprick) were assessed every 2.5 min until a T7 level was achieved and motor changes were assessed by modified Bromage Score. A dose was considered effective if an upper sensory level to pin prick of T7 or above was achieved and no intraoperative epidural supplement was required. ED50 and ED95 were determined with use of a logistic regression model. Results: ED50 (95% confidence interval) of spinal hyperbaric ropivacaine was determined to be 10.37 (5.23~11.59) mg and ED95 (95% confidence interval) to be 15.39 (13.81~23.59) mg. The maximum sensory block levels and the duration of motor block and the rate of hypotension, but not onset of anesthesia, were significantly related to the ropivacaine dose. Conclusion: The ED50 and ED95 of spinal hyperbaric ropivacaine for cesarean delivery under the conditions of this study were 10.37 mg and 15.39 mg, respectively. Ropivacaine is suitable for spinal anesthesia in cesarean delivery. PMID:17111469

Assessment of dedicated low-dose cardiac micro-CT reconstruction algorithms using the left ventricular volume of small rodents as a performance measure.

PubMed

Maier, Joscha; Sawall, Stefan; Kachelrieß, Marc

2014-05-01

Phase-correlated microcomputed tomography (micro-CT) imaging plays an important role in the assessment of mouse models of cardiovascular diseases and the determination of functional parameters as the left ventricular volume. As the current gold standard, the phase-correlated Feldkamp reconstruction (PCF), shows poor performance in case of low dose scans, more sophisticated reconstruction algorithms have been proposed to enable low-dose imaging. In this study, the authors focus on the McKinnon-Bates (MKB) algorithm, the low dose phase-correlated (LDPC) reconstruction, and the high-dimensional total variation minimization reconstruction (HDTV) and investigate their potential to accurately determine the left ventricular volume at different dose levels from 50 to 500 mGy. The results were verified in phantom studies of a five-dimensional (5D) mathematical mouse phantom. Micro-CT data of eight mice, each administered with an x-ray dose of 500 mGy, were acquired, retrospectively gated for cardiac and respiratory motion and reconstructed using PCF, MKB, LDPC, and HDTV. Dose levels down to 50 mGy were simulated by using only a fraction of the projections. Contrast-to-noise ratio (CNR) was evaluated as a measure of image quality. Left ventricular volume was determined using different segmentation algorithms (Otsu, level sets, region growing). Forward projections of the 5D mouse phantom were performed to simulate a micro-CT scan. The simulated data were processed the same way as the real mouse data sets. Compared to the conventional PCF reconstruction, the MKB, LDPC, and HDTV algorithm yield images of increased quality in terms of CNR. While the MKB reconstruction only provides small improvements, a significant increase of the CNR is observed in LDPC and HDTV reconstructions. The phantom studies demonstrate that left ventricular volumes can be determined accurately at 500 mGy. For lower dose levels which were simulated for real mouse data sets, the HDTV algorithm shows the best performance. At 50 mGy, the deviation from the reference obtained at 500 mGy were less than 4%. Also the LDPC algorithm provides reasonable results with deviation less than 10% at 50 mGy while PCF and MKB reconstruction show larger deviations even at higher dose levels. LDPC and HDTV increase CNR and allow for quantitative evaluations even at dose levels as low as 50 mGy. The left ventricular volumes exemplarily illustrate that cardiac parameters can be accurately estimated at lowest dose levels if sophisticated algorithms are used. This allows to reduce dose by a factor of 10 compared to today's gold standard and opens new options for longitudinal studies of the heart.

Everolimus with reduced-dose cyclosporine in de novo renal transplant recipients: Philippine experience.

PubMed

Li, J T; Danguilan, R A; Cabanayan-Casasola, C B; Talusan-Tomacruz, Y; Ona, E T

2008-09-01

The objective of this study was to describe the appropriate dose of everolimus to achieve target trough concentrations in standard-risk Filipino kidney transplant recipients. We reviewed all kidney transplant recipients from December 1, 2006 to June 15, 2007 who were given everolimus (1.5 mg/d) in combination with low-dose cyclosporine (5 mg/kg/d) and prednisone but without induction therapy for their immunosuppressive doses, trough levels, as well as hematologic and blood chemistry profiles. Target everolimus trough concentration was 3-8 ng/mL and C2 level was 1000-1400 ng/mL for the first 3 months. Among 148 patients who underwent transplantation during the study period, 26 comprised the study population but only 15 patients completed the 3-month follow-up and are the subject of this report. Their mean age was 33 years, average PRA 2%, and mean HLA mismatches 3. All were from living donors. At 7 days posttransplantation, all patients achieved or exceeded the target everolimus trough and cyclosporine C2 level. At 1 and 3 months posttransplantation the mean everolimus dose was 1.17 and 0.78 mg/d, respectively, whereas the cyclosporine dose was 195 and 148 mg/d, respectively. Three patients showed elevated alanine aminotransferase (ALT) and all patients had hypercholesterolemia after 1 month, which improved with everolimus dose reduction (half required statins). One patient experienced a Banff Grade IA acute rejection episode at 2 months posttransplantation with a serum creatinine value of 2 mg/dL after steroid pulsing. Most standard-risk Filipino kidney transplant recipients required a maintenance everolimus dose of 1 mg/d at 1 month. The cyclosporine dose requirement was also lower. A larger sample size is needed to provide a level of significance compared with other populations.

Optimizing insulin secretagogue therapy in patients with type 2 diabetes: a randomized double-blind study with repaglinide.

PubMed

Schmitz, Ole; Lund, Sten; Andersen, Per Heden; Jønler, Morten; Pørksen, Nils

2002-02-01

Repaglinide, a novel antidiabetic agent that has a rapid onset and short duration of action, was developed for mealtime dosing. The purpose of this pharmacodynamic study was to validate a prandial regimen of repaglinide by comparing meal-related dosing with a regimen in which the same total daily dose was divided into only two doses at morning and evening meals. The study was a double-blind, randomized, parallel-group trial in 19 antidiabetic agent-naive subjects with type 2 diabetes (mean age 58 years, known duration of diabetes 3.5 years, HbA(1c) 7.3%, and BMI 32 kg/m(2)). Patients were randomly assigned to receive repaglinide either before each of the three main meals or before breakfast and before the evening meal. Patients in both groups received the same total daily dose of repaglinide. Twenty-four hour profiles of blood glucose, plasma insulin, and plasma C-peptide concentrations were measured at baseline and after 4 weeks of treatment. Repaglinide increased postprandial insulin levels and markedly reduced postprandial glucose levels relative to baseline in both groups. Significant reductions were also recorded in fasting blood glucose and HbA(1c) levels. The repaglinide regimen, in which a dose was taken before each main meal, was more effective in improving glycemic control (including postprandial glucose and HbA(1c) levels) than the same total dose of repaglinide divided into morning and evening mealtime doses. These data support the strategy of mealtime dosing with repaglinide. The improvements in glycemic control observed in these patients are encouraging. In addition to classic parameters of glycemic control, improvements in postprandial glucose excursions may prove to be important because postprandial hyperglycemia has been suggested to be an independent risk factor for cardiovascular disease in diabetes.

[The effect of hydra peptide morphogen on the levels of beta-endorphin and some blood and adrenal hormones in albino rats].

PubMed

Murzina, N B; Khomichuk, A Iu; Timoshin, S S; Obukhova, G G; Anosova, O A; Berezina, G P

1991-10-01

The influence of PMH on the level of beta-endorphin and some hormones of blood and adrenal glands was studied. The dose A (10 mkg/kg) and dose W (100 mkg/kg) of PMH were used in our experiments. Earlier it has been discovered, that PMH in such doses stimulated the processes of cell division in 24 hours since the moment of injection. The stimulation was dose-dependent. Within 24 hours PMH in A dose decreased the concentration of beta-endorphin in the blood 2.7-fold, ad in dose W increased it 2 times. The level of corticosterone in blood and adrenal glands after the injection of PMH in dose A exceeded the control data trustworthy in 4 and 24 hours since the moment of injection. In dose B in 4 hours 1.5-fold reduction of corticosterone concentration took place in the blood. Increase in epinephrine level in adrenal glands was observed after PMH administration in two doses. Content of T3 increased in 4 hours after PMH injection in dose B. The role of hormonal changes in stimulating cell division accompanied by PMH injection is discussed. The data received show that PMH influences directly proliferative processes.

Diagnostic reference levels of paediatric computed tomography examinations performed at a dedicated Australian paediatric hospital.

PubMed

Bibbo, Giovanni; Brown, Scott; Linke, Rebecca

2016-08-01

Diagnostic Reference Levels (DRL) of procedures involving ionizing radiation are important tools to optimizing radiation doses delivered to patients and in identifying cases where the levels of doses are unusually high. This is particularly important for paediatric patients undergoing computed tomography (CT) examinations as these examinations are associated with relatively high-dose. Paediatric CT studies, performed at our institution from January 2010 to March 2014, have been retrospectively analysed to determine the 75th and 95th percentiles of both the volume computed tomography dose index (CTDIvol ) and dose-length product (DLP) for the most commonly performed studies to: establish local diagnostic reference levels for paediatric computed tomography examinations performed at our institution, benchmark our DRL with national and international published paediatric values, and determine the compliance of CT radiographer with established protocols. The derived local 75th percentile DRL have been found to be acceptable when compared with those published by the Australian National Radiation Dose Register and two national children's hospitals, and at the international level with the National Reference Doses for the UK. The 95th percentiles of CTDIvol for the various CT examinations have been found to be acceptable values for the CT scanner Dose-Check Notification. Benchmarking CT radiographers shows that they follow the set protocols for the various examinations without significant variations in the machine setting factors. The derivation of DRL has given us the tool to evaluate and improve the performance of our CT service by improved compliance and a reduction in radiation dose to our paediatric patients. We have also been able to benchmark our performance with similar national and international institutions. © 2016 The Royal Australian and New Zealand College of Radiologists.

Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer.

PubMed

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.

Radiation dose to the global flying population.

PubMed

Alvarez, Luis E; Eastham, Sebastian D; Barrett, Steven R H

2016-03-01

Civil airliner passengers and crew are exposed to elevated levels of radiation relative to being at sea level. Previous studies have assessed the radiation dose received in particular cases or for cohort studies. Here we present the first estimate of the total radiation dose received by the worldwide civilian flying population. We simulated flights globally from 2000 to 2013 using schedule data, applying a radiation propagation code to estimate the dose associated with each flight. Passengers flying in Europe and North America exceed the International Commission on Radiological Protection annual dose limits at an annual average of 510 or 420 flight hours per year, respectively. However, this falls to 160 or 120 h on specific routes under maximum exposure conditions.

Assessment of serum magnesium levels and its outcome in neonates of eclamptic mothers treated with low-dose magnesium sulfate regimen

PubMed Central

Das, Monalisa; Chaudhuri, Patralekha Ray; Mondal, Badal C.; Mitra, Sukumar; Bandyopadhyay, Debasmita; Pramanik, Sushobhan

2015-01-01

Objectives: Magnesium historically has been used for treatment and/or prevention of eclampsia. Considering the low body mass index of Indian women, a low-dose magnesium sulfate regime has been introduced by some authors. Increased blood levels of magnesium in neonates is associated with increased still birth, early neonatal death, birth asphyxia, bradycardia, hypotonia, gastrointestinal hypomotility. The objective of this study was to assess safety of low-dose magnesium sulfate regimen in neonates of eclamptic mothers treated with this regimen. Materials and Methods: This was a cross-sectional observational study of 100 eclampsia patients and their neonates. Loading dose and maintenance doses of magnesium sulfate were administered to patients by combination of intravenous and intramuscular routes. Maternal serum and cord blood magnesium levels were estimated. Neonatal outcome was assessed. Results: Bradycardia was observed in 18 (19.15%) of the neonates, 16 (17.02%) of the neonates were diagnosed with hypotonia. Pearson Correlation Coefficient showed Apgar scores decreased with increase in cord blood magnesium levels. Unpaired t-test showed lower Apgar scores with increasing dose of magnesium sulfate. The Chi-square/Fisher's exact test showed significant increase in hypotonia, birth asphyxia, intubation in delivery room, Neonatal Intensive Care Unit (NICU) care requirement, with increasing dose of magnesium sulfate. (P ≤ 0.05). Conclusion: Several neonatal complications are significantly related to increasing serum magnesium levels. Overall, the low-dose magnesium sulfate regimen was safe in the management of eclamptic mothers, without toxicity to their neonates. PMID:26600638

A phase I human trial of mitoguazone and gemcitabine sequential bi-weekly treatment of cancer patients.

PubMed

Ishmael, D Richard; Chen, Wei R; Hamilton, Steven A; Liu, Hong; Nordquist, Robert E

2003-01-01

Our previous studies have demonstrated the existence of synergism in a combination therapy using mitoguazone and gemcitabine when the mitoguazone is administered 24 hours before gemcitabine. Based on the cell culture and animal experimental results, a phase I clinical trial was performed in order to determine the toxicity of the combined treatment. Mitoguazone and gemcitabine were administered sequentially: mitoguazone on day 1 and gemcitabine on day 2. This cycle was repeated every 2 weeks. The dosages of these two drugs were varied between patients. Ten patients were enrolled in the study. Six patients began treatment at dose level 1 (mitoguazone 500 mg/m2, gemcitabine 1500 mg/m2), three at dose level 2 (mitoguazone 500 mg/m2, gemcitabine 2000 mg/m2), and one at dose level 3 (mitoguazone 600 mg/m2, gemcitabine 2000 mg/m2). Dose-limiting toxicity (DLT) was only observed in two patients treated at dose level 1 and one patient treated at dose level 3, while all the other patients only experienced nonhematologic toxicity, such as asthenia and mucositis. Two melanoma patients showed responses (one partial and one minor) to the treatment. One lymphoma patient also showed a brief partial response. This phase I trial indicated that the combination of mitoguazone and gemcitabine had limited but noticeable activity for treatment of cancer patients. Further study on the toxicity and on the effect of the scheduled mitoguazone-gemcitabine combination is needed.

Influence of caffeine and/or coffee consumption on the initiation and promotion phases of 7,12-dimethylbenz(a)anthracene-induced rat mammary gland tumorigenesis.

PubMed

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.

Monitoring of isotretinoin therapy by measuring the plasma levels of isotretinoin and 4-oxo-isotretinoin. A useful tool for management of severe acne.

PubMed

Almond-Roesler, B; Blume-Peytavi, U; Bisson, S; Krahn, M; Rohloff, E; Orfanos, C E

1998-01-01

Isotretinoin for oral therapy in severe acne conglobata and acne nodulocystica represents a significant achievement; however, the drug exerts several mucocutaneous and systemic adverse effects, besides its teratogenic potency. The aim of this study was to investigate the plasma levels of isotretinoin and of 4-oxo-isotretinoin over long-term treatment of severe acne and to assess any correlation with the given dose, the clinical improvement and the occurrence of side effects. Forty-one patients with severe acne and acne-related disorders were studied under long-term oral intake of isotretinoin. Therapeutic effects and side effects were evaluated prior, during and at the end of therapy. The plasma levels of isotretinoin and of its major metabolite 4-oxo-isotretinoin were measured by reversed-phase HPLC and were correlated with the administered oral dose and the number and frequency of side effects. Dose-dependent plasma levels of isotretinoin and its metabolite were observed. At a mean dosage of 0.75-1.0 mg/kg/day, 404 +/- 142 ng/ml were measured, whereas the plasma levels of 4-oxo-isotretinoin were 1-2x higher. The plasma levels correlated well with the orally administered dose of isotretinoin and the observed mucocutaneous side effects. The study demonstrates that measuring of the plasma levels may be a helpful tool to monitor the individual therapeutic dose regimen in patients with severe acne in order to minimize undesired side effects and to control oral intake.

Estimation of 1945 to 1957 food consumption

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

Anderson, D.M.; Bates, D.J.; Marsh, T.L.

This report details the methods used and the results of the study on the estimated historic levels of food consumption by individuals in the Hanford Environmental Dose Reconstruction (HEDR) study area from 1945--1957. This period includes the time of highest releases from Hanford and is the period for which data are being collected in the Hanford Thyroid Disease Study. These estimates provide the food-consumption inputs for the HEDR database of individual diets. This database will be an input file in the Hanford Environmental Dose Reconstruction Integrated Code (HEDRIC) computer model that will be used to calculate the radiation dose. Themore » report focuses on fresh milk, eggs, lettuce, and spinach. These foods were chosen because they have been found to be significant contributors to radiation dose based on the Technical Steering Panel dose decision level.« less

Prospective, open, multicentre Phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and cisplatin for esophageal carcinoma.

PubMed

Ma, Hong-Bing; Di, Zheng-Li; Wen, Jiao; Ke, Yue; Sun, Xiaodong; Ren, Juan

2015-02-01

Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy. Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1-5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m(2) at dose levels 1 and 2, 25 mg/m(2) at dose level 3 on Weeks 1-5) and cisplatin (30 mg/m(2) at dose level 1, 40 mg/m(2) at dose levels 2 and 3 on Weeks 1-5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints. Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m(2) and cisplatin 40 mg/m(2). The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2. Neoadjuvant radiochemotherapy with docetaxel 20 mg/m(2) and cisplatin 40 mg/m(2) was effective and tolerable induction regimen in patients with esophageal tumors. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Phase I study of carboplatin combined with pemetrexed for elderly patients with advanced non-squamous non-small cell lung cancer.

PubMed

Takeoka, Hiroaki; Yamada, Kazuhiko; Azuma, Koichi; Zaizen, Yoshiaki; Yamashita, Fumie; Yoshida, Tsukasa; Naito, Yoshiko; Okayama, Yusuke; Miyamoto, Maki; Hoshino, Tomoaki

2014-05-01

The primary objective of this study was to evaluate the safety and tolerability of carboplatin plus pemetrexed for elderly patients (≥75 years) with chemotherapy-naïve advanced non-squamous non-small cell lung cancer. Patients received escalated doses of carboplatin at an area under the concentration-time curve of 4 (Level 1) or 5 (Level 2) plus pemetrexed (500 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation was decided according to whether dose-limiting toxicity occurred in the first cycle of chemotherapy. A total of 20 patients (6 at Level 1, 14 at Level 2) were enrolled. No dose-limiting toxicities were observed in patients at Level 1 or the first six patients at Level 2, and therefore the combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was considered to be the recommended dose. Among a total of 14 patients in Level 2, only 1 patient experienced dose-limiting toxicity: Grade 3 febrile neutropenia and urticaria. The major toxicities were neutropenia, thrombocytopenia and anemia. Liver dysfunction, fatigue and anorexia were also common, but generally manageable. Six patients showed partial responses, giving the overall response rate of 30%. The median progression-free survival period was 4.8 months (95% confidence interval 2.9-6.7 months). The combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was determined as the recommended dose in chemotherapy-naïve elderly patients (≥75 years) with advanced non-squamous non-small cell lung cancer, in view of overall safety and tolerability.

The reduction methods of operator's radiation dose for portable dental X-ray machines.

PubMed

Cho, Jeong-Yeon; Han, Won-Jeong

2012-08-01

This study was aimed to investigate the methods to reduce operator's radiation dose when taking intraoral radiographs with portable dental X-ray machines. Two kinds of portable dental X-ray machines (DX3000, Dexcowin and Rextar, Posdion) were used. Operator's radiation dose was measured with an 1,800 cc ionization chamber (RadCal Corp.) at the hand level of X-ray tubehead and at the operator's chest and waist levels with and without the backscatter shield. The operator's radiation dose at the hand level was measured with and without lead gloves and with long and short cones. The backscatter shield reduced operator's radiation dose at the hand level of X-ray tubehead to 23 - 32%, the lead gloves to 26 - 31%, and long cone to 48 - 52%. And the backscatter shield reduced operator's radiation dose at the operator's chest and waist levels to 0.1 - 37%. When portable dental X-ray systems are used, it is recommended to select X-ray machine attached with a backscatter shield and a long cone and to wear the lead gloves.

Elucidating rifampin's inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite.

PubMed

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.

Safety assessment of hydroethanolic rambutan rind extract: acute and sub-chronic toxicity studies.

PubMed

Thinkratok, Aree; Suwannaprapha, Parin; Srisawat, Rungrudee

2014-10-01

This study evaluated the safety of rambutan rind extract (RRE) in male Wistar rats. While acute toxicity was evaluated by feeding the rats with single doses of RRE (1000, 2000, 3000, 4000, and 5000 mg/kg) and its sub-chronic toxicity was observed in rats orally administered with RRE (500, 1000, and 2000 mg/kg) daily for 30 days. In acute toxicity study, the LD50 was found to be greater than 5000 mg/kg of RRE. In sub-chronic toxicity study, no mortality and sign of toxicity was found up to 1000 mg/kg/day of RRE. At 2000 mg/kg/day dose, the mortality rate was 12.5%. Significant decreases in body weight gain and food consumption were found in both acute and sub-chronic toxicity studies. In acute toxicity study, all the studied doses of RRE did not alter serum levels of triglyceride (TG), aspartate aminotransferase (AST) andalanine aminotransferase (ALT). In sub-chronic toxicity study, all studied doses of RRE significantly decreased plasma levels of TG and blood urea nitrogen, but did not alter plasma levels of AST and ALT. TC levels did not show any significant change in both the studies. The obtained results provide basic information for in vivo experimental studies of the pharmacological potentiality of RRE.

Glyburide transport across the human placenta.

PubMed

Schwartz, Rachelle A; Rosenn, Barak; Aleksa, Katarina; Koren, Gideon

2015-03-01

To estimate the magnitude of transplacental transfer of glyburide in women with gestational diabetes mellitus (GDM). A prospective, observational study was conducted on women with GDM on glyburide therapy. On delivery admission, the glyburide dose and time of last dose were recorded. Immediately postdelivery, maternal and umbilical venous blood samples were obtained and the concentrations of glyburide were determined by high-performance liquid chromatography-mass spectrometry with a limit of detection of 0.25 ng/mL. Nineteen patient dyads were analyzed. The mean total daily maternal glyburide dose was 6.6±6.3 mg per day and the mean time between last dose and sampling was 13.3±6.5 hours. The mean maternal serum glyburide level at birth was 15.4±20.8 ng/mL, whereas the mean umbilical glyburide level was 7.5±8.2 ng/mL, which showed a statistical correlation (r=0.72, P<.01). There were statistically significant relationships between total maternal glyburide dose (1.25-20 mg per day) and maternal glyburide levels (0.93-70.71 ng/mL; r=0.46, P≤.01) and between total maternal glyburide dose and umbilical glyburide levels (0.95-32.41 ng/mL; r=0.43, P≤.01) However, we observed wide variability in maternal and umbilical glyburide levels at both extremes of the total glyburide dose. Seventy-nine percent of cord samples (15/19) had glyburide levels less than 10 ng/mL (the limit of detection reported in earlier studies) and 37% (7/19) were higher than the corresponding maternal samples. Transplacental transfer of glyburide is highly variable among patients, corroborating ex vivo placental perfusion studies showing a transport-mediated glyburide efflux from the fetal to the maternal circulation. In most neonates (79%), glyburide levels were below 10 ng/mL. III.

Effect of radiation dose reduction and iterative reconstruction on computer-aided detection of pulmonary nodules: Intra-individual comparison.

PubMed

Den Harder, Annemarie M; Willemink, Martin J; van Hamersvelt, Robbert W; Vonken, Evert-Jan P A; Milles, Julien; Schilham, Arnold M R; Lammers, Jan-Willem; de Jong, Pim A; Leiner, Tim; Budde, Ricardo P J

2016-02-01

To evaluate the effect of radiation dose reduction and iterative reconstruction (IR) on the performance of computer-aided detection (CAD) for pulmonary nodules. In this prospective study twenty-five patients were included who were scanned for pulmonary nodule follow-up. Image acquisition was performed at routine dose and three reduced dose levels in a single session by decreasing mAs-values with 45%, 60% and 75%. Tube voltage was fixed at 120 kVp for patients ≥ 80 kg and 100 kVp for patients < 80 kg. Data were reconstructed with filtered back projection (FBP), iDose(4) (levels 1,4,6) and IMR (levels 1-3). All noncalcified solid pulmonary nodules ≥ 4 mm identified by two radiologists in consensus served as the reference standard. Subsequently, nodule volume was measured with CAD software and compared to the reference consensus. The numbers of true-positives, false-positives and missed pulmonary nodules were evaluated as well as the sensitivity. Median effective radiation dose was 2.2 mSv at routine dose and 1.2, 0.9 and 0.6 mSv at respectively 45%, 60% and 75% reduced dose. A total of 28 pulmonary nodules were included. With FBP at routine dose, 89% (25/28) of the nodules were correctly identified by CAD. This was similar at reduced dose levels with FBP, iDose(4) and IMR. CAD resulted in a median number of false-positives findings of 11 per scan with FBP at routine dose (93% of the CAD marks) increasing to 15 per scan with iDose(4) (95% of the CAD marks) and 26 per scan (96% of the CAD marks) with IMR at the lowest dose level. CAD can identify pulmonary nodules at submillisievert dose levels with FBP, hybrid and model-based IR. However, the number of false-positive findings increased using hybrid and especially model-based IR at submillisievert dose while dose reduction did not affect the number of false-positives with FBP. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Selective toxin effects on faster and slower growing individuals in the formation of hormesis at the population level - A case study with Lactuca sativa and PCIB.

PubMed

Belz, Regina G; Sinkkonen, Aki

2016-10-01

Natural plant populations have large phenotypic plasticity that enhances acclimation to local stress factors such as toxin exposures. While consequences of high toxin exposures are well addressed, effects of low-dose toxin exposures on plant populations are seldom investigated. In particular, the importance of 'selective low-dose toxicity' and hormesis, i.e. stimulatory effects, has not been studied simultaneously. Since selective toxicity can change the size distribution of populations, we assumed that hormesis alters the size distribution at the population level, and investigated whether and how these two low-dose phenomena coexist. The study was conducted with Lactuca sativa L. exposed to the auxin-inhibitor 2-(p-chlorophenoxy)-2-methylpropionic acid (PCIB) in vitro. In two separate experiments, L. sativa was exposed to 12 PCIB doses in 24 replicates (50 plants/replicate). Shoot/root growth responses at the population level were compared to the fast-growing (≥90% percentile) and the slow-growing subpopulations (≤10% percentile) by Mann-Whitney U testing and dose-response modelling. In the formation of pronounced PCIB hormesis at the population level, low-dose effects proved selective, but widely stimulatory which seems to counteract low-dose selective toxicity. The selectivity of hormesis was dose- and growth rate-dependent. Stimulation occurred at lower concentrations and stimulation percentage was higher among slow-growing individuals, but partly or entirely masked at the population level by moderate or negligible stimulation among the faster growing individuals. We conclude that the hormetic effect up to the maximum stimulation may be primarily facilitated by an increase in size of the most slow-growing individuals, while thereafter it seems that mainly the fast-growing individuals contributed to the observed hormesis at the population level. As size distribution within a population is related to survival, our study hints that selective effects on slow- and fast-growing individuals may change population dynamics, providing that similar effects can be repeated under field conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

Pediatric chest HRCT using the iDose4 Hybrid Iterative Reconstruction Algorithm: Which iDose level to choose?

NASA Astrophysics Data System (ADS)

Smarda, M.; Alexopoulou, E.; Mazioti, A.; Kordolaimi, S.; Ploussi, A.; Priftis, K.; Efstathopoulos, E.

2015-09-01

Purpose of the study is to determine the appropriate iterative reconstruction (IR) algorithm level that combines image quality and diagnostic confidence, for pediatric patients undergoing high-resolution computed tomography (HRCT). During the last 2 years, a total number of 20 children up to 10 years old with a clinical presentation of chronic bronchitis underwent HRCT in our department's 64-detector row CT scanner using the iDose IR algorithm, with almost similar image settings (80kVp, 40-50 mAs). CT images were reconstructed with all iDose levels (level 1 to 7) as well as with filtered-back projection (FBP) algorithm. Subjective image quality was evaluated by 2 experienced radiologists in terms of image noise, sharpness, contrast and diagnostic acceptability using a 5-point scale (1=excellent image, 5=non-acceptable image). Artifacts existance was also pointed out. All mean scores from both radiologists corresponded to satisfactory image quality (score ≤3), even with the FBP algorithm use. Almost excellent (score <2) overall image quality was achieved with iDose levels 5 to 7, but oversmoothing artifacts appearing with iDose levels 6 and 7 affected the diagnostic confidence. In conclusion, the use of iDose level 5 enables almost excellent image quality without considerable artifacts affecting the diagnosis. Further evaluation is needed in order to draw more precise conclusions.

Plasma Methylphenidate Levels in Youths With Attention Deficit Hyperactivity Disorder Treated With OROS Formulation.

PubMed

Yorbik, Ozgur; Mutlu, Caner; Ozilhan, Selma; Eryilmaz, Gul; Isiten, Nuket; Alparslan, Serdar; Saglam, Esra

2015-06-01

There are limited studies investigating the relationship between oral release osmotic system-methylphenidate (OROS-MPH) doses and plasma methylphenidate (MPH) concentrations in children and adolescents. The aim of this study was to investigate the relationship between the doses of OROS-MPH and the plasma levels of the drug. We also examined the effects of the other drugs including aripiprazole, risperidone, fluoxetine, and sertraline on the levels of the MPH in the plasma. The files of 100 attention deficit hyperactivity disorder (ADHD) subjects (76 male, 24 female) who were diagnosed as ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria, were screened. The ages of subjects were between 6 and 18 years (mean = 11.5 ± 3.8 years). Plasma MPH levels were determined by high-performance liquid chromatography-tandem mass spectrometry assay. Daily mean OROS-MPH dose used in ADHD children was 0.7 ± 0.2 mg/kg (range: 0.3-1.3 mg/kg). The mean plasma OROS-MPH was 11.6 ± 7.3 ng/mL (range: 0.5-43.4 ng/mL). There was no group difference in the mean plasma MPH and dose-related MPH levels between the groups that used any additional drug including aripiprazole (n = 25), risperidone (n = 10), fluoxetine (n = 16), sertraline (n = 10), and did not use these drugs (P > 0.05). There was a positive correlation between the OROS-MPH doses (mg/kg) and the blood MPH levels (Pearson correlation = 0.40; P < 0.001). The plasma levels of MPH were found to be less than 13 ng/mL in 65% of the subjects. Our findings point to the fact that plasma levels of MPH show a wide range of changes at similar doses, correlate positively with the doses and, as expected, are not affected by using risperidone, sertraline, fluoxetine, and aripiprazole. Therapeutic drug monitoring may help to optimize MPH dose in patients not responding to treatment or in those experiencing serious side effects, but not in routine clinical practice. The presence of intermediate dose formulations such as 45-mg tablets for OROS-MPH may contribute to the optimization.

Phytochemical screening, physicochemical properties, acute toxicity testing and screening of hypoglycaemic activity of extracts of Eremurus himalaicus baker in normoglycaemic Wistar strain albino rats.

PubMed

Mushtaq, Ahlam; Akbar, Seema; Zargar, Mohammad A; Wali, Adil F; Malik, Akhtar H; Dar, Mohammad Y; Hamid, Rabia; Ganai, Bashir A

2014-01-01

In the present study EtOAc, MeOH, and aqueous extracts of Eremurus himalaicus were evaluated for hypoglycaemic effect in normal rats using both oral glucose tolerance test and 14-day oral administration study. Phytochemical and physicochemical screening was also done. In oral glucose tolerance test the aqueous and MeOH extracts of Eremurus himalaicus at a dose level of 500 mg/kg body weight prior to glucose load resulted in a significant fall in blood glucose level within 150 min. of glucose administration. The aqueous extract at a dose level of 250 mg/kg body weight and 500 mg/kg body weight also showed good hypoglycaemic response (P < 0.001); this was followed by MeOH extract at a dose level of 500 mg/kg body weight (P < 0.05), while MeOH extract at dose level of 250 mg/kg body weight and ethyl acetate extract at dose level of 250 mg/kg body weight and 500 mg/kg body weight exhibited insignificant effect. Phytochemical screening of extracts revealed the presence of alkaloids, terpenoids, phenolics, tannins, saponins, cardiac glycosides, and flavonoids. The results indicate that aqueous extract possess significant hypoglycaemic activity in normoglycaemic rats which may be attributed to the above-mentioned chemical constituents.

Evaluation of a new very low dose imaging protocol: feasibility and impact on X-ray dose levels in electrophysiology procedures.

PubMed

Bourier, Felix; Reents, Tilko; Ammar-Busch, Sonia; Buiatti, Alessandra; Kottmaier, Marc; Semmler, Verena; Telishevska, Marta; Brkic, Amir; Grebmer, Christian; Lennerz, Carsten; Kolb, Christof; Hessling, Gabriele; Deisenhofer, Isabel

2016-09-01

This study presents and evaluates the impact of a new lowest-dose fluoroscopy protocol (Siemens AG), especially designed for electrophysiology (EP) procedures, on X-ray dose levels. From October 2014 to March 2015, 140 patients underwent an EP study on an Artis zee angiography system. The standard low-dose protocol was operated at 23 nGy (fluoroscopy) and at 120 nGy (cine-loop), the new lowest-dose protocol was operated at 8 nGy (fluoroscopy) and at 36 nGy (cine-loop). Procedural data, X-ray times, and doses were analysed in 100 complex left atrial and in 40 standard EP procedures. The resulting dose-area products were 877.9 ± 624.7 µGym² (n = 50 complex procedures, standard low dose), 199 ± 159.6 µGym² (n = 50 complex procedures, lowest dose), 387.7 ± 36.0 µGym² (n = 20 standard procedures, standard low dose), and 90.7 ± 62.3 µGym² (n = 20 standard procedures, lowest dose), P < 0.01. In the low-dose and lowest-dose groups, procedure times were 132.6 ± 35.7 vs. 126.7 ± 34.7 min (P = 0.40, complex procedures) and 72.3 ± 20.9 vs. 85.2 ± 44.1 min (P = 0.24, standard procedures), radiofrequency (RF) times were 53.8 ± 26.1 vs. 50.4 ± 29.4 min (P = 0.54, complex procedures) and 10.1 ± 9.9 vs. 12.2 ± 14.7 min (P = 0.60, standard procedures). One complication occurred in the standard low-dose and lowest-dose groups (P = 1.0). The new lowest-dose imaging protocol reduces X-ray dose levels by 77% compared with the currently available standard low-dose protocol. From an operator standpoint, lowest X-ray dose levels create a different, reduced image quality. The new image quality did not significantly affect procedure or RF times and did not result in higher complication rates. Regarding radiological protection, operating at lowest-dose settings should become standard in EP procedures. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Life-stage-, sex-, and dose-dependent dietary toxicokinetics and relationship to toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats: implications for toxicity test dose selection, design, and interpretation.

PubMed

Saghir, Shakil A; Marty, Mary S; Zablotny, Carol L; Passage, Julie K; Perala, Adam W; Neal, Barbara H; Hammond, Larry; Bus, James S

2013-12-01

Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥ 1200 ppm (63 mg/kg/day) for P1 males and between 200 and 400 ppm (14-27 mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21-35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies.

Life-Stage-, Sex-, and Dose-Dependent Dietary Toxicokinetics and Relationship to Toxicity of 2,4-Dichlorophenoxyacetic Acid (2,4-D) in Rats: Implications for Toxicity Test Dose Selection, Design, and Interpretation

PubMed Central

Marty, Mary S.

2013-01-01

Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥1200 ppm (63mg/kg/day) for P1 males and between 200 and 400 ppm (14–27mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21–35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies. PMID:24105888

A Phase I study of bizelesin (NSC 615291) in patients with advanced solid tumors.

PubMed

Pitot, Henry C; Reid, Joel M; Sloan, Jeff A; Ames, Matthew M; Adjei, Alex A; Rubin, Joseph; Bagniewski, Pamela G; Atherton, Pamela; Rayson, Daniel; Goldberg, Richard M; Erlichman, Charles

2002-03-01

To evaluate the toxicities, characterize the pharmacokinetics, and determine the maximum-tolerated dose of bizelesin administered once every 4 weeks. Patients with advanced solid tumors received escalating doses of bizelesin as an i.v. push every 4 weeks. Pharmacokinetic studies were performed with the first treatment cycle. Nineteen eligible patients received a total of 54 courses of bizelesin at doses ranging from 0.1 to 1 microg/m(2). Dose-limiting toxicity of neutropenia was seen in 2 of 4 patients treated at the 1 microg/m(2) dose level. Nonhematological toxicity was generally mild with maximum toxicity being

Prediction of Vancomycin Dose for Recommended Trough Concentrations in Pediatric Patients With Cystic Fibrosis.

PubMed

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.

A phase I trial of a new antiemetic drug--clebopride malate--in cisplatin-treated patients.

PubMed

Bleiberg, H; Piccart, M; Lips, S; Panzer, J M; N'Koua Mbon, J B

1992-02-01

Clebopride, a new benzamide derivative, has, in common with the other members of this group, antidopaminergic activity. In animals, its therapeutic ratio is superior to that of metoclopramide at doses free of side effects associated with hyperprolactinemia and extrapyramidal symptoms. The present study was designed to define the maximum tolerated dose (MTD) in patients with advanced histologically-proven cancer, treated with cisplatin at a dose of greater than 50 mg/m2. Most of them were pretreated and refractory to standard antiemetics. Clebopride was started at a dosage of 0.10 mg/kg in a group of 6 patients and escalated by 0.2 mg at each dose level. A total of 30 patients were included. Side effects include somnolence, diarrhea and extrapyramidal-like symptoms. The latter occurred at almost all dose levels in 14% of the cycles and limited continuation of the study. Activity in this group of patients was encouraging but, considering the rate of extrapyramidal symptoms, further dose escalation is not indicated and activity at lower, nontoxic levels should be investigated.

Differential toxic effects of Carbofuran and Diazinon on time of flight in pigeons (Columba livia): Potential for pesticide effects on migration

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

Brasel, Jeffrey M.; Environmental Sciences and Health Graduate Program, University of Nevada, Reno, NV 89557; Collier, Abby C.

Cholinesterase inhibiting compounds such as carbamates and organophosphate insecticides have been widely used in agriculture since the ban on organochlorines in the 1970s. Carbofuran, a carbamate, and diazinon, an organophosphate, are among the most commonly implicated cholinesterase inhibitors in episodes of accidental avian toxicity and mortality. Despite the apparent effects of these compounds, little work has been done to study effects of low-level, environmentally relevant doses at the population level in migratory bird species. In this study, homing pigeons were used as surrogate species to assess the differences in the effect of incrementally low doses (0.0, 0.25, 0.5, and 1.0more » mg/kg) of carbofuran and diazinon on time of flight and determine whether there was a threshold dose of either or both xenobiotics when orally administered at these levels. The results indicate that there is a significant dose-dependent increase in flight time in pigeons dosed with carbofuran while diazinon exposed pigeons showed little effect. More profound effects were noted with carbofuran with pigeons falling off the pace of the flock and a dose for highly significant increase in flight time elucidated between 0.5 and 1.0 mg/kg. The results of the studies validate the homing pigeon as a good subject for comparative studies of cholinesterase inhibitors in birds and the need for further research on repeated low-level exposures on populations of avian species.« less

Cranial CT with adaptive statistical iterative reconstruction: improved image quality with concomitant radiation dose reduction.

PubMed

Rapalino, O; Kamalian, Shervin; Kamalian, Shahmir; Payabvash, S; Souza, L C S; Zhang, D; Mukta, J; Sahani, D V; Lev, M H; Pomerantz, S R

2012-04-01

To safeguard patient health, there is great interest in CT radiation-dose reduction. The purpose of this study was to evaluate the impact of an iterative-reconstruction algorithm, ASIR, on image-quality measures in reduced-dose head CT scans for adult patients. Using a 64-section scanner, we analyzed 100 reduced-dose adult head CT scans at 6 predefined levels of ASIR blended with FBP reconstruction. These scans were compared with 50 CT scans previously obtained at a higher routine dose without ASIR reconstruction. SNR and CNR were computed from Hounsfield unit measurements of normal GM and WM of brain parenchyma. A blinded qualitative analysis was performed in 10 lower-dose CT datasets compared with higher-dose ones without ASIR. Phantom data analysis was also performed. Lower-dose scans without ASIR had significantly lower mean GM and WM SNR (P = .003) and similar GM-WM CNR values compared with higher routine-dose scans. However, at ASIR levels of 20%-40%, there was no statistically significant difference in SNR, and at ASIR levels of ≥60%, the SNR values of the reduced-dose scans were significantly higher (P < .01). CNR values were also significantly higher at ASIR levels of ≥40% (P < .01). Blinded qualitative review demonstrated significant improvements in perceived image noise, artifacts, and GM-WM differentiation at ASIR levels ≥60% (P < .01). These results demonstrate that the use of ASIR in adult head CT scans reduces image noise and increases low-contrast resolution, while allowing lower radiation doses without affecting spatial resolution.

Dose-dependent effect of aspirin on the level of sphingolipids in human blood.

PubMed

Knapp, M; Lisowska, A; Knapp, P; Baranowski, M

2013-01-01

Aspirin is an antiplatelet drug which is commonly used in secondary prevention in ischemic heart disease and cerebrovascular events, and in newly diagnosed myocardial infarction. The aim of the present study was to examine effect of aspirin on the level of selected sphingolipid intermediates in plasma, erythrocytes and platelets. Forty two healthy volunteers participated in the study. They were divided into two groups. In one group aspirin was given orally, daily, for one week in a dose of 75 mg (n=25). The subjects from the second group received one 300 mg dose of the drug (n=17). In both groups the blood was taken 4h after the last dose of aspirin. The following sphingolipid intermediates were quantified using high-pressure liquid chromatography: sphinganine, sphingosine, sphingosine-1-phosphate (S1P), sphinganine-1-phosphate (SA1P) and ceramide. It was found that lower dose of aspirin increased the level of S1P and ceramide in erythrocytes (by 23 and 37%, respectively) having no effect on plasma and platelet sphingolipid levels. Higher dose of the drug reduced S1P and SA1P concentration in the plasma (by 16 and 10%, respectively). We conclude that aspirin interferes with sphingolipid metabolism in blood and that this effect depends on a dose of the drug. Since S1P is a potent cardioprotectant, the reduction in its plasma concentration after the loading dose of aspirin could be undesired side effect of the drug.

Investigations of putative reproductive toxicity of low-dose exposures to vinclozolin in Wistar rats.

PubMed

Flick, Burkhard; Schneider, Steffen; Melching-Kollmuss, Stephanie; Fussell, Karma C; Gröters, Sibylle; Buesen, Roland; Strauss, Volker; van Ravenzwaay, Bennard

2017-04-01

The current investigation examines whether the fungicide vinclozolin, which has an anti-androgenic mode of action, is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology and histopathological examinations. Doses were chosen to represent an effect level (20 mg/kg bw/d), the current NOAEL (4 mg/kg bw/d), and a dose close to the "ADI" (0.005 mg/kg bw/d) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at the effect level but not at lower exposures. Nipple/areola counts appeared to be the most sensitive measure of effect, followed by male sex organ weights at sexual maturation, and finally gross and histopathological findings. The results indicate the absence of evidence for effects at low or very low dose levels. A non-monotonic dose-response relationship was not evident.

Can reduction of uncertainties in cervix cancer brachytherapy potentially improve clinical outcome?

PubMed

Nesvacil, Nicole; Tanderup, Kari; Lindegaard, Jacob C; Pötter, Richard; Kirisits, Christian

2016-09-01

The aim of this study was to quantify the impact of different types and magnitudes of dosimetric uncertainties in cervix cancer brachytherapy (BT) on tumour control probability (TCP) and normal tissue complication probability (NTCP) curves. A dose-response simulation study was based on systematic and random dose uncertainties and TCP/NTCP models for CTV and rectum. Large patient cohorts were simulated assuming different levels of dosimetric uncertainties. TCP and NTCP were computed, based on the planned doses, the simulated dose uncertainty, and an underlying TCP/NTCP model. Systematic uncertainties of 3-20% and random uncertainties with a 5-30% standard deviation per BT fraction were analysed. Systematic dose uncertainties of 5% lead to a 1% decrease/increase of TCP/NTCP, while random uncertainties of 10% had negligible impact on the dose-response curve at clinically relevant dose levels for target and OAR. Random OAR dose uncertainties of 30% resulted in an NTCP increase of 3-4% for planned doses of 70-80Gy EQD2. TCP is robust to dosimetric uncertainties when dose prescription is in the more flat region of the dose-response curve at doses >75Gy. For OARs, improved clinical outcome is expected by reduction of uncertainties via sophisticated dose delivery and treatment verification. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

ESTIMATION OF ADULT PATIENT DOSES FOR CHEST X-RAY EXAMINATIONS AND COMPARISON WITH DIAGNOSTIC REFERENCE LEVELS (DRLs).

PubMed

Bas Mor, H; Altinsoy, N; Söyler, I

2018-05-08

The aim of this study was to evaluate the radiation doses to patient during chest (posterior anterior/and lateral) examinations. The study was performed in three public hospitals of İstanbul province with a total of 300 adult patients. Entrance surface dose (ESD) measurements were conducted on computed radiography, digital radiography and screen film system. ESD was estimated by using International Atomic Energy Agency (IAEA) model and Davies model which are the common indirect models. Results were compared with diagnostic reference levels from the European Commission, IAEA and National Radiological Protection Board. Although the results are compatible with the international diagnostic reference levels, they present variations between the hospitals. Dose variations for the same type of X-ray examination support the idea that further optimization is possible.

Intraperitoneal Vancomycin Concentrations During Peritoneal Dialysis–Associated Peritonitis: Correlation with Serum Levels

PubMed Central

Fish, Richard; Nipah, Robert; Jones, Chris; Finney, Hazel; Fan, Stanley L.S.

2012-01-01

♦ Background: For the treatment of peritoneal dialysis–associated peritonitis (PDP), it has been suggested that serum concentrations of vancomycin be kept above 12 mg/L – 15 mg/L. However, studies correlating vancomycin concentrations in serum and peritoneal dialysate effluent (PDE) during active infection are sparse. We undertook the present study to investigate this issue and to determine whether achieving the recommended serum level of vancomycin results in therapeutic levels intraperitoneally. ♦ Methods: We studied patients treated with intraperitoneal (IP) vancomycin for non-gram-negative PDP. We gave a single dose (approximately 30 mg/kg) at presentation, and we subsequently measured vancomycin levels in PDE on day 5; we wanted to determine if efflux of vancomycin from serum to PDE during a 4-hour dwell was consistent and resulted in therapeutic levels. ♦ Results: Of the 48 episodes of PDP studied, serum vancomycin concentrations exceeding 12 mg/L were achieved in 98% of patients, but in 11 patients (23%), a PDE vancomycin level below 4 mg/L—the minimal inhibitory concentration (MIC) of many gram-positive organisms—was observed at the end of a 4-hour dwell on day 5. The correlation between the concentrations of vancomycin in serum and PDE (from efflux of antibiotic over 4 hours) was statistically significant, but poor (R2 = 0.18). ♦ Conclusions: Our data support the International Society for Peritoneal Dialysis statement that adequate serum vancomycin concentrations can be achieved with intermittent dosing (single dose every 5 days), but cannot guarantee therapeutic PDE levels in the treatment of PDP. Intermittent dosing of vancomycin may not consistently result in PDE concentrations markedly greater than MIC of many important pathogens. Although the clinical significance of this finding remains to be determined, it may be preferable to give smaller but more frequent doses of PDE vancomycin (continuous dosing) for adults with PDP (as is currently recommended for children). PMID:22045102

SU-E-T-48: A Multi-Institutional Study of Independent Dose Verification for Conventional, SRS and SBRT

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

Takahashi, R; Kamima, T; Tachibana, H

2015-06-15

Purpose: To show the results of a multi-institutional study of the independent dose verification for conventional, Stereotactic radiosurgery and body radiotherapy (SRS and SBRT) plans based on the action level of AAPM TG-114. Methods: This study was performed at 12 institutions in Japan. To eliminate the bias of independent dose verification program (Indp), all of the institutions used the same CT-based independent dose verification software (Simple MU Analysis, Triangle Products, JP) with the Clarkson-based algorithm. Eclipse (AAA, PBC), Pinnacle{sup 3} (Adaptive Convolve) and Xio (Superposition) were used as treatment planning system (TPS). The confidence limits (CL, Mean±2SD) for 18 sitesmore » (head, breast, lung, pelvis, etc.) were evaluated in comparison in dose between the TPS and the Indp. Results: A retrospective analysis of 6352 treatment fields was conducted. The CLs for conventional, SRS and SBRT were 1.0±3.7 %, 2.0±2.5 % and 6.2±4.4 %, respectively. In conventional plans, most of the sites showed within 5 % of TG-114 action level. However, there were the systematic difference (4.0±4.0 % and 2.5±5.8 % for breast and lung, respectively). In SRS plans, our results showed good agreement compared to the action level. In SBRT plans, the discrepancy between the Indp was variable depending on dose calculation algorithms of TPS. Conclusion: The impact of dose calculation algorithms for the TPS and the Indp affects the action level. It is effective to set the site-specific tolerances, especially for the site where inhomogeneous correction can affect dose distribution strongly.« less

Valeriana wallichii root extract improves sleep quality and modulates brain monoamine level in rats.

PubMed

Sahu, Surajit; Ray, Koushik; Yogendra Kumar, M S; Gupta, Shilpa; Kauser, Hina; Kumar, Sanjeev; Mishra, Kshipra; Panjwani, Usha

2012-07-15

The present study was performed to investigate the effects of Valeriana wallichi (VW) aqueous root extract on sleep-wake profile and level of brain monoamines on Sprague-Dawley rats. Electrodes and transmitters were implanted to record EEG and EMG in freely moving condition and the changes were recorded telemetrically after oral administration of VW in the doses of 100, 200 and 300 mg/kg body weight. Sleep latency was decreased and duration of non-rapid eye movement (NREM) sleep was increased in a dose dependent manner. A significant decrease of sleep latency and duration of wakefulness were observed with VW at doses of 200 and 300 mg/kg. Duration of NREM sleep as well as duration of total sleep was increased significantly after treatment with VW at the doses of 200 and 300 mg/kg. VW also increased EEG slow wave activity during NREM sleep at the doses of 200 and 300 mg/kg. Level of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and hydroxy indole acetic acid (HIAA) were measured in frontal cortex and brain stem after VW treatment at the dose of 200mg/kg. NE and 5HT level were decreased significantly in both frontal cortex and brain stem. DA and HIAA level significantly decreased only in cortex. DOPAC level was not changed in any brain region studied. In conclusion it can be said that VW water extract has a sleep quality improving effect which may be dependent upon levels of monoamines in cortex and brainstem. Copyright © 2012 Elsevier GmbH. All rights reserved.

Assessment of dedicated low-dose cardiac micro-CT reconstruction algorithms using the left ventricular volume of small rodents as a performance measure

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

Maier, Joscha, E-mail: joscha.maier@dkfz.de; Sawall, Stefan; Kachelrieß, Marc

2014-05-15

Purpose: Phase-correlated microcomputed tomography (micro-CT) imaging plays an important role in the assessment of mouse models of cardiovascular diseases and the determination of functional parameters as the left ventricular volume. As the current gold standard, the phase-correlated Feldkamp reconstruction (PCF), shows poor performance in case of low dose scans, more sophisticated reconstruction algorithms have been proposed to enable low-dose imaging. In this study, the authors focus on the McKinnon-Bates (MKB) algorithm, the low dose phase-correlated (LDPC) reconstruction, and the high-dimensional total variation minimization reconstruction (HDTV) and investigate their potential to accurately determine the left ventricular volume at different dose levelsmore » from 50 to 500 mGy. The results were verified in phantom studies of a five-dimensional (5D) mathematical mouse phantom. Methods: Micro-CT data of eight mice, each administered with an x-ray dose of 500 mGy, were acquired, retrospectively gated for cardiac and respiratory motion and reconstructed using PCF, MKB, LDPC, and HDTV. Dose levels down to 50 mGy were simulated by using only a fraction of the projections. Contrast-to-noise ratio (CNR) was evaluated as a measure of image quality. Left ventricular volume was determined using different segmentation algorithms (Otsu, level sets, region growing). Forward projections of the 5D mouse phantom were performed to simulate a micro-CT scan. The simulated data were processed the same way as the real mouse data sets. Results: Compared to the conventional PCF reconstruction, the MKB, LDPC, and HDTV algorithm yield images of increased quality in terms of CNR. While the MKB reconstruction only provides small improvements, a significant increase of the CNR is observed in LDPC and HDTV reconstructions. The phantom studies demonstrate that left ventricular volumes can be determined accurately at 500 mGy. For lower dose levels which were simulated for real mouse data sets, the HDTV algorithm shows the best performance. At 50 mGy, the deviation from the reference obtained at 500 mGy were less than 4%. Also the LDPC algorithm provides reasonable results with deviation less than 10% at 50 mGy while PCF and MKB reconstruction show larger deviations even at higher dose levels. Conclusions: LDPC and HDTV increase CNR and allow for quantitative evaluations even at dose levels as low as 50 mGy. The left ventricular volumes exemplarily illustrate that cardiac parameters can be accurately estimated at lowest dose levels if sophisticated algorithms are used. This allows to reduce dose by a factor of 10 compared to today's gold standard and opens new options for longitudinal studies of the heart.« less

Developmental toxicity of orally administered sildenafil citrate (Viagra) in SWR/J mice

PubMed Central

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

Developmental toxicity of orally administered sildenafil citrate (Viagra) in SWR/J mice.

PubMed

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.

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

PubMed

Ludvigsson, Johnny; Krisky, David; Casas, Rosaura; Battelino, Tadej; Castaño, Luis; Greening, James; Kordonouri, Olga; Otonkoski, Timo; Pozzilli, Paolo; Robert, Jean-Jacques; Veeze, Henk J; Palmer, Jerry; Samuelsson, Ulf; Elding Larsson, Helena; Åman, Jan; Kärdell, Gunilla; Neiderud Helsingborg, Jan; Lundström, Göran; Albinsson, Eva; Carlsson, Annelie; Nordvall, Maria; Fors, Hans; Arvidsson, Carl-Göran; Edvardson, Stig; Hanås, Ragnar; Larsson, Karin; Rathsman, Björn; Forsgren, Henrik; Desaix, Helena; Forsander, Gun; Nilsson, Nils-Östen; Åkesson, Carl-Göran; Keskinen, Päivi; Veijola, Riitta; Talvitie, Timo; Raile, Klemens; Kapellen, Thomas; Burger, Walter; Neu, Andreas; Engelsberger, Ilse; Heidtmann, Bettina; Bechtold, Suzanne; Leslie, David; Chiarelli, Francesco; Cicognani, Alesandro; Chiumello, Giuseppe; Cerutti, Franco; Zuccotti, Gian Vincenzo; Gomez Gila, Ana; Rica, Itxaso; Barrio, Raquel; Clemente, Maria; López Garcia, Maria José; Rodriguez, Mercedes; Gonzalez, Isabel; Lopez, Juan Pedro; Oyarzabal, Mirentxu; Reeser, H M; Nuboer, Roos; Stouthart, Pauline; Bratina, Natasa; Bratanic, Nina; de Kerdanet, Marc; Weill, Jacques; Ser, Nicole; Barat, Pascal; Bertrand, Anne Marie; Carel, Jean-Claude; Reynaud, Rachel; Coutant, Regis; Baron, Sabine

2012-02-02

The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

Phase I study of the c-raf-1 antisense oligonucleotide ISIS 5132 in combination with carboplatin and paclitaxel in patients with previously untreated, advanced non-small cell lung cancer.

PubMed

Fidias, Panos; Pennell, Nathan A; Boral, Anthony L; Shapiro, Geoffrey I; Skarin, Arthur T; Eder, Joseph P; Kwoh, T Jesse; Geary, Richard S; Johnson, Bruce E; Lynch, Thomas J; Supko, Jeffrey G

2009-09-01

A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c-raf-1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC). Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days. Starting doses were paclitaxel 175 mg/m(2) and carboplatin targeting an area under the free platinum plasma concentration-time curve (AUC(fp)) of 5 mg . min/ml (dose level 1). The carboplatin dose was then increased to AUC(fp) 6 mg . min/ml (dose level 2) after which the paclitaxel dose was increased to 200 mg/m(2) (dose level 3). The maximum tolerated dose was established by toxicity during the first two 21-day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS 5132 infusion. Thirteen patients were treated with the carboplatin/paclitaxel/ISIS 5132 combination. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC(fp) 6 mg . min/ml, paclitaxel 175 mg/m(2), and ISIS 5132 2.0 mg/kg/d for 14 days. There were no objective responses and the concurrent infusion of ISIS 5132 did not alter the plasma pharmacokinetics of paclitaxel or total platinum. ISIS 5132 can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study.

A phase I study of LY317615 (enzastaurin) and temozolomide in patients with gliomas (EORTC trial 26054)

PubMed Central

Rampling, Roy; Sanson, Marc; Gorlia, Thiery; Lacombe, Denis; Lai, Christina; Gharib, Myriam; Taal, Walter; Stoffregen, Clemens; Decker, Rodney; van den Bent, Martin J.

2012-01-01

We report a phase 1 study to examine the safety and recommended dose of the oral protein kinase C-beta inhibitor (anti-angiogenic) enzastaurin in combination with single-agent temozolomide. The study was conducted in patients with recurrent glioblastoma or newly diagnosed disease that was not treatable with standard (chemo)radiotherapy. Patients were treated with standard dose temozolomide (200 mg/m2 for 5 days every 4 weeks) together with daily oral enzastaurin. Three dose levels of enzastaurin were investigated: 250 mg daily (OD), 500 mg OD, and 250 mg twice daily (BID). Dose-limiting toxicity was determined in the first 2 cycles, but treatment continued until limiting toxicity or disease progression was identified. Twenty-eight patients were enrolled. No dose-limiting toxicity was noted at 250 mg OD or 500 mg OD. However, at 250 mg BID, 2 dose-limiting episodes of thrombocytopenia were noted. The recommended dose for enzastaurin in combination with standard 4-weekly temozolomide is therefore 500 mg OD. The pharmacokinetics of enzastaurin in combination with temozolomide was evaluated. Temozolomide did not appear to effect enzastaurin exposures at the 250 mg or 500 mg OD dose levels. PMID:22291006

Measles antibody levels after vaccination with Edmonston-Zagreb and Schwarz measles vaccine at 9 months or at 9 and 18 months of age: a serological study within a randomised trial of different measles vaccines.

PubMed

Martins, Cesario; Garly, May-Lill; Bale, Carlitos; Rodrigues, Amabelia; Benn, Christine S; Whittle, Hilton; Aaby, Peter

2013-11-19

Standard-titre Schwarz (SW) and Edmonston-Zagreb (EZ) measles vaccines (MV) are both used in the routine immunisation programme. Within a trial of different strains of MV, we examined antibody responses in both one-dose and two-dose schedules when the first dose was administered at 9 months. The trial was conducted in an urban area in Guinea-Bissau where we have had a health and demographic surveillance system and studied strategies to prevent measles infection since 1978. In the present study, children were randomised to SW or EZ as the first MV and furthermore randomised to a second dose of the same MV or no vaccine at 18 months of age. We obtained blood samples from 996 children at baseline; post-vaccination blood samples were collected at 18 and 24 months of age to assess measles antibody levels after one or two doses of MV. At age 18 months all had responded to the first dose and only 1% (8/699) of the children had non-protective antibody levels irrespective of vaccine type. SW was associated with significantly higher levels of measles antibodies (geometric mean titre (GMT)=2114 mIU/mL (95%CI 1153-2412)) than EZ (GMT=807 mIU/mL (722-908)) (p=0.001). Antibody concentration was significantly higher in girls than in boys after EZ but not after SW. Antibody levels were higher in the rainy than the dry season. There was no clear indication that a booster dose at 18 months increased the antibody level at 24 months of age. Maternal antibody levels have declined significantly in recent years and 99% had protective levels of measles antibody following primary MV at 9 months of age. It is unlikely that measles prevention and child health will be improved by increasing the age of MV as currently recommended. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Low-dose memantine attenuated morphine addictive behavior through its anti-inflammation and neurotrophic effects in rats.

PubMed

Chen, Shiou-Lan; Tao, Pao-Luh; Chu, Chun-Hsien; Chen, Shih-Heng; Wu, Hsiang-En; Tseng, Leon F; Hong, Jau-Shyong; Lu, Ru-Band

2012-06-01

Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer's disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2-1 mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6 days of morphine treatment, cytokine (IL-1β, IL-6) levels had significantly increased in serum; IL-1β and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects.

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.

Evidence-based Critical Evaluation of Glycemic Potential of Cynodon dactylon

PubMed Central

Singh, Santosh Kumar; Rai, Prashant Kumar; Jaiswal, Dolly

2008-01-01

The present study is an extension of our previous work carried out on Cynodon dactylon. This study deals with the critical evaluation of glycemic potential of ethanolic extract of defatted C. dactylon. The doses of 250, 500 and 750 mg kg−1 bw of the extract were administered orally to normal as well as Streptozotocin-induced diabetic rats to study its glycemic potential. The effect of repeated oral administration of the same doses of ethanolic extract was also studied on serum lipid profile of severely diabetic (SD) rats. The dose of 500 mg kg−1 bw was identified as the most effective dose as it lowered the blood glucose levels of normal by 42.12% and of diabetic by 43.42% during fasting blood glucose (FBG) and glucose tolerance test respectively. The SD rats were also treated daily with this identified dose of 500 mg kg−1 bw for 2 weeks and a significant reduction of 56.34% was observed in FBG level. Total cholesterol, low density lipoprotein and triglyceride levels were also decreased by 32.94, 64.06 and 48.46% respectively in SD rats whereas, cardioprotective high density lipoprotein increased by 16.45%. The reduced urine sugar level and increased body weight are additional advantages. These evidences clearly indicate that the ethanolic extract of defatted C. dactylon has high antidiabetic potential along with good hypolipidemic profile. PMID:18955211

Evaluation of dose‐area product of common radiographic examinations towards establishing a preliminary diagnostic reference levels (PDRLs) in Southwestern Nigeria

PubMed Central

Jibiri, Nnamdi N.

2016-01-01

In Nigeria, a large number of radiographic examinations are conducted yearly for various diagnostic purposes. However, most examinations carried out do not have records of doses received by the patients, and the employed exposure parameters used are not documented; therefore, adequate radiation dose management is hindered. The aim of the present study was to estimate the dose‐area product (DAP) of patients examined in Nigeria, and to propose regional reference dose levels for nine common examinations (chest PA, abdomen AP, pelvis AP, lumbar AP, skull AP, leg AP, knee AP, hand AP, and thigh AP) undertaken in Nigeria. Measurement of entrance surface dose (ESD) was carried out using thermoluminescent dosimeter (TLD). Measured ESDS were converted into DAP using the beam area of patients in 12 purposely selected hospitals. Results of the study show that the maximum/minimum ratio ranged from 3 for thigh AP to 57 in abdomen AP. The range of determined mean and 75th percentile DAPs were 0.18–17.16, and 0.25–28.59 Gy cm2, respectively. Data available for comparison show that 75th percentile DAPs in this study (in chest PA, abdomen AP, pelvis AP, lumbar AP) are higher than NRPB‐HPE reference values. The DAP in this study is higher by factor of 31.4 (chest PA), 9.9 (abdomen AP), 2.2 (pelvis AP), and 2.1 (lumbar AP) than NRPB‐HPE values. The relative higher dose found in this study shows nonoptimization of practice in Nigeria. It is expected that regular dose auditing and dose optimization implementation in Nigeria would lead to lower DAP value, especially in abdomen AP. The 75th percentile DAP distribution reported in this study could be taken as regional diagnostic reference level in the Southwestern Nigeria; however, a more extensive nationwide dose survey is required to establish national reference dose. PACS number(s): 87.53.Bn, 87.59.B PMID:27929511

Virtual single source CT using dual source acquisition: Clinical applicability in run-off CT-angiography for intra-individual comparison of different scan protocols.

PubMed

Werncke, T; Hinrichs, J B; Alikhani, B; Maschke, S; Wacker, F K; Meyer, B C

2018-04-01

Virtual single source computed tomography (VSS-CT) acquisition on a dual source CT (DSCT) has been demonstrated to allow for dose-neutral intra-individual comparison of three acquisition protocols at different radiation dose levels (RDL) within one acquisition in a phantom. The purpose of this study was twofold: first to evaluate the applicability of VSS-CT in patients and second to optimize the task-dependent trade-off between radiation dose and image quality of lower extremity CT angiography (run-off CTA). In this IRB-approved prospective study 52 patients underwent run-off CTA between 06/2012 and 06/2013. VSS-CT acquisition was conducted using a first generation DSCT applying equal X-ray tube settings (120 kVp), collimation (2 × 32 × 0.6 mm), and slice thickness (1.0 mm) but different effective tube current-time products (tube A: 80 mAs, tube B: 40 mAs). Three different image datasets representing three different radiation dose levels (RDL40, RDL80, RDL120) were reconstructed using a soft kernel from the raw data of tube B, tube A or both tubes combined. Dose length products (DLP) of each raw data set were documented. Quantitative image quality (IQ) was assessed for five anatomical levels using image noise and contrast-to-noise ratio (CNR). To investigate dose efficiency of each acquisition, the dose-weighted CNR (CNRD) was determined. Qualitative IQ was evaluated by two blinded readers in consensus using a 5-point Likert scale and compared with a Friedman- and posthoc Wilcoxon test. Mean DLP was 200 ± 40, 400 ± 90 and 600 ± 130 mGy·cm for the RDL40, RDL80 and RDL120, respectively. Image noise and CNR were best for RDL120 and decreased significantly for RDL80 and RDL40, independent of the anatomic level (p < 0.001). CNRD showed no significant differences at the abdominal and pelvic level between the investigated radiation dose levels. However, for thigh to foot level a significant increase of CNRD was noted between RDL120, RDL80 and RDL40. Significant differences of qualitative IQ were observed between RDL120 and RDL40 from the abdominal to the foot level, whereas no difference was seen for the other dose levels. Radiation dose splitting with VSS-CT can be applied to run-off CTA facilitating intra-individual comparison of different acquisition protocols without additional radiation exposure. Furthermore, a radiation dose reduction potential for run-off CTA of approximately 1/3 as compared to the acquisition protocol recommended by the manufacturer could be identified in this study. Copyright © 2018 Elsevier B.V. All rights reserved.

Selection of the initial design for the two-stage continual reassessment method.

PubMed

Jia, Xiaoyu; Ivanova, Anastasia; Lee, Shing M

2017-01-01

In the two-stage continual reassessment method (CRM), model-based dose escalation is preceded by a pre-specified escalating sequence starting from the lowest dose level. This is appealing to clinicians because it allows a sufficient number of patients to be assigned to each of the lower dose levels before escalating to higher dose levels. While a theoretical framework to build the two-stage CRM has been proposed, the selection of the initial dose-escalating sequence, generally referred to as the initial design, remains arbitrary, either by specifying cohorts of three patients or by trial and error through extensive simulations. Motivated by a currently ongoing oncology dose-finding study for which clinicians explicitly stated their desire to assign at least one patient to each of the lower dose levels, we proposed a systematic approach for selecting the initial design for the two-stage CRM. The initial design obtained using the proposed algorithm yields better operating characteristics compared to using a cohort of three initial design with a calibrated CRM. The proposed algorithm simplifies the selection of initial design for the two-stage CRM. Moreover, initial designs to be used as reference for planning a two-stage CRM are provided.

Benchmarking pediatric cranial CT protocols using a dose tracking software system: a multicenter study.

PubMed

De Bondt, Timo; Mulkens, Tom; Zanca, Federica; Pyfferoen, Lotte; Casselman, Jan W; Parizel, Paul M

2017-02-01

To benchmark regional standard practice for paediatric cranial CT-procedures in terms of radiation dose and acquisition parameters. Paediatric cranial CT-data were retrospectively collected during a 1-year period, in 3 different hospitals of the same country. A dose tracking system was used to automatically gather information. Dose (CTDI and DLP), scan length, amount of retakes and demographic data were stratified by age and clinical indication; appropriate use of child-specific protocols was assessed. In total, 296 paediatric cranial CT-procedures were collected. Although the median dose of each hospital was below national and international diagnostic reference level (DRL) for all age categories, statistically significant (p-value < 0.001) dose differences among hospitals were observed. The hospital with lowest dose levels showed smallest dose variability and used age-stratified protocols for standardizing paediatric head exams. Erroneous selection of adult protocols for children still occurred, mostly in the oldest age-group. Even though all hospitals complied with national and international DRLs, dose tracking and benchmarking showed that further dose optimization and standardization is possible by using age-stratified protocols for paediatric cranial CT. Moreover, having a dose tracking system revealed that adult protocols are still applied for paediatric CT, a practice that must be avoided. • Significant differences were observed in the delivered dose between age-groups and hospitals. • Using age-adapted scanning protocols gives a nearly linear dose increase. • Sharing dose-data can be a trigger for hospitals to reduce dose levels.

Characterization of beta-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study.

PubMed

Nakamura, M; Ishii, A; Nakahara, D

1998-05-22

In vivo microdialysis was used to investigate the effect of beta-phenylethylamine on extracellular levels of monoamines and their metabolites in the nucleus accumbens of conscious rats. At all doses tested (1, 10 and 100 microM), infusion of beta-phenylethylamine through the microdialysis probe significantly increased extracellular levels of dopamine in the nucleus accumbens. These increases were dose-related. The increase in dopamine levels induced by 100 microM beta-phenylethylamine was not affected by co-perfusion of 4 microM tetrodotoxin. The ability of 100 microM beta-phenylethylamine to increase the extracellular level of dopamine was comparable to that of the same dose of methamphetamine. On the other hand, beta-phenylethylamine had a much less potent enhancing effect on 5-hydroxytryptamine (5-HT) than dopamine levels. Only the highest dose (100 microM) caused a statistically significant effect on 5-HT levels. Over the dose range tested (1, 10 and 100 microM), beta-phenylethylamine had no effect on extracellular metabolite levels of dopamine and 5-HT. The results suggest that beta-phenylethylamine increases the efflux of monoamines, preferentially dopamine, without affecting monoamine metabolism, in the nucleus accumbens.

Radiation Dose Index of Renal Colic Protocol CT Studies in the United States

PubMed Central

Lukasiewicz, Adam; Bhargavan-Chatfield, Mythreyi; Coombs, Laura; Ghita, Monica; Weinreb, Jeffrey; Gunabushanam, Gowthaman; Moore, Christopher L.

2016-01-01

Purpose To determine radiation dose indexes for computed tomography (CT) performed with renal colic protocols in the United States, including frequency of reduced-dose technique usage and any institutional-level factors associated with high or low dose indexes. Materials and Methods The Dose Imaging Registry (DIR) collects deidentified CT data, including examination type and dose indexes, for CT performed at participating institutions; thus, the DIR portion of the study was exempt from institutional review board approval and was HIPAA compliant. CT dose indexes were examined at the institutional level for CT performed with a renal colic protocol at institutions that contributed at least 10 studies to the registry as of January 2013. Additionally, patients undergoing CT for renal colic at a single institution (with institutional review board approval and informed consent from prospective subjects and waiver of consent from retrospective subjects) were studied to examine individual renal colic CT dose index patterns and explore relationships between patient habitus, demographics, and dose indexes. Descriptive statistics were used to analyze dose indexes, and linear regression and Spearman correlations were used to examine relationships between dose indexes and institutional factors. Results There were 49 903 renal colic protocol CT examinations conducted at 93 institutions between May 2011 and January 2013. Mean age ± standard deviation was 49 years ± 18, and 53.9% of patients were female. Institutions contributed a median of 268 (interquartile range, 77–699) CT studies. Overall mean institutional dose-length product (DLP) was 746 mGy · cm (effective dose, 11.2 mSv), with a range of 307–1497 mGy · cm (effective dose, 4.6–22.5 mSv) for mean DLPs. Only 2% of studies were conducted with a DLP of 200 mGy · cm or lower (a “reduced dose”) (effective dose, 3 mSv), and only 10% of institutions kept DLP at 400 mGy · cm (effective dose, 6 mSv) or less in at least 50% of patients. Conclusion Reduced-dose renal protocol CT is used infrequently in the United States. Mean dose index is higher than reported previously, and institutional variation is substantial. PMID:24484064

Commentary on "randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and Ki67 labeling in prostate cancer patients." Wagner D, Trudel D, Van der Kwast T, Nonn L, Giangreco AA, Li D, Dias A, Cardoza M, Laszlo S, Hersey K, Klotz L, Finelli A, Fleshner N, Vieth R, Department of Nutritional Sciences, University of Toronto, Ontario, Canada.: J Clin Endocrinol Metab 2013;98(4):1498-507 [Epub 2013 Mar 5].

PubMed

Olumi, Aria F

2014-02-01

Vitamin D3 might benefit prostate cancer (PCa) patients because prostate cells can locally synthesize the active hormone calcitriol. Our objective was to determine the effects of oral vitamin D3 on vitamin D metabolites and PCa proliferative activity in prostate tissue. We conducted a double-blind randomized clinical trial at surgical oncology clinics in Toronto, Canada. PCa patients (Gleason 6 or 7) participated in the study. Of 66 subjects who were enrolled, 63 completed the dosing protocol. Vitamin D3 (400, 10000, or 40000 IU/d) was orally administered before radical prostatectomy. We evaluated vitamin D metabolite levels and Ki67 labeling in surgical prostate tissue. Safety measures, PTH, and prostate-specific antigen (PSA) were also assessed. Prostate tissue and serum levels of vitamin D metabolites, including calcitriol, increased dose dependently (P<.03) and were significantly higher in the 40000-IU/d group than in every other dose group (P<.03). Prostate vitamin D metabolites correlated positively with serum levels (P<.0001). Ki67 measures did not differ significantly among vitamin D dose groups. However, cross-sectional analysis indicated that the calcitriol level attained in prostate was inversely associated with Ki67 intensity and Ki67 (3+) percent positive nuclei in PCa and benign tissue (P<.05). Safety measures did not change adversely with dosing. Compared with the 400-IU/d group, serum PTH and PSA were lower in the combined higher-dose groups at the end of the study (P< .02). Oral vitamin D3 raised prostate calcitriol levels (level 1 evidence) and modestly lowered both PSA and PTH. Although Ki67 expression did not differ among dose groups, its levels correlated inversely with prostate calcitriol. These suggestions of clinical benefit justify continued clinical research. Copyright © 2014 Elsevier Inc. All rights reserved.

Analgesic activity of Nelsonia canescens (Lam.) Spreng.root in albino rats

PubMed Central

Mohaddesi, Behzad; Dwivedi, Ravindra; Ashok, B. K.; Aghera, Hetal; Acharya, Rabinarayan; Shukla, V. J.

2013-01-01

Present study was undertaken to evaluate analgesic activity of root of Nelsonia canescens (Lam.) Spreng, a folklore medicinal plant used as the one of the source plant of Rasna. Study was carried out at two dose levels (270 mg/kg and 540 mg/kg) in albino rats. Analgesic activity was evaluated in formalin induced paw licking, and tail flick methods whereas indomethacin and pentazocine were used as standard analgesic drugs, respectively. At both the dose levels, test drug non-significantly decreased paw licking response at both time intervals. In tail flick model, the administration of the test drug increased pain threshold response in a dose dependent manner. In therapeutically equivalent dose level, analgesic activity was observed only after 180 min while in TED ×2 treated group analgesia was observed at 30 min and lasted even up to 240 min. The results suggested that N.canescens root possess moderate analgesic activity. PMID:24250136

Final Technical Report

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

Persistent increase of blood lead level and suppression of δ-ALAD activity in northern bobwhite quail orally dosed with even a single 2-mm spent lead shot.

PubMed

Holladay, S D; Kerr, R; Holladay, J P; Meldrum, B; Williams, S M; Gogal, R M

2012-10-01

Birds that display grit ingestion behavior are potentially at risk of lead (Pb) poisoning from mistaken ingestion of spent Pb shot pellets. The majority of available studies designed to assess such risk have used unspent shot pellets rather than field-obtained spent shot, which is oxidized and otherwise changed by weathering. Available studies also often administered more or heavier shot pellets to a bird than it might be expected to ingest. The current study dosed northern bobwhite quail (Colinus virginianus) weighing 194.6 ± 23.1 g (female birds) and 199.3 ± 12.2 g (male birds) with one to three spent no. 9 Pb shot collected from a skeet range, with particular interest in the toxicity that may occur from ingestion of a single 2-mm, 50 mg shot. An 8 week post-dosing clinical observation period was employed, over which feed consumption, body weight, blood Pb levels, and a battery of blood physiological parameters were made. Weight loss occurred in the birds, including male birds dosed with one Pb pellet. Erythrocyte delta aminolevulinic acid dehydratase (δ-ALAD) levels were decreased for the duration of the study across exposures and to levels associated with injury in wild bird populations. Decreased ALAD was particularly severe in female birds dosed with one Pb pellet and was still 92 % decreased at 8 weeks after dosing. Together, these results suggest that inadvertent ingestion of a single no. 9 Pb shot pellet can adversely affect the health of northern bobwhite quail.

Ascorbic acid treatment elevates follicle stimulating hormone and testosterone plasma levels and enhances sperm quality in albino Wistar rats.

PubMed

Okon, Uduak Akpan; Utuk, Ikponoabasi Ibanga

2016-01-01

Infertility issues have been linked to the effect of oxidative reaction in the reproductive system. This study evaluated the effect of ascorbic acid, on fertility parameters of male albino Wistar rats was studied. Eighteen albino Wistar rats weighed between 178 g and 241 g were used, randomly assigned into three groups. Group 1 was the control group; oral gavaged 5 ml of distilled water; Groups 2 and 3 were administered medium dose (250 mg/kg) and high dose of ascorbic acid (400 mg/kg), respectively; twice daily for 21 days. Blood samples were obtained by cardiac puncture, and blood serum was obtained for hormonal assay, and the testes were harvested for sperm analysis. Follicle stimulating hormone levels significantly increased in the high-dose group as compared to both the control and medium dose groups. Luteinizing hormone levels in the medium dose group decreased significantly as compared to the control group. Testosterone significantly increased in both the medium- and high-dose groups as compared to the control group. Sperm motility increased significantly in the high-dose group as compared to both control and medium-dose groups. Percentage sperm concentration decreased significantly in the medium-dose group when compared to the control and increased significantly in the high-dose group as compared to the medium-dose group. For percentage normal morphology, there was a dose-dependent increase in the test groups when compared to control group. These results are indicative of a positive influence of ascorbic acid on male fertility modulators and may therefore, serve as a potential adjuvant treatment for male infertility cases.

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

PubMed

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

2012-12-01

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

Pulmonary deposition modeling with airborne fiber exposure data: a study of workers manufacturing refractory ceramic fibers.

PubMed

Lentz, Thomas J; Rice, Carol H; Succop, Paul A; Lockey, James E; Dement, John M; LeMasters, Grace K

2003-04-01

Increasing production of refractory ceramic fiber (RCF), a synthetic vitreous material with industrial applications (e.g., kiln insulation), has created interest in potential respiratory effects of exposure to airborne fibers during manufacturing. An ongoing study of RCF manufacturing workers in the United States has indicated an association between cumulative fiber exposure and pleural plaques. Fiber sizing data, obtained from electron microscopy analyses of 118 air samples collected in three independent studies over a 20-year period (1976-1995), were used with a computer deposition model to estimate pulmonary dose of fibers of specified dimensions for 652 former and current RCF production workers. Separate dose correction factors reflecting differences in fiber dimensions in six uniform job title groups were used with data on airborne fiber concentration and employment duration to calculate cumulative dose estimates for each worker. From review of the literature, critical dimensions (diameter <0.4 microm, length <10 microm) were defined for fibers that may translocate to the parietal pleura. Each of three continuous exposure/dose metrics analyzed in separate logistic regression models was significantly related to plaques, even after adjusting for possible past asbestos exposure: cumulative fiber exposure, chi(2) = 15.2 (p < 0.01); cumulative pulmonary dose (all fibers), chi(2) = 14.6 (p < 0.01); cumulative pulmonary dose (critical dimension fibers), chi(2) = 12.4 (p < 0.01). Odds ratios (ORs) were calculated for levels of each metric. Increasing ORs were statistically significant for the two highest dose levels of critical dimension fibers (level three, OR = 11, 95%CI = [1.4, 98]; level four, OR = 25, 95%CI = [3.2, 190]). Similar associations existed for all metrics after adjustment for possible asbestos exposure. It was concluded that development of pleural plaques follows exposure- and dose-response patterns, and that airborne fibers in RCF manufacturing facilities include those with critical dimensions associated with pleural plaque formation. Analysis of additional air samples may improve estimates of the dose-response relationship.

Phase I study of icotinib, an EGFR tyrosine kinase inhibitor combined with IMRT in nasopharyngeal carcinoma.

PubMed

Hu, Wei; Wang, Wei; Yang, Peinong; Zhou, Chao; Yang, Weifang; Wu, Bo; Lu, Hongsheng; Yang, Haihua

2015-01-01

Epidermal growth factor receptor (EGFR) is a new target for nasopharyngeal carcinoma (NPC) therapy. This prospective phase I study sought to determine the safety and recommended phase II dose of icotinib, a novel highly selective oral EGFR tyrosine kinase inhibitor, in combination with intensity-modulated radiotherapy (IMRT) in patients with NPC. Eligible patients with NPC received escalating doses of icotinib during IMRT. We treated six patients at a particular dose level until the maximum tolerated dose (MTD) was determined. The starting dose was 125 mg, once-daily and the dose was escalated to another level 125 mg, twice- and thrice- daily, until dose-limiting toxicity (DLT) occurred in two or more patients at a dose level. Expression and mutation analysis of EGFR were performed in all cases. A total of twelve patients were enrolled. Three patients experienced DLT (250 mg/day cohort) and MTD was 125 mg/day. Mucositis toxicity appears to be the major DLT. While EGFR expression in tumor tissue was detected in 75% (9/12) patients, EGFR mutation was detected in 16.67% (1/6) patients in 125 mg/day cohort, and 50% (3/6) in 250 mg/day cohort. The combination of icotinib (125 mg/day) and IMRT in patients with locally NPC had an acceptable safety profile and was well tolerated.

Variation in dose and plasma level of lamotrigine in patients discharged from a mental health trust.

PubMed

Douglas-Hall, Petrina; Dzahini, Olubanke; Gaughran, Fiona; Bile, Ahmed; Taylor, David

2017-01-01

The objectives of this study were to investigate the dose of lamotrigine when prescribed with an enzyme inhibitor or enzyme inducer in patients discharged from a mental health trust and to determine the corresponding lamotrigine plasma concentrations and the factors that may affect these. All patients discharged on lamotrigine between October 2007 and September 2012 were identified using the pharmacy dispensing database. We recorded demographic details, lamotrigine dose and plasma levels and coprescribed medication. During the designated period, 187 patients were discharged on lamotrigine of whom 117 had their plasma levels recorded. The mean lamotrigine daily dose was 226.1 mg (range 12.5-800 mg) and the mean plasma level 5.9 mg/l (range 0.8-18.1 mg/l). Gender, ethnicity, diagnosis and smoking status had no significant effect on dose or plasma levels. Patients taking an enzyme-inducing drug ( n = 6) had significantly lower plasma levels [mean (SD) 3.40 (1.54) mg/l] than those not taking enzyme inducers [ n = 111; 6.03 (3.13) mg/l; p = 0.043]. Patients taking an enzyme-inhibiting drug ( n = 23) had significantly higher levels [7.47 (3.99) mg/l] than those not taking an inhibitor [ n = 94; 5.52 (2.75) mg/l; p = 0.035]. No significant difference was found between the doses of lamotrigine in patients taking an enzyme inhibitor and those not taking one ( p = 0.376). No significant difference was found between the doses of lamotrigine in patients taking an enzyme-inducing drug and those not taking any ( p = 0.574). Current dosing recommendations indicate that lamotrigine doses should be halved in individuals taking enzyme inhibitors and doubled in those on enzyme inducers. In our survey these recommendations were rarely followed with the consequence that patients received too high or too low a dose of lamotrigine, respectively.

Intradermal Inactivated Poliovirus Vaccine: A Preclinical Dose-Finding Study

PubMed Central

Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

2015-01-01

Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. PMID:25391313

Effect of low-dose valsartan on proteinuria in normotensive immunoglobulin A nephropathy with minimal proteinuria: a randomized trial.

PubMed

Jo, Young-Il; Na, Ha-Young; Moon, Ju-Young; Han, Sang-Woong; Yang, Dong-Ho; Lee, Sang-Ho; Park, Hyeong-Cheon; Choi, Hoon-Young; Lim, So-Dug; Kie, Jeong-Hae; Lee, Yong-Kyu; Shin, Sug-Kyun

2016-03-01

Immunoglobulin A nephropathy (IgAN) is a generally progressive disease, even in patients with favorable prognostic features. In this study, we aimed to investigate the antiproteinuric effect and tolerability of low-dose valsartan (an angiotensin II receptor blocker) therapy in normotensive IgAN patients with minimal proteinuria of less than 0.5 to 1.0 g/day. Normotensive IgAN patients, who had persistent proteinuria with a spot urine protein-to-creatinine ratio of 0.3 to 1.0 mg/mg creatinine, were recruited from five hospitals and randomly assigned to either 40 mg of valsartan as the low-dose group or 80 mg of valsartan as the regular-dose group. Clinical and laboratory data were collected at baseline, and at 4, 8, 12, and 24 weeks after valsartan therapy. Forty-three patients (low-dose group, n = 23; regular-dose group, n = 20) were enrolled in the study. Proteinuria decreased significantly not only in the regular-dose group but also in the low-dose group. The change in urine protein-to-creatinine ratio at week 24 was -41.3% ± 26.1% (p < 0.001) in the regular-dose group and -21.1% ± 45.1% (p = 0.005) in the low-dose group. In the low-dose group, blood pressure was constant throughout the study period, and there was no symptomatic hypotension. In the regular-dose group, blood pressure decreased at weeks 8 and 12. No significant change in glomerular filtration rate, serum creatinine level, or serum potassium level was observed during the study period. Our results suggest that low-dose valsartan can significantly reduce proteinuria without causing any intolerability in normotensive IgAN patients with minimal proteinuria.

Effect of low-dose valsartan on proteinuria in normotensive immunoglobulin A nephropathy with minimal proteinuria: a randomized trial

PubMed Central

Jo, Young-Il; Na, Ha-Young; Moon, Ju-Young; Han, Sang-Woong; Yang, Dong-Ho; Lee, Sang-Ho; Park, Hyeong-Cheon; Choi, Hoon-Young; Lim, So-Dug; Kie, Jeong-Hae; Lee, Yong-Kyu; Shin, Sug-Kyun

2016-01-01

Background/Aims: Immunoglobulin A nephropathy (IgAN) is a generally progressive disease, even in patients with favorable prognostic features. In this study, we aimed to investigate the antiproteinuric effect and tolerability of low-dose valsartan (an angiotensin II receptor blocker) therapy in normotensive IgAN patients with minimal proteinuria of less than 0.5 to 1.0 g/day. Methods: Normotensive IgAN patients, who had persistent proteinuria with a spot urine protein-to-creatinine ratio of 0.3 to 1.0 mg/mg creatinine, were recruited from five hospitals and randomly assigned to either 40 mg of valsartan as the low-dose group or 80 mg of valsartan as the regular-dose group. Clinical and laboratory data were collected at baseline, and at 4, 8, 12, and 24 weeks after valsartan therapy. Results: Forty-three patients (low-dose group, n = 23; regular-dose group, n = 20) were enrolled in the study. Proteinuria decreased significantly not only in the regular-dose group but also in the low-dose group. The change in urine protein-to-creatinine ratio at week 24 was −41.3% ± 26.1% (p < 0.001) in the regular-dose group and −21.1% ± 45.1% (p = 0.005) in the low-dose group. In the low-dose group, blood pressure was constant throughout the study period, and there was no symptomatic hypotension. In the regular-dose group, blood pressure decreased at weeks 8 and 12. No significant change in glomerular filtration rate, serum creatinine level, or serum potassium level was observed during the study period. Conclusions: Our results suggest that low-dose valsartan can significantly reduce proteinuria without causing any intolerability in normotensive IgAN patients with minimal proteinuria. PMID:26874511

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

Barry D. Michael; Kathryn Held; Kevin Prise

The management of the risks of exposure of people to ionizing radiation is important in relation to its uses in industry and medicine, also to natural and man-made radiation in the environment. The vase majority of exposures are at a very low level of radiation dose. The risks are of inducing cancer in the exposed individuals and a smaller risk of inducing genetic damage that can be transmitted to children conceived after exposure. Studies of these risks in exposed population studies with any accuracy above the normal levels of cancer and genetic defects unless the dose levels are high. Inmore » practice, this means that our knowledge depends very largely on the information gained from the follow-up of the survivors of the atomic bombs dropped on Japanese cities. The risks calculated from these high-dose short-duration exposures then have to be projected down to the low-dose long-term exposures that apply generally. Recent research using cells in culture has revealed that the relations hi between high- and low-dose biological damage may be much more complex than had previously been thought. The aims of this and other projects in the DOE's Low-Dose Program are to gain an understanding of the biological actions of low-dose radiation, ultimately to provide information that will lead to more accurate quantification of low-dose risk. Our project is based on the concept that the processes by which radiation induces cancer start where the individual tracks of radiation impact on cells and tissues. At the dose levels of most low-dose exposures, these events are rare and any individual cells only ''sees'' radiation tracks at intervals averaging from weeks to years apart. This contracts with the atomic bomb exposures where, on average, each cell was hit by hundreds of tracks instantaneously. We have therefore developed microbeam techniques that enable us to target cells in culture with any number of tracks, from one upwards. This approach enables us to study the biological basis of the relationship between high- and low-dose exposures. The targeting approach also allows us to study very clearly a newly recognized effect of radiation, the ''bystander effect'', which appears to dominate some low-dose responses and therefore may have a significant role in low-dose risk mechanisms. Our project also addresses the concept that the background of naturally occurring oxidative damage that takes place continually in cells due to byproducts of metabolism may play a role in treatments that modify the levels of oxidative damage, either alone or in combination with low-dose irradiation. In this project, we have used human and rodent cell lines and each set of experiments has been carried out on a single cell type. However, low-dose research has to extend into tissues because signaling between cells of different types is likely to influence the responses. Our studies have therefore also included microbeam experiments using a model tissue system that consists of an explant of a small piece of pig ureter grown in culture. The structure of this tissue is similar to that of epithelium and there it relates to the tissues in which carcinoma arises. Our studies have been able to measure bystander-induced changes in the cells growing out from the tissue fragment after it has been targeted with a few radiation tracks to mimic a low-dose exposure.« less

Effect of high-dose rosuvastatin loading before percutaneous coronary intervention in Chinese patients with acute coronary syndrome: A systematic review and meta-analysis

PubMed Central

Su, Qiang; Guo, Wenqin; Dai, Weiran; Li, Hongqing; Yang, Huafeng; Li, Lang

2017-01-01

Background Acute coronary syndrome (ACS) is an important disease threatening human life and health. Many studies have shown that the loading dose of atorvastatin can significantly improve the prognosis of patients with ACS, and reduce the mortality. However, this conclusion is not consistent. Thus, we aimed to evaluate the effect of high-dose rosuvastatin loading before percutaneous coronary intervention (PCI) in Chinese patients with ACS using a meta-analysis based on a systematic review of published articles. Methods We systematically reviewed published studies, evaluating the effect of high-dose rosuvastatin loading before percutaneous coronary intervention in Chinese patients with ACS. The retrieval time is limited from inception to 2 November 2016, and the retrieved databases included PubMed, Embase, the Cochrane Library, Web of Science, CBM, CNKI, the VIP database and the Wang Fang database. Two researchers independently assessed the quality of the included studies and then extracted the data. Stata 11.0 was used for data analysis. Results In total, 11 articles, which included 802 patients, were included in our meta-analysis. Among these patients, 398 patients were in the high-dose group (20 mg/day) and 404 patients were in the conventional dose group (10 mg/day). Meta-analysis results showed that compared with the conventional dose group: 1) The loading dose of rosuvastatin can significantly reduce the hs-CRP level after PCI, including at 24 hours (SMD = -0.65, 95%CI -0.84 ~ -0.47, P = 0.000), 48 hours (SMD = -0.40, 95%CI -0.68 ~ -0.11, P = 0.006), and four weeks (SMD = -1.64, 95%CI -2.01 ~ -1.26, P = 0.000). 2) The loading dose of rosuvastatin can significantly reduce the levels of LDL-C and cTnT, including the level of LDL-C at 30 d after PCI (SMD = -0.89, 95%CI -1.10 ~ -0.69, P = 0.000), and the level of cTnT at 24 h after PCI (SMD = -1.93, 95%CI -2.28 ~ -1.59, P = 0.000), and increase the level of HDL-C at 48 h after PCI (SMD = 0.61, 95%CI 0.34 ~ 0.88, P = 0.000). 3) The loading dose of rosuvastatin can significantly reduce the levels of TG and TC, including the level of TG at 30 d after PCI (SMD = -0.94, 95%CI -1.17 ~ -0.71, P = 0.000), the level of TC at 48 h after PCI (SMD = -0.35, 95%CI -0.68 ~ -0.01, P = 0.043), and the level of TC at 30 d after PCI (SMD = -0.77, 95%CI -0.98 ~ -0.56, P = 0.000). Conclusions Our systematic review and meta-analysis showed that, compared with the conventional dose, the loading dose of rosuvastatin was more beneficial to patients with ACS in China and is suitable for clinical application. Due to the limitations of the quality and quantity of included articles, this conclusion still needs to be confirmed by multicenter clinical trials. PMID:28231287

Chemical and toxicological evaluation of methanol extract of Cuscuta reflexa Roxb. stem and Corchorus olitorius Linn. seed on hematological parameters and hepatorenal functions in mice.

PubMed

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.

Drug safety evaluation through biomarker analysis-A toxicity study in the cynomolgus monkey using an antibody-cytotoxic conjugate against ovarian cancer

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

Hsieh, Frank Y.; Tengstrand, Elizabeth; Lee, J.-W.

2007-10-01

Antibody-cytotoxin conjugates are complex novel therapeutic agents whose toxicological properties are not presently well understood. The objective of this study was to identify serum biomarkers that correlate with MLN8866 (an Antibody-Cytotoxic Conjugate, mAb8866-CT) pathological events in monkeys and to predict the maximal tolerated dose (MTD) level using biomarkers. Cynomolgus monkeys were administered a single dose MLN8666 (5, 15 or 30 mg/kg) by intravenous infusion and evaluated over a 7-day period. Exposure levels were determined by quantifying MLN8866 levels (C{sub max} and AUC{sub 0-96h}) in serum. The increase in MLN8866 C{sub max} and AUC{sub 0-96h} was approximately dose proportional. Two biomarkersmore » in serum (m/z 316 and m/z 368) were identified to be correlated with MLN8866 toxicological outcomes. The predicted MTD, 11.4 mg/kg, was within the MTD range set by pathology results (5-15 mg/kg). Administration of MLN8866 at 15 mg/kg and 30 mg/kg dose levels resulted in changes in hematology parameters associated with impaired hematopoiesis and bone marrow toxicity. The projected MLN8866 MTD exposure level was integrated with toxicokinetic analysis and showed C{sub max} = 236 {mu}g/mL and AUC{sub 0-96h} = 7246 h mg/mL. The safety of three different MLN8866 dosing regimens with three dosing schedules was explored with pharmacokinetic modeling.« less

Dosimetry for radiobiological studies of the human hematopoietic system

NASA Technical Reports Server (NTRS)

Beck, W. L.; Stokes, T. R.; Lushbaugh, C. C.

1972-01-01

A system for estimating individual bone marrow doses in therapeutic radiation exposures of leukemia patients was studied. These measurements are used to make dose response correlations and to study the effect of dose protraction on peripheral blood cell levels. Three irradiators designed to produce a uniform field of high energy gamma radiation for total body exposures of large animals and man are also used for radiobiological studies.

Towards quantitative imaging: stability of fully automated nodule segmentation across varied dose levels and reconstruction parameters in a low-dose CT screening patient cohort

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.

Population Pharmacokinetics of Enoxaparin in Pediatric Patients.

PubMed

Moffett, Brady S; Lee-Kim, YoungNa; Galati, Marianne; Mahoney, Donald; Shah, Mona D; Teruya, Jun; Yee, Donald

2018-02-01

There are no studies evaluating the pharmacokinetics of enoxaparin in the hospitalized pediatric patient population. To characterize the pharmacokinetics of enoxaparin in pediatric patients. A retrospective review of inpatients 1 to 18 years of age admitted to our institution who received enoxaparin with anti-factor Xa activity level monitoring was performed. Demographic variables, enoxaparin dosing, and anti-factor Xa activity levels were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. Simulation (n = 10 000) was performed to determine the percentage who achieved targeted anti-Xa levels at various doses. A total of 853 patients (male 52.1%, median age = 12.2 years; interquartile range [IQR] = 4.6-15.8 years) received a mean enoxaparin dose of 0.86 ± 0.31 mg/kg/dose. A median of 3 (IQR = 1-5) anti-factor Xa levels were sampled at 4.4 ± 1.3 hours after a dose, with a mean anti-factor Xa level of 0.52 ± 0.23 U/mL. A 1-compartment model best fit the data, and significant covariates included allometrically scaled weight, serum creatinine, and hematocrit on clearance, and platelets on volume of distribution. Simulations were run for patients both without and with reduced kidney function (creatinine clearance of ≤30 mL/min/1.73 m 2 ). A dose of 1 mg/kg/dose every 12 hours had the highest probability (72.3%) of achieving an anti-Xa level within the target range (0.5-1 U/mL), whereas a dose reduction of ~30% achieved the same result in patients with reduced kidney function. Pediatric patients should initially be dosed at 1-mg/kg/dose subcutaneously every 12 hours for treatment of thromboembolism followed by anti-Xa activity monitoring. Dose reductions of ~30% for creatinine clearance ≤30 mL/min/1.73 m 2 are required.

Stable and unstable chromosomal aberrations among Finnish nuclear power plant workers.

PubMed

Lindholm, C

2001-01-01

Twenty nuclear power plant workers with relatively high recorded cumulative doses were studied using FISH chromosome painting and dicentric analysis after solid Giemsa staining. The results indicated that chronic exposure to ionising radiation can be detected on the group level using translocation analysis after chromosome painting, although the mean cumulative dose was approximately 100 mSv. A significant association between translocation frequency and cumulative dose was observed. Variability in the translocation yields among workers with similar recorded doses was large, resulting in a poor correlation between translocation frequencies and documented doses on the individual level. The yields of dicentric and acentric chromosomes were not correlated with the cumulative dose, indicating the inability of unstable aberrations to monitor long-term exposures. It was also shown that the unstable aberrations were not correlated with the most recent annual dose.

Hepatic effects of orally administered styrene in rats.

PubMed

Srivastava, S P; Das, M; Mushtaq, M; Chandra, S V; Seth, P K

1982-08-01

Adult male rats receiving styrene by gavage (200 or 400 mg kg-1, 6 days a week) for 100 days exhibited a significant dose-dependent increase in hepatic benzo[a]pyrene hydroxylase and aminopyrine-N-demethylase, a decrease in glutathione-S-transferase and no change in glucose-6-phosphatase. A decrease in the activity of mitochondrial succinic dehydrogenase and beta-glucuronidase was also observed. Activity of acid phosphatase was decreased only at the higher dose level. Levels of serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were elevated only at the higher dose level. The absolute and relative weights of the liver of control and treated animals showed no significant difference. Histopathological studies of the liver tissue revealed tiny areas of focal necrosis, consisting of few degenerated hepatocytes and inflammatory cells at the higher dose level only.

A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers.

PubMed

Chi, K N; Yu, E Y; Jacobs, C; Bazov, J; Kollmannsberger, C; Higano, C S; Mukherjee, S D; Gleave, M E; Stewart, P S; Hotte, S J

2016-06-01

Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer. Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated. Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response. Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway. NCT00487786. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Intake of kale suppresses postprandial increases in plasma glucose: A randomized, double-blind, placebo-controlled, crossover study

PubMed Central

Kondo, Sumio; Suzuki, Asahi; Kurokawa, Mihoko; Hasumi, Keiji

2016-01-01

Kale (Brassica oleracea var. acephala), a vegetable in the family Brassicaceae, has beneficial effects on health, including hypoglycemic effects. In our previous study with a limited number of subjects, intake of kale-containing food at a dose of 14 g decreased postprandial plasma glucose levels. In the present study, the effective dose of kale-containing food was investigated in a randomized, double-blind, placebo-controlled, crossover trial. The trial was conducted on 42 Japanese subjects aged 21–64 years with fasting plasma glucose levels of ≤125 mg/dl and 30-min postprandial plasma glucose levels of 140–187 mg/dl. The subjects consumed placebo or kale-containing food [7 or 14 g; low-dose (active-L) or high-dose (active-H) kale, respectively] together with a high-carbohydrate meal. At 30–120 min after the test meal intake, the plasma levels of glucose and insulin were determined. The postprandial plasma glucose levels in subjects with intake of active-L or active-H were significantly lower than those in subjects with intake of placebo, with the maximum plasma concentration (Cmax; 163±24 mg/dl for active-L and 162±23 mg/dl for active-H compared with 176±26 mg/dl for placebo [values presented as means ± standard deviation (SD); P<0.01]. The area under the plasma glucose concentration-time curve for 0–2 h (AUC0–2 h) values (means ± SD) were significantly lower for active-L (268±43 mg/h/dl) and active-H (266±42 mg/h/dl) than for the placebo (284±43 mg/h/dl; P<0.05). No significant differences were identified in the postprandial plasma insulin levels between the three conditions. No adverse events associated with intake of either dose of kale were observed. Our findings suggest that intake of kale suppresses postprandial increases in plasma glucose levels at a single dose of 7 g, and that a dose as high as 14 g is safe. PMID:27882216

Intake of kale suppresses postprandial increases in plasma glucose: A randomized, double-blind, placebo-controlled, crossover study.

PubMed

Kondo, Sumio; Suzuki, Asahi; Kurokawa, Mihoko; Hasumi, Keiji

2016-11-01

Kale ( Brassica oleracea var. acephala ), a vegetable in the family Brassicaceae, has beneficial effects on health, including hypoglycemic effects. In our previous study with a limited number of subjects, intake of kale-containing food at a dose of 14 g decreased postprandial plasma glucose levels. In the present study, the effective dose of kale-containing food was investigated in a randomized, double-blind, placebo-controlled, crossover trial. The trial was conducted on 42 Japanese subjects aged 21-64 years with fasting plasma glucose levels of ≤125 mg/dl and 30-min postprandial plasma glucose levels of 140-187 mg/dl. The subjects consumed placebo or kale-containing food [7 or 14 g; low-dose (active-L) or high-dose (active-H) kale, respectively] together with a high-carbohydrate meal. At 30-120 min after the test meal intake, the plasma levels of glucose and insulin were determined. The postprandial plasma glucose levels in subjects with intake of active-L or active-H were significantly lower than those in subjects with intake of placebo, with the maximum plasma concentration (C max ; 163±24 mg/dl for active-L and 162±23 mg/dl for active-H compared with 176±26 mg/dl for placebo [values presented as means ± standard deviation (SD); P<0.01]. The area under the plasma glucose concentration-time curve for 0-2 h (AUC 0-2 h ) values (means ± SD) were significantly lower for active-L (268±43 mg/h/dl) and active-H (266±42 mg/h/dl) than for the placebo (284±43 mg/h/dl; P<0.05). No significant differences were identified in the postprandial plasma insulin levels between the three conditions. No adverse events associated with intake of either dose of kale were observed. Our findings suggest that intake of kale suppresses postprandial increases in plasma glucose levels at a single dose of 7 g, and that a dose as high as 14 g is safe.

Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism.

PubMed

Shimatsu, Akira; Teramoto, Akira; Hizuka, Naomi; Kitai, Kazuo; Ramis, Joaquim; Chihara, Kazuo

2013-01-01

The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

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

Shaib, Walid L.; Hawk, Natalyn; Cassidy, Richard J.

Purpose: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV,more » and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.« less

Cumulative effective dose associated with radiography and CT of adolescents with spinal injuries.

PubMed

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.

Developmental toxicity study of sodium molybdate dihydrate administered in the diet to Sprague Dawley rats.

PubMed

Jay Murray, F; Tyl, Rochelle W; Sullivan, Frank M; Tiwary, Asheesh K; Carey, Sandra

2014-11-01

Molybdenum is an essential nutrient for humans and animals and is a constituent of several important oxidase enzymes. It is normally absorbed from the diet and to a lesser extent from drinking water and the typical human intake is around 2μg/kg bodyweight per day. No developmental toxicity studies to contemporary standards have been published and regulatory decisions have been based primarily on older studies where the nature of the test material, or the actual dose levels consumed is uncertain. In the current study the developmental toxicity of sodium molybdate dihydrate as a representative of a broad class of soluble molybdenum(VI) compounds, was given in the diet to Sprague Dawley rats in accordance with OECD Test Guideline 414. Dose levels of 0, 3, 10, 20 and 40mgMo/kgbw/day were administered from GD6 to GD20. No adverse effects were observed at any dose level on the dams, or on embryofetal survival, fetal bodyweight, or development, with no increase in malformations or variations. Significant increases in serum and tissue copper levels were observed but no toxicity related to these was observed. The NOAEL observed in this study was 40mgMo/kgbw/day, the highest dose tested. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.

PubMed

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.

Ten-year oral toxicity study with Norlestrin in rhesus monkeys.

PubMed

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.

TU-C-18A-01: Models of Risk From Low-Dose Radiation Exposures: What Does the Evidence Say?

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

Bushberg, J; Boreham, D; Ulsh, B

2014-06-15

At dose levels of (approximately) 500 mSv or more, increased cancer incidence and mortality have been clearly demonstrated. However, at the low doses of radiation used in medical imaging, the relationship between dose and cancer risk is not well established. As such, assumptions about the shape of the dose-response curve are made. These assumptions, or risk models, are used to estimate potential long term effects. Common models include 1) the linear non-threshold (LNT) model, 2) threshold models with either a linear or curvilinear dose response above the threshold, and 3) a hormetic model, where the risk is initially decreased belowmore » background levels before increasing. The choice of model used when making radiation risk or protection calculations and decisions can have significant implications on public policy and health care decisions. However, the ongoing debate about which risk model best describes the dose-response relationship at low doses of radiation makes informed decision making difficult. This symposium will review the two fundamental approaches to determining the risk associated with low doses of ionizing radiation, namely radiation epidemiology and radiation biology. The strengths and limitations of each approach will be reviewed, the results of recent studies presented, and the appropriateness of different risk models for various real world scenarios discussed. Examples of well-designed and poorly-designed studies will be provided to assist medical physicists in 1) critically evaluating publications in the field and 2) communicating accurate information to medical professionals, patients, and members of the general public. Equipped with the best information that radiation epidemiology and radiation biology can currently provide, and an understanding of the limitations of such information, individuals and organizations will be able to make more informed decisions regarding questions such as 1) how much shielding to install at medical facilities, 2) at what dose level are risk vs. benefit discussions with patients appropriate, 3) at what dose level should we tell a pregnant woman that the baby’s health risk from a prenatal radiation exposure is “significant”, 4) is informed consent needed for patients undergoing medical imaging, and 5) at what dose level is evacuation appropriate after a radiological accident. Examples of the tremendous impact that choosing different risks models can have on the answers to these types of questions will be given.A moderated panel discussion will allow audience members to pose questions to the faculty members, each of whom is an established expert in his respective discipline. Learning Objectives: Understand the fundamental principles, strengths and limitations of radiation epidemiology and radiation biology for determining the risk from exposures to low doses of ionizing radiation Become familiar with common models of risk used to describe the dose-response relationship at low dose levels Learn to identify strengths and weaknesses in studies designed to measure the effect of low doses of ionizing radiation Understand the implications of different risk models on public policy and health care decisions.« less

Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis.

PubMed Central

Larsen, R A; Bauer, M; Weiner, J M; Diamond, D M; Leal, M E; Ding, J C; Rinaldi, M G; Graybill, J R

1996-01-01

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone. However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11. In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies. In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole. These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 micrograms/g daily). PMID:8878602

A national patient dose survey and setting of reference levels for interventional radiology in Bulgaria.

PubMed

Zotova, R; Vassileva, J; Hristova, J; Pirinen, M; Järvinen, H

2012-06-01

A national study on patient dose values in interventional radiology and cardiology was performed in order to assess current practice in Bulgaria, to estimate the typical patient doses and to propose reference levels for the most common procedures. Fifteen units and more than 1,000 cases were included. Average values of the measured parameters for three procedures-coronary angiography (CA), combined procedure (CA + PCI) and lower limb arteriography (LLA)--were compared with data published in the literature. Substantial variations were observed in equipment and procedure protocols used. This resulted in variations in patient dose: air-kerma area product ranges were 4-339, 6-1,003 and 0.2-288 Gy cm(2) for CA, CA + PCI and LLA respectively. Reference levels for air kerma-area product were proposed: 40 Gy cm(2) for CA, 140 Gy cm(2) for CA + PCI and 45 Gy cm(2) for LLA. Auxiliary reference intervals were proposed for other dose-related parameters: fluoroscopy time, number of images and entrance surface air kerma rate in fluoroscopy and cine mode. There is an apparent necessity for improvement in the classification of peripheral procedures and for standardisation of the protocols applied. It is important that patient doses are routinely recorded and compared with reference levels. • Patient doses in interventional radiology are high and vary greatly • Better standardisation of procedures and techniques is needed to improve practice • Dose reference levels for most common procedures are proposed.

Anemia management trends in hospital-based dialysis centers (HBDCs), 2010 to 2013.

PubMed

Coritsidis, George N; Maglinte, Gregory A; Acharya, Anjali; Saxena, Anjali; Chang, Chun-Lan; Hill, Jerrold; Gitlin, Matthew; Lafayette, Richard A

2014-03-01

Few data have been reported on anemia management practices in hospital-based dialysis centers (HBDCs), which are uniquely different from other freestanding dialysis centers. Examining data from HBDCs would help determine if HBDCs and the general US dialysis population have similar trends related to how anemia is managed in dialysis patients. Given recent changes in the prescribing information of erythropoiesis-stimulating agents (ESAs) and in end-stage renal disease-related health policy and reimbursement, this study describes trends in anemia management practices in HBDCs from January 2010 through March 2013. Electronic medical records of 5404 adult hemodialysis patients in 50 US-based HBDCs were analyzed retrospectively. Patients included in the study cohort were aged ≥18 years and had at least 1 hemoglobin (Hb) measurement and 1 dose of an ESA between January 2010 and March 2013. End points included Hb concentration, darbepoetin alfa dosing, epoetin alfa dosing, and iron biomarkers (transferrin saturation and ferritin) and dosing. From 2010 to 2013, mean monthly Hb levels declined from 11.4 to 10.7 g/dL; the percentage of patients with mean monthly Hb levels <10 g/dL increased from 11.3% to 24.4%; and the percentage of patients with mean monthly Hb levels >12 g/dL declined from 30.1% to 11.2%. The median darbepoetin alfa cumulative 4-week dose also declined 38.8%, and the weekly epoetin alfa dose declined 24%. From January 2010 to March 2013, the percentage of patients with transferrin saturation >30% increased from 35.8% to 43.6%, the percentage of patients with ferritin levels >500 ng/mL increased from 62.0% to 77.9%, the percentage of patients with ferritin levels ≥800 ng/mL increased from 28.9% to 47.3%, and the median cumulative 4-week intravenous iron dose increased 50%. These study results support growing evidence that meaningful changes have occurred over the last 3 years in how anemia is clinically managed in US hemodialysis patients. Study limitations include that changes in patient clinical/demographic characteristics over time were not controlled for and that study findings may not be applicable to HBDCs that have different patient populations and/or do not use an electronic medical record system. Continuing to evaluate anemia management practices in HBDCs would provide additional information on the risks and benefits of anemia care. Consistent with national data, the findings from this study indicate that from 2010 to 2013, HBDCs modified anemia management practices for dialysis patients, as evidenced by reductions in mean monthly Hb levels and ESA dosing and by increases in iron biomarkers and dosing. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

PubMed

Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

2009-06-01

The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P < 0.05) the time spent and the distance covered in the central zone of the open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P < 0.05) after exposing the animals to the open field test.

[Effect of Jianpi Yangzheng Xiaozheng Recipe on Apoptosis and Autophagy of Subcutaneous Transplanted Tumor in Nude Mice: an Experimental Study on Mechanism].

PubMed

Wu, Jian; Liu, Shen-lin; Zhang, Xing-xing; Chen, Min; Zou, Xi

2015-09-01

To observe the effect of Jianpi Yangzheng Xiaozheng Recipe (JYXR) on the tumor inhibition rate of subcutaneous transplanted tumor gastric cancer cell line MGC-803 in BALB/c nude mice, and to study its molecular mechanism of apoptosis and autophagy. Gastric cancer cell line MGC-803 was subcutaneously inoculated to nude mice for preparing transplanted gastric cancer models. Totally 32 BALB/c nude mice were randomly divided into 4 groups according to random digit table, i.e., the negative control group, the positive control group, the high dose JYXR group, the low dose JYXR group, 8 in each group. Normal saline was administered to mice in the negative control group by gastrogavage. 5-fluorouracil (5-Fu) at 2. 5 mg/kg was administered to mice in the positive control group by gastrogavage. JYXR at 85 and 43 g/kg was administered to mice in the high dose JYXR group and the low dose JYXR group by gastrogavage, once per day for 10 successive days. The effect of JYXR on the tumor inhibition rate of subcutaneous transplanted tumor was observed. Effects of JYXR on gene expression levels of Bax, Bcl-2, Fas, Cyclin D1, Cyclin D2, and Cyclin D3 in transplanted tumor were observed by real-time PCR. Effects of JYXR on protein expression levels of Procaspase-3, Procaspase-8, Procaspase-9, cleaved-PARP, Beclin-1, and LC3B were detected using Western blot. (1) Compared with the negative control group, the tumor weight was obviously reduced in the rest three groups (P <0. 05). The tumor weight was higher in the high dose JYXR group and the low dose JYXR group than in the positive control group (P <0. 05). (2) Results of RT-PCR indicated that, compared with the negative control group, expression levels of Bax were up-regulated, but expression levels of Bcl-2, Cyclin D1, Cyclin D2, and Cyclin D3 were down-regulated in the positive control group and JYXR groups (P <0. 05). The expression level of Fas was up-regulated in the positive control group and the high dose JYXR group (P <0. 05). Compared with the positive control group, expression levels of Fas, and Bax were all down-regulated, but expression levels of Bcl-2, Cyclin D2, and Cyclin D3 were all up-regulated in the high dose JYXR group and the low dose JYXR group (all P <0. 05). The expression level of Cyclin D1 was down-regulated in the high dose JYXR group, but it was up-regulated in the low dose JYXR group ( both P <0. 05). (3) Results of Western blot showed, compared with the negative control group, expression levels of Procaspase-3, Procaspase-8, and Procaspase-9 were down-regulated, but expression levels of cleaved-PARP, Beclin-1, and LC3B II were up-regulated in the high dose JYXR group and the low dose JYXR group (all P <0.05). Compared with the negative control group, expression levels of Procaspase-3, Procaspase-8, Procaspase-9, and LC3B II were down-regulated, but expression levels of cleaved-PARP, Beclin-1, and LC3B I were up-regulated in the positive control group (all P <0. 05). JYXR showed significant inhibition on subcutaneous transplanted tumor gastric cancer cell line MGC-803 in BALB/c nude mice. Its mechanism might be associated with activating apoptosis and autophagy correlated factors.

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

PubMed

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

2017-02-01

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

Total and free cortisol levels during 1 μg, 25 μg, and 250 μg cosyntropin stimulation tests compared to insulin tolerance test: results of a randomized, prospective, pilot study.

PubMed

Peechakara, Seenia; Bena, James; Clarke, Nigel J; McPhaul, Michael J; Reitz, Richard E; Weil, Robert J; Recinos, Pablo; Kennedy, Laurence; Hamrahian, Amir H

2017-09-01

The appropriate cosyntropin dose during cosyntropin stimulation tests remains uncertain. We conducted a prospective, randomized pilot study to compare 1 μg IV low dose cosyntropin test, 25 μg IM medium dose cosyntropin test, and 250 μg IM standard dose cosyntropin test to evaluate secondary adrenal insufficiency. Insulin tolerance test was used as the gold standard. The study included patients with hypothalamic/pituitary disease (n  = 10) with at least one pituitary axis deficiency other than ACTH deficiency and controls (n  = 12). All tests were done in random order. Sensitivity and specificity were calculated for total cortisol and serum free cortisol cut-off levels during cosyntropin stimulation tests. The median (range) age and F/M sex ratios for patients and controls were 54 years (23-62), 2/8, and 33 years (21-51), 6/6, respectively. The best total cortisol cut-off during low dose cosyntropin test, medium dose cosyntropin test, 30 min and 60 min standard dose cosyntropin test were 14.6 μg/dL (100% sensitivity & specificity), 18.7 μg/dL (100% sensitivity, 88% specificity), 16.1 (100% sensitivity & specificity), and 19.5 μg/dL (100% sensitivity & specificity), respectively. There was no difference in the ROC curve for cortisol values between the cosyntropin stimulation tests (p  > 0.41). Using a cortisol cut-off of 18 μg/dL during cosyntropin stimulation tests, only cortisol level at 30 min during standard dose cosyntropin test provided discrimination similar to insulin tolerance test. The best peak free cortisol cut-off levels were 1 μg/dL for insulin tolerance test, 0.9 μg/dL for low dose cosyntropin test, 0.9 μg/dL for medium dose cosyntropin test, and 0.9 μg/dL and 1.3 μg/dL for 30 min and 60 min standard dose cosyntropin test, respectively. All cosyntropin stimulation tests had excellent correlations with insulin tolerance test, when appropriate cut-offs were used. This pilot study does not suggest an advantage in using 25 μg cosyntropin dose during the cosyntropin stimulation test. A serum free cortisol cut-off of 0.9 μg/dL may be used as pass criterion during low dose cosyntropin test, standard dose cosyntropin test cosyntropin test, and 30 min standard dose cosyntropin test.

Correlation of Noncancer Benchmark Doses in Short- and Long-Term Rodent Bioassays.

PubMed

Kratchman, Jessica; Wang, Bing; Fox, John; Gray, George

2018-05-01

This study investigated whether, in the absence of chronic noncancer toxicity data, short-term noncancer toxicity data can be used to predict chronic toxicity effect levels by focusing on the dose-response relationship instead of a critical effect. Data from National Toxicology Program (NTP) technical reports have been extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Best-fit, minimum benchmark dose (BMD), and benchmark dose lower limits (BMDLs) have been modeled for all NTP pathologist identified significant nonneoplastic lesions, final mean body weight, and mean organ weight of 41 chemicals tested by NTP between 2000 and 2012. Models were then developed at the chemical level using orthogonal regression techniques to predict chronic (two years) noncancer health effect levels using the results of the short-term (three months) toxicity data. The findings indicate that short-term animal studies may reasonably provide a quantitative estimate of a chronic BMD or BMDL. This can allow for faster development of human health toxicity values for risk assessment for chemicals that lack chronic toxicity data. © 2017 Society for Risk Analysis.

Visual grading analysis of digital neonatal chest phantom X-ray images: Impact of detector type, dose and image processing on image quality.

PubMed

Smet, M H; Breysem, L; Mussen, E; Bosmans, H; Marshall, N W; Cockmartin, L

2018-07-01

To evaluate the impact of digital detector, dose level and post-processing on neonatal chest phantom X-ray image quality (IQ). A neonatal phantom was imaged using four different detectors: a CR powder phosphor (PIP), a CR needle phosphor (NIP) and two wireless CsI DR detectors (DXD and DRX). Five different dose levels were studied for each detector and two post-processing algorithms evaluated for each vendor. Three paediatric radiologists scored the images using European quality criteria plus additional questions on vascular lines, noise and disease simulation. Visual grading characteristics and ordinal regression statistics were used to evaluate the effect of detector type, post-processing and dose on VGA score (VGAS). No significant differences were found between the NIP, DXD and CRX detectors (p>0.05) whereas the PIP detector had significantly lower VGAS (p< 0.0001). Processing did not influence VGAS (p=0.819). Increasing dose resulted in significantly higher VGAS (p<0.0001). Visual grading analysis (VGA) identified a detector air kerma/image (DAK/image) of ~2.4 μGy as an ideal working point for NIP, DXD and DRX detectors. VGAS tracked IQ differences between detectors and dose levels but not image post-processing changes. VGA showed a DAK/image value above which perceived IQ did not improve, potentially useful for commissioning. • A VGA study detects IQ differences between detectors and dose levels. • The NIP detector matched the VGAS of the CsI DR detectors. • VGA data are useful in setting initial detector air kerma level. • Differences in NNPS were consistent with changes in VGAS.

The effect of metoprolol and practolol on lung function and blood pressure in hypertensive asthmatics

PubMed Central

Formgren, H.

1976-01-01

1 The effect of metoprolol, a new β1-adrenoceptor blocking agent, was compared to practolol in the treatment of hypertension in seventeen asthmatics during concurrent optimum bronchodilator therapy with a selective β2-adrenoceptor-stimulant. 2 The two β-adrenoceptor antagonists were given at two dose levels, practolol (200 mg and 400 mg) daily, and metoprolol (100 mg and 200 mg) daily, in a twice-daily dosage schedule, at 12 h intervals, for 17 days. The comparison was made double-blind and a crossover design was used. The drugs were given in randomized order. The study started with a run-in placebo period and there was a washout period on placebo between the treatment periods. Spirometry, blood pressures and heart rates were recorded in a standardized manner. 3 At the lower dose levels no influence on FEV1 was noted, and no difference was found between the two active drugs. At the higher dose level FEV1 was reduced by both β-adrenoceptor-blocking drugs. Four out of twelve patients given the higher dose experienced exacerbation of their asthma. The heart rate fell with both drugs and at both dose levels. During the placebo period a marked increase of heart rate was noted. The blood pressure fell at both dose levels compared to placebo, no difference being recorded between the two drugs. 4 Metoprolol and practolol are equally effective β1-adrenoceptor blocking drugs. In this study it was found that metoprolol could be used in asthmatics who had indications for β-adrenoceptor blockade, provided that the total daily dose did not exceed 100 mg. Optimal bronchodilator treatment with a bronchoselective β-adrenoceptor agonist is an absolute prerequisite in order to avoid the risk of aggravation of asthma. PMID:22216522

Using quality of life measures in a Phase I clinical trial of noni in patients with advanced cancer to select a Phase II dose.

PubMed

Issell, Brian F; Gotay, Carolyn C; Pagano, Ian; Franke, Adrian A

2009-01-01

ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.

Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose in Future Studies. A Response to the Counterpoints.

PubMed

Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

2016-01-01

We recently conducted a retrospective analysis of data collected from 29 Tg.rasH2 carcinogenicity studies conducted at our facility to determine how successful was the strategy of choosing the high dose of the 26-week studies based on an estimated maximum tolerated dose (MTD). As a result of our publication, 2 counterviews were expressed. Both counterviews illustrate very valid points in their interpretation of our data. In this article, we would like to highlight clarifications based on several points and issues they have raised in their papers, namely, the dose-level selection, determining if MTD was exceeded in 26-week studies, and a discussion on the number of dose groups to be used in the studies. © The Author(s) 2015.

Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

PubMed

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.

The value of fixed rasburicase dosing versus weight-based dosing in the treatment and prevention of tumor lysis syndrome.

PubMed

Boutin, Alyssa; Blackman, Alison; O'Sullivan, David M; Forcello, Nicholas

2018-01-01

Background Rasburicase is a recombinant urate oxidase enzyme used for the treatment and prevention of tumor lysis syndrome. Our objective was to assess the efficacy of indication-based, low-dose rasburicase administration compared to the Food and Drug Administration-approved weight-based dosing. Methods This was a retrospective cohort study utilizing data from a tertiary medical center including patients admitted from 2012 to 2016, who received at least one dose of rasburicase. The primary outcome was achieving a uric acid level less than 7.5 mg/dl after a single dose of rasburicase in the preprotocol (Food and Drug Administration-approved weight-based dosing) and postprotocol (indication-based, low-dose) groups. Secondary outcomes included the change in uric acid levels between the pre- and postprotocol groups, adherence to the new institutional protocol, need for repeat rasburicase doses, and a cost analysis. Results Sixty-four patients received at least one dose of rasburicase between 1 January 2012 and 1 December 2016. Twenty-seven (79.4%) doses in the preprotocol group and 28 (82.4%) doses in the postprotocol group successfully achieved a uric acid level less than 7.5 mg/dl after a single dose of rasburicase (p=1.000). The average total monthly cost of rasburicase was reduced by 59.9% after adoption of the new protocol. Conclusions Indication-based, low-dose rasburicase displayed significantly more value when compared to weight-based dosing as shown by achieving cost savings without compromising clinical efficacy.

Efficacy of an extract from garlic, Allium sativum, against infection with the furunculosis bacterium, Aeromonas salmonicida, in rainbow trout, Oncorhynchus mykiss

USGS Publications Warehouse

Breyer, Kate E.; Getchell, Rodman G.; Cornwell, Emily R.; Wooster, Gregory A.; Ketola, H. George; Bowser, Paul R.

2015-01-01

Juvenile rainbow trout, Oncorhynchus mykiss, were fed diets containing 0, 0.5, 1.0, and 2.0% of a garlic extract, challenged with a modified 50% lethal dose of Aeromonas salmonicida and monitored for 28 d. There were significant increases in survival of trout fed 0.5 and 1.0% garlic extract as compared to the control and 2.0% garlic extract groups. A target animal safety study was performed at varying increments using the target dose of 0.5% garlic extract at 0× (0% garlic extract), 1× (0.5% garlic extract), 3× (1.5% garlic extract), and 5× (2.5% garlic extract) for 3× (6 wk) the duration of the original study. There was a significant increase in the level of circulating lymphocytes and a significant decrease in the level of circulating monocytes. The latter correlated to an increased level of pigment-containing macrophage centers within the renal tissue as garlic extract dosing increased, denoting a potential deleterious inflammatory effect as macrophage infiltration became severe at the highest dose. These studies suggest that feeding low-dose (0.5% or 1.0%) garlic extract improves survivability in rainbow trout when challenged with A. salmonicida and appears safe; however, higher levels do not appear to be effective and may cause deleterious effects on health.

A new fully human recombinant FSH (follitropin epsilon): two phase I randomized placebo and comparator-controlled pharmacokinetic and pharmacodynamic trials.

PubMed

Abd-Elaziz, Khalid; Duijkers, Ingrid; Stöckl, Lars; Dietrich, Bruno; Klipping, Christine; Eckert, Kelvin; Goletz, Steffen

2017-08-01

What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters. Recombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule. Both studies were randomized, placebo- and comparator-controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing. In the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or 150 IU once daily [QD], or 150 IU every other day [QAD], 10 subjects each) and 27 subjects received 150 IU Gonal-f, 150 IU Bravelle, or placebo for 7 days (11/10/6 subjects). Blood samples for measuring PK as well as PD parameters were collected systematically before, during and after dosing. Adverse events (AEs) and other relevant safety parameters were recorded. Data were summarized using descriptive statistics. The single- and multiple-dose PK parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) increased in a linear fashion with increasing dose levels of follitropin epsilon. Follitropin epsilon showed PK characteristics comparable to the comparators indicating that well established treatment schemes could be applied. There was a dose-response effect of single and multiple doses of follitropin epsilon on follicular growth, which was shown for the biomarker inhibin B as well as for the mean number and size of follicles. Multiple doses of 75 IU follitropin epsilon given daily, as well as 150 IU follitropin epsilon every second day, showed a follicle growth comparable with 150 IU Gonal-f given daily, while in case of daily administration of 150 IU Bravelle only weak follicle stimulation was observed. Multiple doses of 150 IU follitropin epsilon induced a much higher follicle growth compared to the same dose of Gonal-f. All single and multiple follitropin epsilon doses tested were safe and well tolerated, and overall there were no relevant differences between follitropin epsilon and the comparators in terms of safety. The average number of AEs increased with increasing dose levels. No clinically relevant abnormalities were reported for any of the other safety parameters assessed. No follitropin epsilon anti-drug antibodies were observed. The studies were conducted as a single-blind design. Hormone levels or other parameters assessed in serum are generally not considered as being subject to bias. Other assessments directly performed by the investigators, such as transvaginal ultrasound assessments, may have been subject to personal bias. No prospective calculations of statistical power had been made, as is common practice for first in human and early phase I studies in healthy volunteers. These early development studies showed that follitropin epsilon exhibits comparable PK characteristics, as well as inducing stronger PD effects in terms of follicle growth and serum inhibin B, than the comparators. Follitropin epsilon induced a dose-dependent increase in follicular growth. The results warrant further studies with this new fully human recombinant FSH. The studies were sponsored by GLYCOTOPE GmbH, Berlin, Germany. K.A-E. is an employee of QPS-Netherlands, B.V., which received funding for the studies from Glycotope GmbH; I.D. and C.K. are employees of Dinox B.V., which received funding for the studies from Glycotope GmbH; L.S. and S.G. are employees and shareholders of Glycotope GmbH; B.D. and K.E. are employees of Glycotope GmbH. www.clinicaltrials.gov: NCT01354886 (single-dose); NCT01477073 (multiple-dose). The single-dose trial was registered on 11 May 2011 while the multiple-dose trial was registered on 09 November 2011. First subject was enroled in the single-dose trial in 27 April 2011 and in the multiple-dose trial in 02 October 2011. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

[Experimental and clinical studies of BRL 25000 (clavulanic acid-amoxicillin) granules in the field of pediatrics].

PubMed

Minamitani, M; Hachimori, K; Kaneda, K

1985-02-01

BRL 25000 granules, a formulation consisting of amoxicillin (AMPC) and clavulanic acid (CVA), was evaluated in the field of pediatrics. In a pharmacokinetic study, serum concentrations were determined in a patient after oral administration of BRL 25000 granules in the non-fasting state at a dose of 11.76 mg/kg. The serum levels of amoxicillin (AMPC) and clavulanic acid (CVA) 1 hour after administration were 7.76 micrograms/ml and 6.64 micrograms/ml, with biological half-lives of 0.86 hour and 0.88 hour respectively. The serum concentration profile at a dose of 31.58 mg/kg showed almost the same tendency as at 11.76 mg/kg, although the peak level and biological half-life of the serum concentrations were not obtained. These serum levels and their peak levels were considered reasonable compared with those obtained in adults at similar dose levels. In clinical studies, 34 patients were evaluated including 8 patients with acute pharyngitis or acute tonsillitis, 1 patient with acute bronchitis, 1 patient with bronchopneumonia, 23 patients with scarlet fever and 1 patient with pertussis. BRL 25000 granules were administered orally 3-4 times per day for 4-8 days to 2 patients at doses of 20 approximately less than 30 mg/kg/day, to 18 patients at doses of 30 approximately less than 40 mg/kg/day, to 11 patients at doses of 40 less than approximately 50 mg/kg/day, and to 3 patients at doses of 50-60 mg/kg/day. The clinical response was assessed excellent in 13 cases and good in 21 cases giving an overall clinical efficacy rate of 100% (34/34). The causative organisms were isolated in 17 cases and included 12 strains of Streptococcus group A, 2 S. pneumoniae, 3 H. influenzae and 1 H. parainfluenzae.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I study of 3-weekly combination chemotherapy using epirubicin, oxaliplatin, and S-1 (EOS) in patients with previously untreated advanced gastric cancer.

PubMed

Sym, Sun Jin; Hong, Junsik; Jung, Minkyu; Park, Jinny; Cho, Eun Kyung; Lee, Woon Ki; Chung, Min; Kim, Hyung-Sik; Lee, Jae Hoon; Shin, Dong Bok

2012-08-01

This study was performed to determine the recommended dose (RD) and dose-limiting toxicity (DLT) associated with epirubicin, oxaliplatin, and S-1 (EOS) combination therapy in patients with previously untreated advanced gastric cancer (AGC). Previously untreated patients with histologically proven metastatic AGC, with an ECOG performance status of 0-2, were enrolled in this study. A fixed dose of epirubicin (50 mg/m(2)) and oxaliplatin (130 mg/m(2)) was intravenously administered on day 1 of treatment, followed by oral S-1 administration twice daily on days 1-14. The S-1 dose was escalated according to the following schedule: level I, 35 mg/m(2); level II, 40 mg/m(2); level III, 45 mg/m(2); Level IV, 50 mg/m(2). Each cycle was repeated every 21 days. DLTs were evaluated during the first two cycles of treatment. Nineteen patients with a median age of 53 years (range, 40-71 years) were enrolled in this study. One case of DLT (grade 4 neutropenia lasting more than 5 days) developed from among the six dose level II patients, while 2 DLTs (grade 3 diarrhea and nausea) were observed among the 4 dose level III patients. Based on these results, dose level II was determined as the RD. Of the 13 patients with measurable lesions, eight achieved partial response, three showed stable disease, and the objective response rate was 61.5 % (95 % confidence interval (CI), 13.3-66.6 %). The median progression-free survival and overall survival of all patients was 6.8 months (95 % CI, 1.4-9.5 months) and 13.3 months (95 % CI, 1.9-24.6 months), respectively. The RD of the EOS regimen in patients with previously untreated AGC was 50 mg/m(2) of epirubicin and 130 mg/m(2) of oxaliplatin on day 1, with administration of 40 mg/m(2) of S-1 twice a day on days 1-14 for each 21-day cycle. The EOS regimen described produced promising results.

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

PubMed

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).

Vitamin D Replacement in Children, Adolescents and Pregnant Women in the Middle East and North Africa

PubMed Central

Chakhtoura, M; El Ghandour, S; Shawwa, K; Akl, EA; Arabi, A; Mahfoud, Z; Habib, RH; Hoballah, H; El Hajj Fuleihan, G

2017-01-01

Introduction Hypovitaminosis D affects one-third to two-thirds of children and pregnant women from the Middle East and North Africa (MENA) region. Objective To evaluate in infants, children, adolescents and pregnant women, from the MENA region, the effect of supplementation with different vitamin D doses on the change in 25-hydroxyvitamin D [25(OH)D] level reached, and other skeletal and non-skeletal outcomes. Methods This is a systematic review of randomized controlled trials of vitamin D supplementation conducted in the MENA region. We conducted a comprehensive literature search in 7 databases, without language or time restriction, until November 2016. Two reviewers abstracted data from the included studies, independently and in duplicate. We calculated the mean difference (MD) and 95% CI of 25(OH)D level reached when at least 2 studies were eligible in each comparison (low (< 800 IU), intermediate (800–2,000 IU) or high (> 2,000 IU) daily dose of vitamin D, or placebo). We pooled data using RevMan version 5.3. Results We identified a total of 15 eligible trials: one in infants, 4 in children and adolescents and 10 in pregnant women. In children and adolescents, an intermediate vitamin D dose (1,901 IU/d), resulted in a mean difference in 25(OH)D level of 13.5 (95% Confidence Interval (CI) 8.1;18.8) ng/ml, compared to placebo, favoring the intermediate dose (p < 0.001). The proportion of children and adolescents reaching a 25(OH)D level ≥ 20 ng/ml was 74% in the intermediate dose group. In pregnant women, four trials started supplementation at 12–16 weeks of gestation and continued until delivery, and six trials started supplementation at 20–28 weeks gestation and stopped it at delivery. The MD in 25(OH)D level reached was 8.6 (95% CI 5.3–11.9) ng/ml (p <0.001) comparing the high dose (3,662 IU/d) to the intermediate dose (1,836 IU/d), and 12.3 (95% CI 6.4–18.2) ng/ml (p <0.001), comparing the high dose (3,399 IU/d) to the low dose (375 IU/d). Comparing the intermediate (1,832 IU/d) to the low dose (301 IU/d), the MD in 25(OH)D level achieved was 7.8 (95% CI 4.5–10.8) ng/ml (p < 0.001). The proportion of pregnant women reaching a 25(OH)D level ≥ 20 ng/ml was 80–90%, 73% and 27–43% in the high, intermediate, and low dose groups, respectively. The risk of bias in the included studies, for children, adolescents and pregnant women, ranged from low to high. Conclusion In children, adolescents and pregnant women from the MENA, an intermediate vitamin D dose of 1,000–2,000 IU seems necessary to allow for the majority of the population to reach a desirable 25(OH)D level of 20 ng/ml. Further high quality RCTs are required to confirm/refute the beneficial impact of vitamin D supplementation on various clinically important outcomes. PMID:28403940

A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state

PubMed Central

O’Bryant, C. L.; Lieu, C. H.; Leong, S.; Boinpally, R.; Basche, M.; Gore, L.; Leonardi, K.; Schultz, M. K.; Hariharan, S.; Chow, L.; Diab, S.; Gibbs, A.; Eckhardt, S. G.

2010-01-01

Purpose To evaluate the safety, pharmacokinetics and determine the recommended dose of the selective apoptotic antineoplastic drug, OSI-461 administered on a twice-daily regimen to patients with advanced solid malignancies. Methods In this phase I trial, 33 patients were treated with OSI-461 doses ranging from 400 to 1,200 mg given twice daily in 4-week cycles. Pharmacokinetic studies were performed to characterize the plasma disposition of OSI-461 and the effect of food intake on OSI-461 absorption. Secondary biomarker studies were performed to assess the biologic activity of OSI-461 including the measurement of pGSK-3β, a PKG substrate, and pharmacogenetic studies to identify polymorphisms of CYP3A that influence drug metabolism and of ABCG2, involved in drug resistance. Results Thirty-three patients were treated with 86 courses of OSI-461. The dose-limiting toxicities were grade 3 abdominal pain, found in one patient at the 1,000 mg BID fed dose level and all patients at the 1,200 mg BID fed dose level. There was also one episode each of grade 3 fatigue and grade 3 constipation at the 1,000 and 1,200 mg BID fed dose levels, respectively. Other common toxicities included mild to moderate fatigue, nausea, anorexia and mild elevation in bilirubin. Pharmacokinetic studies of OSI-461 revealed approximately a twofold increase in AUC0–24 when OSI-461 was administered with food. An increase in pGSK-3β post-dose was seen in the majority of patients and was greater at higher dose levels. No patients exhibited CYP3A4 polymorphisms, while 100% of patients were found to have the CYP3A5*3/CYP3A5*3 polymorphism. Two known polymorphisms of the ABCG2 gene, G34 → A34 and C421 → A421, occurred at frequencies of 11.76 and 29%, respectively. Conclusions Toxicity and pharmacodynamic data show that the recommended oral dose of OSI-461 is 800 mg twice daily administered with food. The drug appears to be well-tolerated, and overall bioavailability appears to be markedly increased when the drug is administered with food. These results support further disease-directed evaluations of OSI-461 at a dose of 800 mg BID in combination with other chemotherapeutic agents. PMID:18509645

The effects of phototherapy and melanocytes on keratinocytes

PubMed Central

Tang, Luyan; Wu, Wenyu; Fu, Wenwen; Hu, Yao

2018-01-01

Phototherapy is widely used in the treatment of vitiligo. Previous studies have focused on the effects of ultraviolet (UV) radiation on melanocytes; however, the biological effects of phototherapy and melanocytes on keratinocytes remain to be elucidated. To investigate and assess the effects of clinically doses of broad band (BB)-UVA, narrow band (NB)-UVB and melanocytes on human keratinocytes in vitro, clinical doses of BB-UVA or NB-UVB radiation and human melanoma cell A375 co-culture were performed as stress divisors to HaCaT cells. Cell proliferation, expression of protease-activated receptor-2 (PAR-2) and nuclear factor E2-related factor 2 mRNA, lipid peroxidation and intracellular antioxidant level of keratinocytes were analyzed. It was demonstrated that UV radiation inhibited the proliferation of cells apart from following exposure to low dose (1 J/cm2) UVA. Medium dose (5 J/cm2) UVA radiation had no adverse effects on lipid peroxidation and increased antioxidant levels in HaCaT cells. Medium (200 mJ/cm2) and high (400 mJ/cm2) doses of UVB radiation induced cellular damage due to increased lipid peroxidation as indicated by levels of malondialdehyde. Furthermore, A375 co-culture treatment induced a similar effect on the lipid peroxidation of HaCaT as with low dose UVB radiation. Therefore, the results of the present study determined that clinical doses of BB-UVA and NB-UVB radiation had varying effects on proliferation and related protein levels in HaCaT cells. Co-culture with A375 had similar effects as those of low dose UVA and UVB radiation, in which the PAR-2 expression was significantly upregulated. PMID:29545869

Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test

PubMed Central

Hu, Yi-Min; Zhou, Zhi-Qiang; Zhang, Guang-Fen

2013-01-01

Introduction Previous studies have shown that a single sub-anesthetic dose of ketamine exerts fast-acting antidepressant effects in patients and in animal models of depression. However, the underlying mechanisms are not totally understood. This study aims to investigate the effects of acute administration of different doses of ketamine on the immobility time of rats in the forced swimming test (FST) and to determine levels of hippocampal brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR). Methods Forty male Wistar rats weighing 180–220 g were randomly divided into four groups (n = 10 each): group saline and groups ketamine 5, 10, and 15 mg/kg. On the first day, all animals were forced to swim for 15 min. On the second day ketamine (5, 10, and 15 mg/kg, respectively) was given intraperitoneally, at 30 min before the second episode of the forced swimming test. Immobility times of the rats during the forced swimming test were recorded. The animals were then decapitated. The hippocampus was harvested for determination of BDNF and mTOR levels. Results Compared with group saline, administration of ketamine at a dose of 5, 10, and 15 mg/kg decreased the duration of immobility (P < 0.05 for all doses). Ketamine at doses of both 10 and 15 mg/kg showed a significant increase in the expression of hippocampal BDNF (P < 0.05 for both doses). Ketamine given at doses of 5, 10, and 15 mg/kg showed significant increases in relative levels of hippocampal p-mTOR (P < 0.05 for all doses) Conclusion The antidepressant effect of ketamine might be related to the increased expression of BDNF and mTOR in the hippocampus of rats. PMID:22970723

Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test.

PubMed

Yang, Chun; Hu, Yi-Min; Zhou, Zhi-Qiang; Zhang, Guang-Fen; Yang, Jian-Jun

2013-03-01

Previous studies have shown that a single sub-anesthetic dose of ketamine exerts fast-acting antidepressant effects in patients and in animal models of depression. However, the underlying mechanisms are not totally understood. This study aims to investigate the effects of acute administration of different doses of ketamine on the immobility time of rats in the forced swimming test (FST) and to determine levels of hippocampal brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR). Forty male Wistar rats weighing 180-220 g were randomly divided into four groups (n = 10 each): group saline and groups ketamine 5, 10, and 15 mg/kg. On the first day, all animals were forced to swim for 15 min. On the second day ketamine (5, 10, and 15 mg/kg, respectively) was given intraperitoneally, at 30 min before the second episode of the forced swimming test. Immobility times of the rats during the forced swimming test were recorded. The animals were then decapitated. The hippocampus was harvested for determination of BDNF and mTOR levels. Compared with group saline, administration of ketamine at a dose of 5, 10, and 15 mg/kg decreased the duration of immobility (P < 0.05 for all doses). Ketamine at doses of both 10 and 15 mg/kg showed a significant increase in the expression of hippocampal BDNF (P < 0.05 for both doses). Ketamine given at doses of 5, 10, and 15 mg/kg showed significant increases in relative levels of hippocampal p-mTOR (P < 0.05 for all doses) The antidepressant effect of ketamine might be related to the increased expression of BDNF and mTOR in the hippocampus of rats.

Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study.

PubMed

Eisbruch, A; Shewach, D S; Bradford, C R; Littles, J F; Teknos, T N; Chepeha, D B; Marentette, L J; Terrell, J E; Hogikyan, N D; Dawson, L A; Urba, S; Wolf, G T; Lawrence, T S

2001-02-01

To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure

PubMed Central

Thomas, Reuben; Hubbard, Alan E.; McHale, Cliona M.; Zhang, Luoping; Rappaport, Stephen M.; Lan, Qing; Rothman, Nathaniel; Vermeulen, Roel; Guyton, Kathryn Z.; Jinot, Jennifer; Sonawane, Babasaheb R.; Smith, Martyn T.

2014-01-01

Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from <1 ppm to >10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings. PMID:24786086

Comparison of internal dose estimates obtained using organ-level, voxel S value, and Monte Carlo techniques

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

Grimes, Joshua, E-mail: grimes.joshua@mayo.edu; Celler, Anna

2014-09-15

Purpose: The authors’ objective was to compare internal dose estimates obtained using the Organ Level Dose Assessment with Exponential Modeling (OLINDA/EXM) software, the voxel S value technique, and Monte Carlo simulation. Monte Carlo dose estimates were used as the reference standard to assess the impact of patient-specific anatomy on the final dose estimate. Methods: Six patients injected with{sup 99m}Tc-hydrazinonicotinamide-Tyr{sup 3}-octreotide were included in this study. A hybrid planar/SPECT imaging protocol was used to estimate {sup 99m}Tc time-integrated activity coefficients (TIACs) for kidneys, liver, spleen, and tumors. Additionally, TIACs were predicted for {sup 131}I, {sup 177}Lu, and {sup 90}Y assuming themore » same biological half-lives as the {sup 99m}Tc labeled tracer. The TIACs were used as input for OLINDA/EXM for organ-level dose calculation and voxel level dosimetry was performed using the voxel S value method and Monte Carlo simulation. Dose estimates for {sup 99m}Tc, {sup 131}I, {sup 177}Lu, and {sup 90}Y distributions were evaluated by comparing (i) organ-level S values corresponding to each method, (ii) total tumor and organ doses, (iii) differences in right and left kidney doses, and (iv) voxelized dose distributions calculated by Monte Carlo and the voxel S value technique. Results: The S values for all investigated radionuclides used by OLINDA/EXM and the corresponding patient-specific S values calculated by Monte Carlo agreed within 2.3% on average for self-irradiation, and differed by as much as 105% for cross-organ irradiation. Total organ doses calculated by OLINDA/EXM and the voxel S value technique agreed with Monte Carlo results within approximately ±7%. Differences between right and left kidney doses determined by Monte Carlo were as high as 73%. Comparison of the Monte Carlo and voxel S value dose distributions showed that each method produced similar dose volume histograms with a minimum dose covering 90% of the volume (D90) agreeing within ±3%, on average. Conclusions: Several aspects of OLINDA/EXM dose calculation were compared with patient-specific dose estimates obtained using Monte Carlo. Differences in patient anatomy led to large differences in cross-organ doses. However, total organ doses were still in good agreement since most of the deposited dose is due to self-irradiation. Comparison of voxelized doses calculated by Monte Carlo and the voxel S value technique showed that the 3D dose distributions produced by the respective methods are nearly identical.« less

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

PubMed

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

2017-03-01

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

Knowledge-based iterative model reconstruction: comparative image quality and radiation dose with a pediatric computed tomography phantom.

PubMed

Ryu, Young Jin; Choi, Young Hun; Cheon, Jung-Eun; Ha, Seongmin; Kim, Woo Sun; Kim, In-One

2016-03-01

CT of pediatric phantoms can provide useful guidance to the optimization of knowledge-based iterative reconstruction CT. To compare radiation dose and image quality of CT images obtained at different radiation doses reconstructed with knowledge-based iterative reconstruction, hybrid iterative reconstruction and filtered back-projection. We scanned a 5-year anthropomorphic phantom at seven levels of radiation. We then reconstructed CT data with knowledge-based iterative reconstruction (iterative model reconstruction [IMR] levels 1, 2 and 3; Philips Healthcare, Andover, MA), hybrid iterative reconstruction (iDose(4), levels 3 and 7; Philips Healthcare, Andover, MA) and filtered back-projection. The noise, signal-to-noise ratio and contrast-to-noise ratio were calculated. We evaluated low-contrast resolutions and detectability by low-contrast targets and subjective and objective spatial resolutions by the line pairs and wire. With radiation at 100 peak kVp and 100 mAs (3.64 mSv), the relative doses ranged from 5% (0.19 mSv) to 150% (5.46 mSv). Lower noise and higher signal-to-noise, contrast-to-noise and objective spatial resolution were generally achieved in ascending order of filtered back-projection, iDose(4) levels 3 and 7, and IMR levels 1, 2 and 3, at all radiation dose levels. Compared with filtered back-projection at 100% dose, similar noise levels were obtained on IMR level 2 images at 24% dose and iDose(4) level 3 images at 50% dose, respectively. Regarding low-contrast resolution, low-contrast detectability and objective spatial resolution, IMR level 2 images at 24% dose showed comparable image quality with filtered back-projection at 100% dose. Subjective spatial resolution was not greatly affected by reconstruction algorithm. Reduced-dose IMR obtained at 0.92 mSv (24%) showed similar image quality to routine-dose filtered back-projection obtained at 3.64 mSv (100%), and half-dose iDose(4) obtained at 1.81 mSv.

Estimation of low-level neutron dose-equivalent rate by using extrapolation method for a curie level Am-Be neutron source.

PubMed

Li, Gang; Xu, Jiayun; Zhang, Jie

2015-01-01

Neutron radiation protection is an important research area because of the strong radiation biological effect of neutron field. The radiation dose of neutron is closely related to the neutron energy, and the connected relationship is a complex function of energy. For the low-level neutron radiation field (e.g. the Am-Be source), the commonly used commercial neutron dosimeter cannot always reflect the low-level dose rate, which is restricted by its own sensitivity limit and measuring range. In this paper, the intensity distribution of neutron field caused by a curie level Am-Be neutron source was investigated by measuring the count rates obtained through a 3 He proportional counter at different locations around the source. The results indicate that the count rates outside of the source room are negligible compared with the count rates measured in the source room. In the source room, 3 He proportional counter and neutron dosimeter were used to measure the count rates and dose rates respectively at different distances to the source. The results indicate that both the count rates and dose rates decrease exponentially with the increasing distance, and the dose rates measured by a commercial dosimeter are in good agreement with the results calculated by the Geant4 simulation within the inherent errors recommended by ICRP and IEC. Further studies presented in this paper indicate that the low-level neutron dose equivalent rates in the source room increase exponentially with the increasing low-energy neutron count rates when the source is lifted from the shield with different radiation intensities. Based on this relationship as well as the count rates measured at larger distance to the source, the dose rates can be calculated approximately by the extrapolation method. This principle can be used to estimate the low level neutron dose values in the source room which cannot be measured directly by a commercial dosimeter. Copyright © 2014 Elsevier Ltd. All rights reserved.

Relationship Between Physical Activity, Body Mass Index, and Risk of Heart Failure

PubMed Central

Pandey, Ambarish; LaMonte, Michael; Klein, Liviu; Ayers, Colby; Psaty, Bruce; Eaton, Charles; Allen, Norrina; de Lemos, James A.; Carnethon, Mercedes; Greenland, Philip; Berry, Jarett D.

2018-01-01

Background Lower leisure-time physical activity (LTPA) and higher body mass index (BMI) are independently associated with risk of heart failure (HF). However, it is unclear if this relationship is consistent for both HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Objective This study sought to quantify dose-response associations between LTPA, BMI, and the risk of different HF subtypes. Methods Individual-level data from 3 cohort studies (WHI, MESA, and CHS) were pooled and participants were stratified into guideline-recommended categories of LTPA and BMI. Associations between LTPA, BMI, and risk of overall HF, HFpEF (ejection fraction [EF] ≥45%) and HFrEF (EF <45%) were assessed used multivariable adjusted Cox models and restricted cubic splines. Results The study included 51,451 participants with 3,180 HF events (1,252 HFpEF, 914 HFrEF, 1,014 missing EF). In adjusted analysis, there was a dose-dependent association between higher LTPA levels, lower BMI, and overall HF risk. Among HF subtypes, LTPA in any dose range was not associated with HFrEF risk. In contrast, lower levels of LTPA (<500 metabolic equivalents of task [MET]-min/week) were not associated with HFpEF risk, and dose-dependent associations with lower HFpEF risk were observed at higher levels. Compared with no LTPA, higher than twice the guideline-recommended minimum LTPA levels (>1,000 MET-min/week) were associated with an 19% lower risk of HFpEF (HR: 0.81; 95% CI: 0.68 to 0.97). The dose-response relationship for BMI with HFpEF risk was also more consistent than with HFrEF risk, such that increasing BMI above the normal range (≥ 25 kg/m2) was associated with greater increase in risk of HFpEF than HFrEF. Conclusion Our study findings demonstrate strong, dose-dependent associations between LTPA levels, BMI, and risk of overall HF. Among HF subtypes, higher LTPA levels and lower BMI were more consistently associated with lower risk of HFpEF compared with HFrEF. PMID:28254175

Glycerol Phenylbutyrate Treatment in Children with Urea Cycle Disorders: Pooled Analysis of Short and Long-term Ammonia Control and Outcomes

PubMed Central

Berry, Susan A.; Lichter-Konecki, Uta; Diaz, George A.; McCandless, Shawn E.; Rhead, William; Smith, Wendy; LeMons, Cynthia; Nagamani, Sandesh C.S.; Coakley, Dion F.; Mokhtarani, Masoud; Scharschmidt, Bruce F.; Lee, Brendan

2015-01-01

Objective To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs). Study Design UCD patients (n=26) ages 2 months through 17 years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0–24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acids levels, and patient growth. Results Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC0–24: 627 [302] vs. 872 [516] µmol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p = 0.02). Mean ammonia levels remained within the normal range during 12 months of GPB dosing and, when compared with the 12 months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] µmol/L; p=0.114) and mean glutamine and branched chain amino acids levels, as well as other essential amino acids, remained within the normal range during 12 months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12 months of GPB treatment. Conclusions Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12 month period preceding enrollment. PMID:24630270

A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study

PubMed Central

Thaker, Premal H.; Brady, William E.; Lankes, Heather A.; Odunsi, Kunle; Bradley, William H.; Moore, Kathleen N.; Muller, Carolyn Y.; Anwer, Khursheed; Schilder, Russell J.; Alvarez, Ronald D.; Fracasso, Paula M.

2017-01-01

Objective The study’s purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). Methods Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3 + 3 phase I dose escalation design with patients receiving intravenous PLD 40 mg/m2 (dose level 1 and 2) or 50 mg/m2 (dose level 3) every 28 days and intraperitoneal GEN-1 at 24 mg/m2 (dose level 1) or 36 mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28 day cycle. Cycles were repeated every 28 days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. Results Sixteen evaluable patients received a median of 4 cycles (range 1–8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. Conclusions GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1. PMID:28802766

Comparative toxicity of 4 commonly used intravitreal corticosteroids on rat retina.

PubMed

Citirik, Mehmet; Dilsiz, Nihat; Batman, Cosar; Zilelioglu, Orhan

2009-06-01

To investigate the effects of 4 commonly used steroids (dexamethasone, triamcinolone, betamethasone, and methylprednisolone) on 50 retinas of 25 adult pigmented rats. Experimental animal study. Twenty-five pigmented Long-Evans male rats. Each steroid drug with 2 different doses (0.025 mL and 0.050 mL) was injected into the vitreous of each eye of 5 rats. The low drug dose was injected into the right eye and the high dose was injected into the left eye. Ten eyes of 5 randomly selected rats were used as a control group and intravitreal saline was injected into these eyes. Oxidative damage and intrinsic antioxidative capacity were determined by measuring retinal malondialdehyde (MDA) and glutathione (GSH) levels, respectively. No statistically meaningful difference was observed in retinal GSH and MDA measurements in the low- and high-dose triamcinolone (1 and 2 mg), low-dose betamethasone (0.075 mg), and low-dose dexamethasone (0.1 mg) groups, compared with the control group. Both doses of methylprednisolone (1.6 mg and 3.2 mg), high-dose betamethasone (0.15 mg), and high-dose dexamethasone (0.2 mg) markedly altered retinal GSH and MDA levels. The results of our study show that the toxicity of triamcinolone is not evident even in high doses. It may be used safely. We also suggest that intravitreal use of low doses of betamethasone and dexamethasone is safer than higher doses of these drugs and both doses of methylprednisolone.

TOXICITY STUDIES OF EPICHLOROHYDRIN IN SPRAGUE-DAWLEY RATS

EPA Science Inventory

Adult male and female Sprague-Dawley rats received epichlorohydrin via gavage in distilled water for 10 consecutive days at dose levels of 3, 7, 19, and 46 mg/kg-day, and for 90 days at dose levels of 1, 5, and 25 mg/kg-day. Epichlorohydrin did not adversely effect mortality, but...

The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM

PubMed Central

Koopmeiners, Joseph S.; Wey, Andrew

2017-01-01

The primary object of a phase I clinical trial is to determine the maximum tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation study, where initial subjects are treated at the lowest dose level and subsequent subjects are treated at progressively higher dose levels until the MTD is identified. The continual reassessment method (CRM) is a popular model-based dose-escalation design, which utilizes a formal model for the relationship between dose and toxicity to guide dose-finding. Recently, it was shown that the CRM has a tendency to get “stuck” on a dose-level, with little escalation or de-escalation in the late stages of the trial, due to the long-memory property of the CRM. We propose the randomized CRM (rCRM), which introduces random escalation and de-escalation into the standard CRM dose-finding algorithm, as well as a hybrid approach that incorporates escalation and de-escalation only when certain criteria are met. Our simulation results show that both the rCRM and the hybrid approach reduce the trial-to-trial variability in the number of cohorts treated at the MTD but that the hybrid approach has a more favorable trade-off with respect to the average number treated at the MTD. PMID:28340333

The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM.

PubMed

Koopmeiners, Joseph S; Wey, Andrew

2017-01-01

The primary object of a Phase I clinical trial is to determine the maximum tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation study, where initial subjects are treated at the lowest dose level and subsequent subjects are treated at progressively higher dose levels until the MTD is identified. The continual reassessment method (CRM) is a popular model-based dose-escalation design, which utilizes a formal model for the relationship between dose and toxicity to guide dose finding. Recently, it was shown that the CRM has a tendency to get "stuck" on a dose level, with little escalation or de-escalation in the late stages of the trial, due to the long-memory property of the CRM. We propose the randomized CRM (rCRM), which introduces random escalation and de-escalation into the standard CRM dose-finding algorithm, as well as a hybrid approach that incorporates escalation and de-escalation only when certain criteria are met. Our simulation results show that both the rCRM and the hybrid approach reduce the trial-to-trial variability in the number of cohorts treated at the MTD but that the hybrid approach has a more favorable tradeoff with respect to the average number treated at the MTD.

High dose vitamin D may improve lower urinary tract symptoms in postmenopausal women.

PubMed

Oberg, Johanna; Verelst, Margareta; Jorde, Rolf; Cashman, Kevin; Grimnes, Guri

2017-10-01

Lower urinary tract symptoms (LUTS) are common in postmenopausal women, and have been reported inversely associated with vitamin D intake and serum 25-hydroxyvitamin D (25(OH)D) levels. The aim of this study was to investigate if high dose vitamin D supplementation would affect LUTS in comparison to standard dose. In a randomized controlled study including 297 postmenopausal women with low bone mineral density, the participants were allocated to receive capsules of 20 000IU of vitamin D 3 twice a week (high dose group) or similar looking placebo (standard dose group). In addition, all the participants received 1g of calcium and 800IU of vitamin D daily. A validated questionnaire regarding LUTS was filled in at baseline and after 12 months. At baseline, 76 women in the high dose group and 82 in the standard dose group reported any LUTS. Levels of serum 25(OH)D increased significantly more in the high dose group (from 64.7 to 164.1nmol/l compared to from 64.1 to 81.8nmol/l, p<0.01). No differences between the groups were seen regarding change in LUTS except for a statistically significant reduction in the reported severity of urine incontinence in the high dose group as compared to the standard dose group after one year (p<0.05). The results need confirmation in a study specifically designed for this purpose. Copyright © 2017 Elsevier Ltd. All rights reserved.

Galactic cosmic ray radiation levels in spacecraft on interplanetary missions

NASA Technical Reports Server (NTRS)

Shinn, J. L.; Nealy, J. E.; Townsend, L. W.; Wilson, J. W.; Wood, J.S.

1994-01-01

Using the Langley Research Center Galactic Cosmic Ray (GCR) transport computer code (HZETRN) and the Computerized Anatomical Man (CAM) model, crew radiation levels inside manned spacecraft on interplanetary missions are estimated. These radiation-level estimates include particle fluxes, LET (Linear Energy Transfer) spectra, absorbed dose, and dose equivalent within various organs of interest in GCR protection studies. Changes in these radiation levels resulting from the use of various different types of shield materials are presented.

Glucosamine for the Treatment of Osteoarthritis: The Time Has Come for Higher-Dose Trials.

PubMed

McCarty, Mark F; O'Keefe, James H; DiNicolantonio, James J

2018-04-18

Although clinical trials with glucosamine in osteoarthritis have yielded mixed results, leading to doubts about its efficacy, the utility of glucosamine for preventing joint destruction and inflammation is well documented in rodent models of arthritis, including models of spontaneous osteoarthritis. The benefit of oral glucosamine in adjuvant arthritis is markedly dose dependent, likely reflecting a modulation of tissue levels of UDP-N-acetylglucosamine that in turn influences mucopolysaccharide synthesis and the extent of protein O-GlcNAcylation. Importantly, the minimal oral dose of glucosamine that exerts a detectible benefit in adjuvant arthritis achieves plasma glucosamine levels similar to those achieved when the standard clinical dose of glucosamine, 1.5 g daily, is administered as a bolus. The response of plasma glucosamine levels to an increase in glucosamine intake is nearly linear. Remarkably, every published clinical trial with glucosamine has employed the same 1.5 g dose that Rottapharm recommended for its proprietary glucosamine sulfate product decades ago, yet there has never been any published evidence that this dose is optimal with respect to efficacy and side effects. If this dose is on the edge of demonstrable clinical efficacy when experimental design is ideal, then variations in the patient populations targeted, the assessment vehicles employed, and the potency of glucosamine preparations tested could be expected to yield some null results. Failure to employ bolus dosing may also be a factor in the null results observed in the GAIT study and other trials. Clinical studies evaluating the dose dependency of glucosamine's influence on osteoarthritis are long overdue.

Pharmacokinetics of buprenorphine: a comparison of sublingual tablet versus liquid after chronic dosing.

PubMed

Compton, Peggy; Ling, Walter; Chiang, C Nora; Moody, David E; Huber, Alice; Ling, Debbie; Charuvastra, Charles

2007-06-01

Although buprenorphine is approved for use in the outpatient treatment of opioid addiction in 2 tablet formulations, a monoproduct containing buprenorphine only (Subutex) and a buprenorphine/naloxone combination product (Suboxone), much of the clinical data that support the approval by the U.S. Food and Drug Administration were generated by using a sublingual liquid. To interpret the literature in prescribing parameters for tablet buprenorphine, this study was designed to determine steady state buprenorphine plasma levels for the 2 formulations and to assess the relative bioavailability of each. A randomized, double-blind, crossover study with dose increases was conducted during a 12-week period at an outpatient treatment clinic. Of the 184 subjects initially randomized to treatment, 133 (72.3%) were evaluated for the steady-state trough plasma concentration, 16 (8.7%) for relative bioavailability, and 31 (16.8%) for dose proportionality. At steady state, differences in the trough plasma concentrations of buprenorphine between the 2 formulations were found across all the dose levels. Average plasma concentration (Cavg) of the tablet at twice the milligram dose of the liquid was twice that of the liquid; intersubject variability was greater for the tablet. At double the dose of tablet, there is no difference in steady state plasma concentrations. The bioavailability seems equivalent for the 2 formulations across all the dose levels.

First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

PubMed

Böttcher, M; Lentini, S; Arens, E R; Kaiser, A; van der Mey, D; Thuss, U; Kubitza, D; Wensing, G

2018-07-01

Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l -1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l -1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia. © 2018 The British Pharmacological Society.

(90)Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia: a phase 1 dose-escalation study.

PubMed

Chevallier, Patrice; Eugene, Thomas; Robillard, Nelly; Isnard, Françoise; Nicolini, Franck; Escoffre-Barbe, Martine; Huguet, Françoise; Hunault, Mathilde; Marcais, Antoine; Gaschet, Joelle; Cherel, Michel; Guillaume, Thierry; Delaunay, Jacques; Peterlin, Pierre; Eveillard, Marion; Thomas, Xavier; Ifrah, Norbert; Lapusan, Simona; Bodet-Milin, Caroline; Barbet, Jacques; Faivre-Chauvet, Alain; Ferrer, Ludovic; Bene, Marie C; Le Houerou, Claire; Goldenberg, David M; Wegener, William A; Kraeber-Bodéré, Françoise

2015-03-01

Prognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22 epratuzumab tetraxetan ((90)Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3 + 3 phase 1 study. Adults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of (90)Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m(2) (92·5 MBq/m(2); level 1), 5·0 mCi/m(2) (185 MBq/m(2); level 2), 7·5 mCi/m(2) (277·5 MBq/m(2); level 3), and 10·0 mCi/m(2) (370 MBq/m(2); level 4). The primary objective was to identify the maximum tolerated dose of (90)Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457. Between Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27-77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3-4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4). (90)Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2 × 10·0 mCi/m(2) 1 week apart per cycle for phase 2 studies. Immunomedics and Direction de la Recherche Clinique of Nantes. Copyright © 2015 Elsevier Ltd. All rights reserved.

OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models.

PubMed

Garton, Andrew J; Crew, Andrew P A; Franklin, Maryland; Cooke, Andrew R; Wynne, Graham M; Castaldo, Linda; Kahler, Jennifer; Winski, Shannon L; Franks, April; Brown, Eric N; Bittner, Mark A; Keily, John F; Briner, Paul; Hidden, Chris; Srebernak, Mary C; Pirrit, Carrie; O'Connor, Matthew; Chan, Anna; Vulevic, Bojana; Henninger, Dwight; Hart, Karen; Sennello, Regina; Li, An-Hu; Zhang, Tao; Richardson, Frank; Emerson, David L; Castelhano, Arlindo L; Arnold, Lee D; Gibson, Neil W

2006-01-15

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.

Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors.

PubMed

Pardo, Beatriz; Paz-Ares, Luis; Tabernero, Josep; Ciruelos, Eva; García, Margarita; Salazar, Ramón; López, Ana; Blanco, María; Nieto, Antonio; Jimeno, José; Izquierdo, Miguel Angel; Trigo, José Manuel

2008-02-15

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available. Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 microg/m(2), and dose escalation proceeded based on the worst toxicity found in the previous cohort. Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 microg/m(2). Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 microg/m(2), and the recommended dose for phase II studies was 650 microg/m(2). No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent. The maximum tolerated dose was 800 microg/m(2). Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 microg/m(2) was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.

High-dose vitamin B6 decreases homocysteine serum levels in patients with schizophrenia and schizoaffective disorders: a preliminary study.

PubMed

Miodownik, Chanoch; Lerner, Vladimir; Vishne, Tali; Sela, Ben-Ami; Levine, Joseph

2007-01-01

Vitamin B6 plays an essential role in the normal functioning of the central nervous system. Normal homocysteine (Hcy) serum level is maintained by remethylation of Hcy to methionine by enzymes that require folic acid and vitamin B12 and by catabolism to cysteine by a vitamin B6-dependent enzyme. These findings may be consistent with the hypothesis that the vitamin B6 status may influence plasma Hcy levels. The aims of this preliminary study were (1) to determine whether a correlation exists between Hcy and vitamin B6 levels in patients with schizophrenia and schizoaffective disorders and (2) to investigate whether treatment with high-dose vitamin B6 may reduce Hcy levels in these patients. In this preliminary study, we enrolled 11 patients with schizophrenia or schizoaffective disorders (7 men and 4 women; mean age +/- SD, 50 +/- 12 years) receiving high doses of vitamin B6 treatment (1200 mg/d) for 12 weeks. Blood samples for the assessment of pyridoxal-5-phosphate and Hcy serum levels were obtained at baseline and after 12 weeks of treatment. Age was significantly positively correlated with Hcy levels at baseline (r = 0.392, P = 0.004). All other parameters, including diagnosis, disease duration, and pyridoxal-5-phosphate serum level, were not correlated with Hcy serum levels at baseline. After vitamin B6 treatment, Hcy serum levels significantly decreased (14.2 +/- 3.4 vs. 11.8 +/- 2.0 micromol/L, respectively, t = 2.679, P = 0.023); this decrease being statistically significant in men but not in women. High doses of vitamin B6 lead to a decrease in Hcy serum level in male patients with schizophrenia or schizoaffective disorder.

Green tea (Camellia sinensis) administration induces expression of immune relevant genes and biochemical parameters in rainbow trout (Oncorhynchus mykiss).

PubMed

Nootash, Shahab; Sheikhzadeh, Najmeh; Baradaran, Behzad; Oushani, Ali Khani; Maleki Moghadam, Mohammad Reza; Nofouzi, Katayoon; Monfaredan, Amir; Aghebati, Leili; Zare, Fatemeh; Shabanzadeh, Sadigheh

2013-12-01

Present study elucidates the efficacy of green tea (Camellia sinensis) on growth performance, immune and antioxidant systems and cytokine gene expression in rainbow trout tissues. Green tea was supplemented at 20, 100, and 500 mg kg(-1) diet and fed to fish (average weight: 23.5 g) for 35 days. No remarkable changes in growth performance were observed among all test groups. Lower lipid peroxidation product and higher superoxide dismutase activity were noted in fish received the medium dose of green tea. Significant increase in serum bactericidal activity and total protein were recorded in all treatment groups. All doses of green tea up-regulated Interleukin-1β transcription in the spleen, while Interleukin-1β mRNA level decreased significantly in the kidney of low dose of green tea. Interleukin-6 mRNA level was up-regulated in the spleen of high dose of green tea and liver of middle and high doses of green tea. High dose and medium dose of green tea up-regulated the interleukin-8 transcription in the kidney and liver, respectively. Meanwhile, green tea inhibited the production of interleukin-10 in all treatment groups compared with control group. Medium dose of green tea up-regulated tumor necrosis factor-α transcription in all fish tissues, while high dose and low dose of green tea enhanced tumor necrosis factor-α mRNA levels in the kidney and spleen, respectively. Present study suggests that green tea especially at 100 mg kg(-1) feed may effectively enhance the antioxidant system and immune system in rainbow trout. Copyright © 2013 Elsevier Ltd. All rights reserved.

Integrated molecular analysis indicates undetectable change in DNA damage in mice after continuous irradiation at ~ 400-fold natural background radiation.

PubMed

Olipitz, Werner; Wiktor-Brown, Dominika; Shuga, Joe; Pang, Bo; McFaline, Jose; Lonkar, Pallavi; Thomas, Aline; Mutamba, James T; Greenberger, Joel S; Samson, Leona D; Dedon, Peter C; Yanch, Jacquelyn C; Engelward, Bevin P

2012-08-01

In the event of a nuclear accident, people are exposed to elevated levels of continuous low dose-rate radiation. Nevertheless, most of the literature describes the biological effects of acute radiation. DNA damage and mutations are well established for their carcinogenic effects. We assessed several key markers of DNA damage and DNA damage responses in mice exposed to low dose-rate radiation to reveal potential genotoxic effects associated with low dose-rate radiation. We studied low dose-rate radiation using a variable low dose-rate irradiator consisting of flood phantoms filled with 125Iodine-containing buffer. Mice were exposed to 0.0002 cGy/min (~ 400-fold background radiation) continuously over 5 weeks. We assessed base lesions, micronuclei, homologous recombination (HR; using fluorescent yellow direct repeat mice), and transcript levels for several radiation-sensitive genes. We did not observe any changes in the levels of the DNA nucleobase damage products hypoxanthine, 8-oxo-7,8-dihydroguanine, 1,N6-ethenoadenine, or 3,N4-ethenocytosine above background levels under low dose-rate conditions. The micronucleus assay revealed no evidence that low dose-rate radiation induced DNA fragmentation, and there was no evidence of double strand break-induced HR. Furthermore, low dose-rate radiation did not induce Cdkn1a, Gadd45a, Mdm2, Atm, or Dbd2. Importantly, the same total dose, when delivered acutely, induced micronuclei and transcriptional responses. These results demonstrate in an in vivo animal model that lowering the dose-rate suppresses the potentially deleterious impact of radiation and calls attention to the need for a deeper understanding of the biological impact of low dose-rate radiation.

A randomised controlled trial evaluating IGF1 titration in contrast to current GH dosing strategies in children born small for gestational age: the North European Small-for-Gestational-Age Study.

PubMed

Jensen, Rikke Beck; Thankamony, Ajay; O'Connell, Susan M; Kirk, Jeremy; Donaldson, Malcolm; Ivarsson, Sten-A; Söder, Olle; Roche, Edna; Hoey, Hilary; Dunger, David B; Juul, Anders

2014-10-01

Short children born small for gestational age (SGA) are treated with a GH dose based on body size, but treatment may lead to high levels of IGF1. The objective was to evaluate IGF1 titration of GH dose in contrast to current dosing strategies. In the North European Small-for-Gestational-Age Study (NESGAS), 92 short pre-pubertal children born SGA were randomised after 1 year of high-dose GH treatment (67 μg/kg per day) to three different regimens: high dose (67 μg/kg per day), low dose (35 μg/kg per day) or IGF1 titration. The average dose during the second year of the randomised trial did not differ between the IGF1 titration group (38 μg/kg per day, s.d. 0.019) and the low-dose group (35 μg/kg per day, s.d. 0.002; P=0.46), but there was a wide variation in the IGF1 titration group (range 10-80 μg/kg per day). The IGF1 titration group had significantly lower height gain (0.17 SDS, s.d. 0.18) during the second year of the randomised trial compared with the high-dose group (0.46 SDS, s.d. 0.25), but not significantly lower than the low-dose group (0.23 SDS, s.d. 0.15; P=0.17). The IGF1 titration group had lower IGF1 levels after 2 years of the trial (mean 1.16, s.d. 1.24) compared with both the low-dose (mean 1.76, s.d. 1.48) and the high-dose (mean 2.97, s.d. 1.63) groups. IGF1 titration of GH dose in SGA children proved less effective than current dosing strategies. IGF1 titration resulted in physiological IGF1 levels with a wide range of GH dose and a poorer growth response, which indicates the role of IGF1 resistance and highlights the heterogeneity of short SGA children. © 2014 European Society of Endocrinology.

Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies.

PubMed

Magnuson, B A; Burdock, G A; Doull, J; Kroes, R M; Marsh, G M; Pariza, M W; Spencer, P S; Waddell, W J; Walker, R; Williams, G M

2007-01-01

Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener.

Tumor susceptibility in two mouse strains with varying doses of carcinogen

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

Bernfeld, P.; Homburger, F.

Administration of 3-methylcholanthrene to C3H/HeJ and C57BL/6J mice at four dose levels over a 1:125 range resulted in a practically equal tumor response in both strains at all dose levels. Using a different method of carcinogen administration, a reversal of tumor susceptibility was found when varying the dose of carcinogen, a phenomenon not observed by us. Our study suggests that Prehn and Lawler's results may have been influenced, at least in part, by the practice of the latter authors to exclude data of substantial numbers of tumor-free mice from the evaluation. (JMT)

Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies.

PubMed

Paranjpe, Madhav G; Belich, Jessica; Vidmar, Tom J; Elbekai, Reem H; McKeon, Marie; Brown, Caren

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

The acute physiological and mood effects of tea and coffee: the role of caffeine level.

PubMed

Quinlan, P T; Lane, J; Moore, K L; Aspen, J; Rycroft, J A; O'Brien, D C

2000-05-01

The objective of this study was to determine the effect of caffeine level in tea and coffee on acute physiological responses and mood. Randomised full crossover design in subjects after overnight caffeine abstention was studied. In study 1 (n = 17) the caffeine level was manipulated naturalistically by preparing tea and coffee at different strengths (1 or 2 cups equivalent). Caffeine levels were 37.5 and 75 mg in tea, 75 and 150 mg in coffee, with water and no-drink controls. In study 2 (n = 15) caffeine level alone was manipulated (water, decaffeinated tea, plus 0, 25, 50, 100, and 200 mg caffeine). Beverage volume and temperature (55 degrees C) were constant. SBP, DBP, heart rate, skin temperature, skin conductance, and mood were monitored over each 3-h study session. In study 1, tea and coffee produced mild autonomic stimulation and an elevation in mood. There were no effects of tea vs. coffee or caffeine dose, despite a fourfold variation in the latter. Increasing beverage strength was associated with greater increases in DBP and energetic arousal. In study 2, caffeinated beverages increased SBP, DBP, and skin conductance and lowered heart rate and skin temperature compared to water. Significant dose-response relationships to caffeine were seen only for SBP, heart rate, and skin temperature. There were significant effects of caffeine on energetic arousal but no consistent dose-response effects. Caffeinated beverages acutely stimulate the autonomic nervous system and increase alertness. Although caffeine can exert dose-dependent effects on a number of acute autonomic responses, caffeine level is not an important factor. Factors besides caffeine may contribute to these acute effects.

ESTIMATION OF EXPOSURE DOSES FOR THE SAFE MANAGEMENT OF NORM WASTE DISPOSAL.

PubMed

Jeong, Jongtae; Ko, Nak Yul; Cho, Dong-Keun; Baik, Min Hoon; Yoon, Ki-Hoon

2018-03-16

Naturally occurring radioactive materials (NORM) wastes with different radiological characteristics are generated in several industries. The appropriate options for NORM waste management including disposal options should be discussed and established based on the act and regulation guidelines. Several studies calculated the exposure dose and mass of NORM waste to be disposed in landfill site by considering the activity concentration level and exposure dose. In 2012, the Korean government promulgated an act on the safety control of NORM around living environments to protect human health and the environment. For the successful implementation of this act, we suggest a reference design for a landfill for the disposal of NORM waste. Based on this reference landfill, we estimate the maximum exposure doses and the relative impact of each pathway to exposure dose for three scenarios: a reference scenario, an ingestion pathway exclusion scenario, and a low leach rate scenario. Also, we estimate the possible quantity of NORM waste disposal into a landfill as a function of the activity concentration level of U series, Th series and 40K and two kinds of exposure dose levels, 1 and 0.3 mSv/y. The results of this study can be used to support the establishment of technical bases of the management strategy for the safe disposal of NORM waste.

A correlation study of eye lens dose and personal dose equivalent for interventional cardiologists.

PubMed

Farah, J; Struelens, L; Dabin, J; Koukorava, C; Donadille, L; Jacob, S; Schnelzer, M; Auvinen, A; Vanhavere, F; Clairand, I

2013-12-01

This paper presents the dosimetry part of the European ELDO project, funded by the DoReMi Network of Excellence, in which a method was developed to estimate cumulative eye lens doses for past practices based on personal dose equivalent values, H(p)(10), measured above the lead apron at several positions at the collar, chest and waist levels. Measurement campaigns on anthropomorphic phantoms were carried out in typical interventional settings considering different tube projections and configurations, beam energies and filtration, operator positions and access routes and using both mono-tube and biplane X-ray systems. Measurements showed that eye lens dose correlates best with H(p)(10) measured on the left side of the phantom at the level of the collar, although this correlation implicates high spreads (41 %). Nonetheless, for retrospective dose assessment, H(p)(10) records are often the only option for eye dose estimates and the typically used chest left whole-body dose measurement remains useful.

Definition of Local Diagnostic Reference Levels in a Radiology Department Using a Dose Tracking Software.

PubMed

Ghetti, C; Ortenzia, O; Palleri, F; Sireus, M

2017-06-01

Dose optimization in radiological examinations is a mandatory issue: in this study local Diagnostic Reference Levels (lDRLs) for Clinical Mammography (MG), Computed Tomography (CT) and Interventional Cardiac Procedures (ICP) performed in our Radiology Department were established. Using a dose tracking software, we have collected Average Glandular Dose (AGD) for two clinical mammographic units; CTDIvol, Size-Specific Dose Estimate (SSDE), Dose Length Product (DLP) and total DLP (DLPtot) for five CT scanners; Fluoro Time, Fluoro Dose Area Product (DAP) and total DAP (DAPtot) for two angiographic systems. Data have been compared with Italian Regulation and with the recent literature. The 75th percentiles of the different dosimetric indices have been calculated. Automated methods of radiation dose data collection allow a fast and detailed analysis of a great amount of data and an easy determination of lDRLs for different radiological procedures. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

PubMed Central

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

[Study on effect of aqueous extracts from aconite on "dose-time-toxicity" relationships in mice hearts].

PubMed

Feng, Qun; Li, Xiao-yu; Luan, Yong-fu; Sun, Sai-nan; Sun, Rong

2015-03-01

To study the effect of single administration of aqueous extracts from aconite on "dose-toxicity" relationship and "time-toxicity" relationship of mice hearts, through changes in electrocardiogram (ECG) and serum biochemical indexes. Mice were grouped according to different drug doses and time points, and orally administered with water extracts from aconite for once to observe the changes of mice ECG before and after the administration, calculate visceral indexes heart, liver and kidney, and detect levels of CK, LDH, BNP and CTn-I in serum. According to the "time-toxicity" relationship study, at 5 min after oral administration with aqueous extracts from aconite in mice, the heart rate of mice began rising, reached peak at 60 min and then slowly reduced; QRS, R amplitude, T duration and amplitude and QT interval declined at 5 min, reduced to the bottom at 60 min and then gradually elevated. The levels of CK, LDH, BNP and CTn-I in serum elevated at 5 min and reached the peak at 60 min, with no significant change in ratios of organs to body at different time points. On the basis of the "dose-toxicity" relationship, with the increase in single dose of aqueous extracts from aconite, the heart rate of mice. QRS, T duration and amplitude and QT interval declined gradually, and levels of CK, LDH, BNP and CTn-I in serum slowly elevated, with a certain dose dependence and no significant change in ratios of organs to body in mice. Single oral administration of different doses of aqueous extracts from aconite could cause different degrees of heart injury at different time points, with a certain dose dependence. Its peak time of toxicity is at 60 min after the administration of aqueous extracts from aconite.

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

PubMed

Pasi, K John; Rangarajan, Savita; Georgiev, Pencho; Mant, Tim; Creagh, Michael D; Lissitchkov, Toshko; Bevan, David; Austin, Steve; Hay, Charles R; Hegemann, Inga; Kazmi, Rashid; Chowdary, Pratima; Gercheva-Kyuchukova, Liana; Mamonov, Vasily; Timofeeva, Margarita; Soh, Chang-Heok; Garg, Pushkal; Vaishnaw, Akshay; Akinc, Akin; Sørensen, Benny; Ragni, Margaret V

2017-08-31

Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Patient dose measurement in common medical X-ray examinations and propose the first local dose reference levels to diagnostic radiology in Iran

NASA Astrophysics Data System (ADS)

Rasuli, Behrouz; Tabari Juybari, Raheleh; Forouzi, Meysam; Ghorbani, Mohammad

2017-09-01

Introduction: The main purpose of this study was to investigate patient dose in pelvic and abdomen x-ray examinations. This work also provided the LDRLs (local diagnostic reference levels) in Khuzestan region, southwest of Iran to help establish the NDRLs (national diagnostic reference levels). Methods: Patient doses were assessed from patient's anatomical data and exposure parameters based on the IAEA indirect dosimetry method. With regard to this method, exposure parameters such as tube output, kVp, mAs, FFD and patient anatomical data were used for calculating ESD (entrance skin dose) of patients. This study was conducted on 250 standard patients (50% men and 50% women) at eight high-patient-load imaging centers. Results: The results indicate that mean ESDs for the both pelvic and abdomen examinations were lower than the IAEA and EC reference levels, 2.3 and 3.7 mGy, respectively. Mean applied kVps were 67 and 70 and mean FFDs were 103 and 109, respectively. Tube loadings obtained in this study for pelvic examination were lower than all the corresponding values in the reviewed literature. Likewise, the average annual patient load across all hospitals were more than 37000 patients, i.e. more than 100 patients a day. Conclusions: The authors recommend that DRLs (diagnostic reference levels) obtained in this region, which are the first available data, can be used as local DRLs for pelvic and abdomen procedures. This work also provides that on-the-job training programs for staffs and close cross collaboration between physicists and physicians should be strongly considered.

Comparison of potential risks of lactic acidosis induction by biguanides in rats.

PubMed

Bando, Kiyoko; Ochiai, Shoko; Kunimatsu, Takeshi; Deguchi, Jiro; Kimura, Juki; Funabashi, Hitoshi; Seki, Takaki

2010-10-01

Lactic acidosis has been considered to be a side effect of some biguanides, after phenformin was withdrawn from the market because of its association with lactic acidosis. The potential of lactic acidosis induced by biguanides at human therapeutic exposure levels, however, has not been examined. Then, we compared the risk of lactic acid at doses providing exposure levels comparable to human therapeutic doses. Metformin and phenformin were orally administered to rats for up to 28 days, and plasma drug concentrations and blood lactic acid levels were examined. Metformin did not elevate lactic acid levels at the dose corresponding to higher systemic drug exposure than human therapeutic level, even for repeated doses. In contrast, phenformin elevated lactic acid levels at the dose corresponding to lower exposure than human therapeutic level, and sustained high levels were observed up to 24h post-dose; furthermore, these changes were enhanced by repeated doses. Direct comparison at each rat equivalent dose clearly indicated that lactic acid levels of phenformin were higher than those of metformin. These non-clinical findings suggest that metformin dose not increase lactic acid levels like phenformin does, and therefore may not increase the risk for lactic acidosis at human therapeutic exposure level. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Inhalation and Ingestion Intakes with Associated Dose Estimates for Level II and Level III Personnel Using Capstone Study Data

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

Effective and safe mannitol administration in patients undergoing supratentorial tumor surgery: A prospective, randomized and double blind study.

PubMed

Akcil, Eren Fatma; Dilmen, Ozlem Korkmaz; Karabulut, Esra Sultan; Koksal, Serdar Selcuk; Altindas, Fatis; Tunali, Yusuf

2017-08-01

Although osmotic diuresis with mannitol is commonly used to provide brain relaxation, there is no consensus regarding its optimal dose and combination with loop diuretics. The aim of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity in patients undergoing supratentorial tumor surgery. This prospective, randomized, double blind, placebo-controlled study included 51 patients (ASA I-III) scheduled for elective supratentorial craniotomy. Different doses and combinations of diuretics were administered after the bone flap removal. The Group 1 received mannitol at 0.5gkg -1 and furosemide at 0.5mgkg -1 , the Group 2 received mannitol at 1gkg -1 and furosemide at 0.5mgkg -1 , and the Group 3 received mannitol at 0.5gkg -1 and placebo. The primary end-point of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and the secondary end-points are to evaluate their effects on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity. This study shows that mannitol alone (0.5gkg -1 ), and the combinations of furosemide (0.5mgkg -1 ) with different doses of mannitol (0.5gkg -1 -1gkg -1 ) provides adequate brain relaxation. However, administration of furosemide with low or high doses of mannitol may cause reduction in the sodium and chloride levels as well as rise in the lactate level. Moreover it may cause high urine output and negative intra-operative fluid balance. Administration of 0.5gkg -1 mannitol provides adequate brain relaxation without causing systemic side effects in patients undergoing supratentorial tumor surgery. This study is registered to clinical trials (Clinical Trials.gov identifier NCT02712476). Copyright © 2017 Elsevier B.V. All rights reserved.

[Effect of Acaí (Euterpe oleracea) on biological expression characteristics of deficiency-heat and deficiency-cold rats].

PubMed

Wang, Lin-Yuan; Zhang, Jian-Jun; Wang, Chun; Zhu, Ying-Li; Wang, Zi-Chen; He, Cheng; Qu, Yan; Wang, Sha

2016-10-01

To study the effects of Acaí on biological expression characteristics in rats with deficiency-heat and deficiency-cold syndromes, SD rats were divided into blank group, deficiency-heat model group, deficiency-heat+Phellodendri Chinensis Cortex group, deficiency-heat+Acaí high dose and low dose groups, deficiency-cold model group, deficiency-cold+Cinnamomi Cortex group, deficiency-cold+Acaí high dose and low dose groups. The rats were treated with intramuscular injection of hydrocortisone (20 mg•kg⁻¹) or dexamethasone sodium phosphate (0.35 mg•kg⁻¹) for 21 days to set up deficiency-heat model and deficiency-cold models. The levels of cAMP, cGMP, T3, T4 and rT3 were detected by radioimmunoassay. The levels of TP, UA, TC, TG and ALB were detected by colorimetry. The level of cAMP, cAMP/cGMP in serum were reduced in Acaí high dose group (P<0.05, P<0.001). The levels of T3, T4 and rT3 were significantly reduced in the Acaí high dose group (P<0.01, P<0.001, P<0.05). The levels of TP, UA, TC, TG and ALB were significantly reduced in the Acaí high dose group (P<0.001, P<0.05, P<0.05, P<0.05, P<0.01). However, Acaí had no obvious effects on deficiency-cold models. Acaí showed the same effect with Phellodendri Chinensis Cortex in adjusting the levels of deficiency-heat rats; but unlike Cinnamomi Cortex, Acaí showed no obvious effects in adjusting the levels of deficiency-cold rats. Copyright© by the Chinese Pharmaceutical Association.

Simultaneous integrated boost to intraprostatic lesions using different energy levels of intensity-modulated radiotherapy and volumetric-arc therapy

PubMed Central

Sonmez, S; Erbay, G; Guler, O C; Arslan, G

2014-01-01

Objective: This study compared the dosimetry of volumetric-arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) with a dynamic multileaf collimator using the Monte Carlo algorithm in the treatment of prostate cancer with and without simultaneous integrated boost (SIB) at different energy levels. Methods: The data of 15 biopsy-proven prostate cancer patients were evaluated. The prescribed dose was 78 Gy to the planning target volume (PTV78) including the prostate and seminal vesicles and 86 Gy (PTV86) in 39 fractions to the intraprostatic lesion, which was delineated by MRI or MR-spectroscopy. Results: PTV dose homogeneity was better for IMRT than VMAT at all energy levels for both PTV78 and PTV86. Lower rectum doses (V30–V50) were significantly higher with SIB compared with PTV78 plans in both IMRT and VMAT plans at all energy levels. The bladder doses at high dose level (V60–V80) were significantly higher in IMRT plans with SIB at all energy levels compared with PTV78 plans, but no significant difference was observed in VMAT plans. VMAT plans resulted in a significant decrease in the mean monitor units (MUs) for 6, 10, and 15 MV energy levels both in plans with and those without SIB. Conclusion: Dose escalation to intraprostatic lesions with 86 Gy is safe without causing serious increase in organs at risk (OARs) doses. VMAT is advantageous in sparing OARs and requiring less MU than IMRT. Advances in knowledge: VMAT with SIB to intraprostatic lesion is a feasible method in treating prostate cancer. Additionally, no dosimetric advantage of higher energy is observed. PMID:24319009

Effects of acetaldehyde and L-carnitine on morphology and enzyme activity of myocardial mitochondria in rats.

PubMed

Jin, Yuan-Zhe; Wang, Guo-Feng; Wang, Qi; Zhang, Xue-Ying; Yan, Bin; Hu, Wei-Na

2014-12-01

This study aimed to investigate the effects of acetaldehyde (AA) and L-carnitine (LC) on morphology and enzyme activity of myocardial mitochondria in rats. Sixty-five Wistar rats were randomly divided into 4 groups: the control group (n = 20), the AA low-dose group (n = 15), the AA high-dose group (n = 15) and the AA + LC group (n = 15). Different doses (110 mg/kg and 220 mg/kg) AA was injected intraperitoneally once a day for 4 weeks. After 4 weeks administration, transmission electron microscope (TEM) observation of morphology of rat myocardial mitochondria was performed. Serum levels of succinate dehydrogenase (SDH), superoxide dismutase (SOD), malondialdehyde (MDA) and cardiac troponin I (cTnI) were detected to evaluate mitochondrial enzymes activities. Light micrograph of rat myocardiocytes in the control group showing normal architecture of myocytes. The numerical density and number of mitochondria in both low-dose and high-dose AA groups were lower than that of the control group. After administration of LC, the rats in the AA + LC group showed an obvious increase in the numerical density and number of mitochondria. TEM showed that both low-dose and high-dose AA could induce myocardial mitochondrial damage in rats in a dose-dependent manner, such as mitochondrial swelling, disruptions of crest and membrane, mitochondrial deficiency. The degree of mitochondrial damage of the AA + LC group was significantly decreased after administration of LC. Our results showed that serum levels of SDH and SOD in the AA + LC and control groups were also higher than those of the low-dose and high-dose AA groups; while the MDA level in the AA + LC and control groups were lower than that of the low-dose and high-dose AA groups. The low-dose AA, high-dose AA and AA + LC groups exhibited a higher level of serum cTnI than that of the control group. However, there was no significant difference in serum cTnI level among the low-dose AA, high-dose AA and AA + LC groups. Our findings indicate that AA may lead to myocardial mitochondrial damage and the induction of enzyme activity in rats, while administration of LC could alleviate AA-related damage of rat myocardial mitochondria.

Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial.

PubMed

Isanaka, Sheila; Mugusi, Ferdinand; Hawkins, Claudia; Spiegelman, Donna; Okuma, James; Aboud, Said; Guerino, Chalamilla; Fawzi, Wafaie W

2012-10-17

Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. INTERVENTION The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. The composite of HIV disease progression or death from any cause. The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96-1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11-1.87) vs standard-dose supplementation. CONCLUSION In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. Clinicaltrials.gov Identifier: NCT00383669.

The c-Abl signaling network in the radioadaptive response

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

Chi-Min, Yuan

2014-01-28

The radioadaptive response, or radiation hormesis, i.e. a low dose of radiation can protect cells and organisms from the effects of a subsequent higher dose, is a widely recognized phenomenon. Mechanisms underlying such radiation hormesis, however, remain largely unclear. Preliminary studies indicate an important role of c-Abl signaling in mediating the radioadaptive response. We propose to investigate how c-Abl regulates the crosstalk between p53 and NFκB in response to low doses irradiation. We found in our recent study that low dose IR induces a reciprocal p53 suppression and NFκB activation, which induces HIF-a and subsequently a metabolic reprogramming resulting inmore » a transition from oxidative phosphorylation to glycolysis. Of importance is that this glycolytic switch is essential for the radioadaptive response. This low-dose radiationinduced HIF1α activation was in sharp contrast with the high-dose IR-induced p53 activation and HIF1α inhibition. HIF1α and p53 seem to play distinct roles in mediating the radiation dose-dependent metabolic response. The induction of HIF1α-mediated glycolysis is restricted to a low dose range of radiation, which may have important implications in assessing the level of radiation exposure and its potential health risk. Our results support a dose-dependent metabolic response to IR. When IR doses are below the threshold of causing detectable DNA damage (<0.2Gy) and thus little p53 activation, HIF1α is induced resulting in induction of glycolysis and increased radiation resistance. When the radiation dose reaches levels eliciting DNA damage, p53 is activated and diminishes the activity of HIF1α and glycolysis, leading to the induction of cell death. Our work challenges the LNT model of radiation exposure risk and provides a metabolic mechanism of radioadaptive response. The study supports a need for determining the p53 and HIF1α activity as a potential reliable biological readout of radiation exposure in humans. The exquisite sensitivity of cellular metabolism to low doses of radiation could also serve as a valuable biomarker for estimating the health effects of low-level radiation exposure.« less

Nonclinical Safety and Toxicokinetics of MnTnBuOE-2-PyP5+ (BMX-001).

PubMed

Gad, Shayne Cox; Sullivan, Dexter W; Spasojevic, Ivan; Mujer, Cesar V; Spainhour, Charles B; Crapo, James D

2016-07-01

BMX-001, a manganese porphyrin that has anti-inflammatory, antioxidant, and antitumor properties, is being developed as a potential therapeutic for high-grade glioma (HGG) and head and neck (H&N) cancer. An IND has been opened for BMX-001 in the treatment of HGG (NCT02655601) and another is in preparation for H&N. The safety of BMX-001 has been evaluated in a battery of nonclinical Good Laboratory Practice (GLP)-compliant studies. Systemic toxicity has been evaluated using the intended cGMP product administered subcutaneously for periods of up to 5 weeks in both the mouse and the monkey and included toxicokinetic evaluations to characterize systemic exposure and tissue distribution and clearance of BMX-001. In additional GLP studies, BMX-001 was not irritating to the skin or eye and caused no changes in cardiac rate or rhythm or blood pressure. Mixed results for genotoxicity were seen with the weight of evidence indicating that BMX-001 poses no genotoxic risk in humans. In systemic mouse and monkey studies, loading/maintenance dose no observed adverse effect levels were 12/2 mg/kg/dose and 6/2 mg/kg/dose, respectively, with maintenance doses administered every 3 days after the initial loading dose. Systemic data were used to determine a Food and Drug Administration-approved safe starting dose for the initial clinical study in patients with HGG. BMX-001 was detected in analyzed tissues, including the brain, persisting well past the short plasma clearance period. The highest levels of BMX-001 were seen in the liver and kidneys, with amounts in these tissues returning to close to undetectable levels after a 2-week cessation of dosing. © The Author(s) 2016.

Black pepper constituent piperine: genotoxicity studies in vitro and in vivo.

PubMed

Thiel, Anette; Buskens, Carin; Woehrle, Tina; Etheve, Stéphane; Schoenmakers, Ankie; Fehr, Markus; Beilstein, Paul

2014-04-01

Piperine is responsible for the hot taste of black pepper. Publications on genotoxicity of piperine are reported: negative Ames Tests and one in vitro micronucleus test (MNT). In vivo tests were mainly negative. In the majority of the data the administered dose levels did not follow the dose selection requirements of regulatory guidelines of having dose levels up to the maximum tolerated dose (MTD). The only oral high dose studies were a positive in vivo MNT in mice in contrast to a negative in vivo chromosome aberration test in rats. Thus, conflicting results in genotoxicity testing are published. To investigate this further, we administered piperine to mice up to the MTD and determined micronuclei-frequency. Piperine reduces core body temperature and interferes with blood cells both being known to result in irrelevant positive in vivo MNTs. Therefore we added mechanistic endpoints: core body temperature, haematology, erythropoietin level, and organ weights. Additionally an in vitro MNT in Chinese hamster ovary cells was performed. Piperine was negative in the in vitro MNT. It caused significant reduction of core body temperature, decrease of white blood cells and spleen weights but no increase in the micronucleus-frequency. Thus, in our studies piperine was not genotoxic. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of jojoba oil as a low-energy fat. 1. A 4-week feeding study in rats.

PubMed

Verschuren, P M

1989-01-01

The nutritional properties of jojoba oil (JO) were examined in a 4-wk feeding study of rats fed a diet with JO at dose levels of 2.2, 4.5 and 9%, supplemented with a conventional fat up to 18%. General health, survival and food intake were not adversely affected. Body-weight gains showed a dose-related decline, which amounted to 20% of the body weight in the high-dose group of both sexes. Clinical chemistry revealed significantly increased levels of various enzymes that were indicative of cell damage. Haematology showed a dose-related increase in white blood cells. On necropsy an apparent distension of the small intestine was found. Histopathological evaluation revealed marked intestinal changes characterized by massive vacuolization and lipid deposition in the enterocytes, accompanied by distension of the villi and an increased cell turnover of small intestinal cells. Faeces production and faeces lipid content were increased with increasing JO levels. The recovery of JO in the faeces also increased in a dose-related manner and was found to be correlated with the intestinal histopathological changes. The significant adverse clinical and histopathological effects observed in this study imply that JO cannot be considered as a promising alternative dietary fat with a low digestibility.

Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone.

PubMed

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.

Six-month treatment with low-dose dexamethasone further reduces androgen levels in PCOS women treated with diet and lifestyle advice, and metformin.

PubMed

Vanky, E; Salvesen, K A; Carlsen, S M

2004-03-01

The purpose of this study was to investigate the effect of low-dose dexamethasone on androgen levels in women with polycystic ovary syndrome (PCOS) treated with diet and lifestyle counselling, and metformin. A prospective, randomized, double blind, placebo-controlled study was carried out. Thirty-eight women with PCOS were randomized to either dexamethasone 0.25 mg daily or placebo for 26 weeks. All received diet and lifestyle counselling at inclusion and metformin 850 mg three times daily during the whole study. Main outcome measures were: androgen levels, body mass index (BMI), insulin c-peptide, fasting glucose and serum lipids. Two-tailed t-tests and Pearson's statistics were used. Compared with the placebo, dexamethasone reduced testosterone by 27%, androstenedione by 21%, dehydroepiandrosterone sulphate by 46% and free testosterone index by 50% in women with PCOS treated with diet and lifestyle advice, and metformin. BMI, fasting glucose, insulin c-peptide and serum lipid levels were unaffected. Six-month, low-dose dexamethasone treatment further reduces androgen levels in metformin-treated PCOS women.

Improving spot-scanning proton therapy patient specific quality assurance with HPlusQA, a second-check dose calculation engine.

PubMed

Mackin, Dennis; Li, Yupeng; Taylor, Michael B; Kerr, Matthew; Holmes, Charles; Sahoo, Narayan; Poenisch, Falk; Li, Heng; Lii, Jim; Amos, Richard; Wu, Richard; Suzuki, Kazumichi; Gillin, Michael T; Zhu, X Ronald; Zhang, Xiaodong

2013-12-01

The purpose of this study was to validate the use of HPlusQA, spot-scanning proton therapy (SSPT) dose calculation software developed at The University of Texas MD Anderson Cancer Center, as second-check dose calculation software for patient-specific quality assurance (PSQA). The authors also showed how HPlusQA can be used within the current PSQA framework. The authors compared the dose calculations of HPlusQA and the Eclipse treatment planning system with 106 planar dose measurements made as part of PSQA. To determine the relative performance and the degree of correlation between HPlusQA and Eclipse, the authors compared calculated with measured point doses. Then, to determine how well HPlusQA can predict when the comparisons between Eclipse calculations and the measured dose will exceed tolerance levels, the authors compared gamma index scores for HPlusQA versus Eclipse with those of measured doses versus Eclipse. The authors introduce the αβγ transformation as a way to more easily compare gamma scores. The authors compared measured and calculated dose planes using the relative depth, z∕R × 100%, where z is the depth of the measurement and R is the proton beam range. For relative depths than less than 80%, both Eclipse and HPlusQA calculations were within 2 cGy of dose measurements on average. When the relative depth was greater than 80%, the agreement between the calculations and measurements fell to 4 cGy. For relative depths less than 10%, the Eclipse and HPlusQA dose discrepancies showed a negative correlation, -0.21. Otherwise, the correlation between the dose discrepancies was positive and as large as 0.6. For the dose planes in this study, HPlusQA correctly predicted when Eclipse had and had not calculated the dose to within tolerance 92% and 79% of the time, respectively. In 4 of 106 cases, HPlusQA failed to predict when the comparison between measurement and Eclipse's calculation had exceeded the tolerance levels of 3% for dose and 3 mm for distance-to-agreement. The authors found HPlusQA to be reasonably effective (79% ± 10%) in determining when the comparison between measured dose planes and the dose planes calculated by the Eclipse treatment planning system had exceeded the acceptable tolerance levels. When used as described in this study, HPlusQA can reduce the need for patient specific quality assurance measurements by 64%. The authors believe that the use of HPlusQA as a dose calculation second check can increase the efficiency and effectiveness of the QA process.

Real-world utilization of darbepoetin alfa in cancer chemotherapy patients.

PubMed

Pan, Xiaoyun Lucy; Nordstrom, Beth L; MacLachlan, Sharon; Lin, Junji; Xu, Hairong; Sharma, Anjali; Chandler, David; Li, Xiaoyan Shawn

2017-01-01

Objectives To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. Study design This is a retrospective cohort study using a proprietary outpatient oncology database. Methods Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. Results Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. Conclusion The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.

Study of runaway electrons using dosimetry of hard x-ray radiations in Damavand tokamak

NASA Astrophysics Data System (ADS)

Rasouli, C.; Pourshahab, B.; Hosseini Pooya, S. M.; Orouji, T.; Rasouli, H.

2014-05-01

In this work several studies have been conducted on hard x-ray emissions of Damavand tokamak based on radiation dosimetry using the Thermoluminescence method. The goal was to understand interactions of runaway electrons with plasma particles, vessel wall, and plasma facing components. Total of 354 GR-200 (LiF:Mg,Cu,P) thermoluminescence dosimeter (TLD) crystals have been placed on 118 points - three TLDs per point - to map hard x-ray radiation doses on the exterior of the vacuum vessel. Results show two distinctive levels of x-ray radiations doses on the exterior of the vessel. The low-dose area on which measured dose is about 0.5 mSv/shot. In the low-dose area there is no particular component inside the vessel. On the contrary, on high-dose area of the vessel, x-ray radiations dose exceeds 30 mSv/shot. The high-dose area coincides with the position of limiters, magnetic probe ducts, and vacuum vessel intersections. Among the high-dose areas, the highest level of dose is measured in the position of the limiter, which could be due to its direct contact with the plasma column and with runaway electrons. Direct collisions of runaway electrons with the vessel wall and plasma facing components make a major contribution for production of hard x-ray photons in Damavand tokamak.

Study of runaway electrons using dosimetry of hard x-ray radiations in Damavand tokamak.

PubMed

Rasouli, C; Pourshahab, B; Hosseini Pooya, S M; Orouji, T; Rasouli, H

2014-05-01

In this work several studies have been conducted on hard x-ray emissions of Damavand tokamak based on radiation dosimetry using the Thermoluminescence method. The goal was to understand interactions of runaway electrons with plasma particles, vessel wall, and plasma facing components. Total of 354 GR-200 (LiF:Mg,Cu,P) thermoluminescence dosimeter (TLD) crystals have been placed on 118 points--three TLDs per point--to map hard x-ray radiation doses on the exterior of the vacuum vessel. Results show two distinctive levels of x-ray radiations doses on the exterior of the vessel. The low-dose area on which measured dose is about 0.5 mSv/shot. In the low-dose area there is no particular component inside the vessel. On the contrary, on high-dose area of the vessel, x-ray radiations dose exceeds 30 mSv/shot. The high-dose area coincides with the position of limiters, magnetic probe ducts, and vacuum vessel intersections. Among the high-dose areas, the highest level of dose is measured in the position of the limiter, which could be due to its direct contact with the plasma column and with runaway electrons. Direct collisions of runaway electrons with the vessel wall and plasma facing components make a major contribution for production of hard x-ray photons in Damavand tokamak.

The effectiveness of low-dose and high-dose tranexamic acid in posterior lumbar interbody fusion: a double-blinded, placebo-controlled randomized study.

PubMed

Kim, Ki-Tack; Kim, Cheung-Kue; Kim, Yong-Chan; Juh, Hyung-Suk; Kim, Hyo-Jong; Kim, Hyeon-Soo; Hong, Se Jung; Hey, Hwee Weng Dennis

2017-11-01

Tranexamic acid is a proven drug used for reduction of intraoperative blood loss in spinal surgery. However, optimal dosing considering risk/benefits is not well established owing to the heterogeneity in patient selection and surgical procedures of previous studies. This study aimed to evaluate the effectiveness and safety of various tranexamic acid regimens in reducing perioperative blood loss in single-level posterior lumbar interbody fusion (PLIF). Patients were randomly grouped into three different interventions: low-dose tranexamic acid (LD), high-dose tranexamic acid (HD), and placebo-controlled (PC) groups. The HD and LD groups received 10 and 5 mg/kg of bolus loading dose and 2 and 1 mg/kg of continuous infusion until 5 h after surgery, respectively. Data on patient demographics and preoperative and 24-h postoperative laboratory values were collected. Outcome parameters include intraoperative blood loss, 24-h postoperative blood loss, and blood loss during removal of the last drain. Seventy-two patients (mean age 63.3 ± 7.6 years) showed similar baseline characteristics. Intraoperatively, blood loss was reduced by the administration of tranexamic acid (P = 0.04), contributed predominantly by a difference between the LD and HD groups (123 mL; P < 0.01). The 24-h postoperative blood loss was reduced (P < 0.01), contributed predominantly by a difference between the PC and LD groups (144 mL; P = 0.02). During the removal of the last drain, statistical difference was found between the PC and HD groups (125 mL; P = 0.00). No complications or side effects from tranexamic acid use were noted. Tranexamic acid administration for single-level PLIF was effective and safe in reducing perioperative blood loss in a dose-dependent manner. An HD regimen comprising 10 mg/kg of bolus loading dose and 2 mg/kg/h of continuous infusion is recommended. Level 1 study according to Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence.

Demand- and supply-side determinants of diphtheria-pertussis-tetanus nonvaccination and dropout in rural India.

PubMed

Ghosh, Arpita; Laxminarayan, Ramanan

2017-02-15

Although 93% of 12- to 23-month-old children in India receive at least one vaccine, typically Bacillus Calmette-Guérin, only 75% complete the recommended three doses of diphtheria-pertussis-tetanus (DPT, also referred to as DTP) vaccine. Determinants can be different for nonvaccination and dropout but have not been examined in earlier studies. We use the three-dose DPT series as a proxy for the full sequence of recommended childhood vaccines and examine the determinants of DPT nonvaccination and dropout between doses 1 and 3. We analyzed data on 75,728 6- to 23-month-old children in villages across India to study demand- and supply-side factors determining nonvaccination with DPT and dropout between DPT doses 1 and 3, using a multilevel approach. Data come from the District Level Household and Facility Survey 3 (2007-08). Individual- and household-level factors were associated with both DPT nonvaccination and dropout between doses 1 and 3. Children whose mothers had no schooling were 2.3 times more likely not to receive any DPT vaccination and 1.5 times more likely to drop out between DPT doses 1 and 3, compared with children whose mothers had 10 or more years of schooling. Although supply-side factors related to availability of public health facilities and immunization-related health workers in villages were not correlated with dropout between DPT doses 1 and 3, children in districts where 46% or more villages had a healthcare subcentre were 1.5 times more likely to receive at least one dose of DPT vaccine compared with children in districts where 30% or fewer villages had subcentres. Nonvaccination with DPT in India is influenced by village- and district-level contextual factors over and above individuals' background characteristics. Dropout between DPT doses 1 and 3 is associated more strongly with demand-side factors than with village- and district-level supply-side factors. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Phase I Study of Conformal Radiotherapy and Concurrent Full-Dose Gemcitabine With Erlotinib for Unresected Pancreatic Cancer

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

Robertson, John M., E-mail: jrobertson@beaumont.edu; Margolis, Jeffrey; Jury, Robert P.

2012-02-01

Purpose: To determine the recommended dose of radiotherapy when combined with full-dose gemcitabine and erlotinib for unresected pancreas cancer. Methods and Materials: Patients with unresected pancreatic cancer (Zubrod performance status 0-2) were eligible for the present study. Gemcitabine was given weekly for 7 weeks (1,000 mg/m{sup 2}) with erlotinib daily for 8 weeks (100 mg). A final toxicity assessment was performed in Week 9. Radiotherapy (starting at 30 Gy in 2-Gy fractions, 5 d/wk) was given to the gross tumor plus a 1-cm margin starting with the first dose of gemcitabine. A standard 3 plus 3 dose escalation (an additionalmore » 4 Gy within 2 days for each dose level) was used, except for the starting dose level, which was scheduled to contain 6 patients. In general, Grade 3 or greater gastrointestinal toxicity was considered a dose-limiting toxicity, except for Grade 3 anorexia or Grade 3 fatigue alone. Results: A total of 20 patients were treated (10 men and 10 women). Nausea, vomiting, and infection were significantly associated with the radiation dose (p = .01, p = .03, and p = .03, respectively). Of the 20 patients, 5 did not complete treatment and were not evaluable for dose-escalation purposes (3 who developed progressive disease during treatment and 2 who electively discontinued it). Dose-limiting toxicity occurred in none of 6 patients at 30 Gy, 2 of 6 at 34 Gy, and 1 of 3 patients at 38 Gy. Conclusion: The results of the present study have indicated that the recommended Phase II dose is 30 Gy in 15 fractions.« less

Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes.

PubMed

Berry, Susan A; Lichter-Konecki, Uta; Diaz, George A; McCandless, Shawn E; Rhead, William; Smith, Wendy; Lemons, Cynthia; Nagamani, Sandesh C S; Coakley, Dion F; Mokhtarani, Masoud; Scharschmidt, Bruce F; Lee, Brendan

2014-05-01

To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs). UCD patients (n=26) ages 2months through 17years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth. Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC0-24: 627 [302] vs. 872 [516] μmol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p=0.02). Mean ammonia levels remained within the normal range during 12months of GPB dosing and, when compared with the 12months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] μmol/L; p=0.114) and mean glutamine and branched chain amino acid levels, as well as other essential amino acids, remained within the normal range during 12months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12months of GPB treatment. Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12month period preceding enrollment. Copyright © 2014 Elsevier Inc. All rights reserved.

Extended-interval Dosing of Gentamicin in Premature Neonates Born at <32 Weeks' Gestation and >7 Days of age.

PubMed

Sundaram, Arun; Alshaikh, Belal; Dersch-Mills, Deonne; Dobry, Jenna; Akierman, Albert R; Yusuf, Kamran

2017-06-01

Extended-interval dosing (EID) regimens of gentamicin have been validated for treating confirmed or suspected early- and late-onset sepsis in preterm infants in the first week of life. Despite the marked changes in volume of distribution and renal clearance in preterm infants after the first few days of life, few studies have validated EID regimens of gentamicin in this population. The objective of the study was to evaluate an EID regimen of gentamicin in infants born at <32 weeks' gestational age and aged >7 days. This observational study of an EID regimen was conducted in 39 infants. Dosing interval was based on the serum drug concentration at 22 hours after the administration of the first dose of 5 mg/kg. Gentamicin peak (5-12 µg/mL) and trough (<2 µg/mL) levels were compared to those in a historical control group of 39 infants who received traditional-interval dosing (TID) of 2.5 mg/kg of gentamicin with dosing intervals of 8, 12, or 24 hours. There were no differences in birthweight, gestational age at birth, postmenstrual age, weight at the start of gentamicin administration, postnatal age, small for gestational age status, antenatal corticosteroid use, or postnatal indomethacin exposure between the 2 groups. In the EID group, dosing intervals were 24 hours in 30 infants, 36 hours in 6 infants, and 48 hours in 3 infants. Compared with the TID group (n = 39), the EID group had a significantly higher peak level (median, 9.0 vs 4.7 µg/mL) and a significantly lower trough level (median, 0.7 vs 1.1 µg/mL) (both, P < 0.001). On regression analysis, the postmenstrual age was correlated significantly with trough levels in the EID group. There was no adverse effect on renal function in either group. On follow-up, 1 infant in the EID group and 2 infants in the TID group had evidence of sensorineural hearing loss. In infants born at <32 weeks' gestation and >7 days of age, an EID gentamicin regimen, with a dosing interval based on a single concentration measurement at 22 hours after the administration of the first dose, achieved therapeutic peak and trough levels and performed significantly better than did a TID regimen in reaching target peak and trough levels. Larger-scale trials are needed for assessing the clinical efficacy (treatment failure/success) of these regimens. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Low-dose intradermal and intramuscular vaccination against hepatitis B.

PubMed

Bryan, J P; Sjogren, M H; Perine, P L; Legters, L J

1992-03-01

Hepatitis B and its sequelae are global problems preventable by immunization. Expense limits the use of hepatitis B vaccines, but low-dose intradermal immunization has been evaluated as a cost-saving strategy in numerous studies. With few exceptions, low-dose intradermal plasma-derived vaccines have elicited protective levels of antibody in 82%-100% of young healthy adults--a proportion similar to that noted with full-dose regimens; peak levels of antibody to hepatitis B surface antigen (HBsAg) are lower with reduced doses, however. Although children respond well to low-dose intradermal immunization, this procedure is technically difficult in neonates and should not be used for those born to HBsAg-positive mothers. For persons at high risk, antibody to HBsAg must be assessed after immunization to determine the need for a booster dose. A fourth dose 1-2 years after the initial series substantially increases antibody concentrations. In low intradermal doses, recombinant vaccine elicits lower rates of seroconversion than plasma-derived vaccine. However, low intramuscular doses of recombinant vaccine give favorable results. In short, low-dose intradermal or intramuscular immunization offers protection against hepatitis B at significant savings and may be useful for mass immunization of populations at high risk.

Hierarchical dose response of E. coli O157:H7 from human outbreaks incorporating heterogeneity in exposure.

PubMed

Teunis, P F M; Ogden, I D; Strachan, N J C

2008-06-01

The infectivity of pathogenic microorganisms is a key factor in the transmission of an infectious disease in a susceptible population. Microbial infectivity is generally estimated from dose-response studies in human volunteers. This can only be done with mildly pathogenic organisms. Here a hierarchical Beta-Poisson dose-response model is developed utilizing data from human outbreaks. On the lowest level each outbreak is modelled separately and these are then combined at a second level to produce a group dose-response relation. The distribution of foodborne pathogens often shows strong heterogeneity and this is incorporated by introducing an additional parameter to the dose-response model, accounting for the degree of overdispersion relative to Poisson distribution. It was found that heterogeneity considerably influences the shape of the dose-response relationship and increases uncertainty in predicted risk. This uncertainty is greater than previously reported surrogate and outbreak models using a single level of analysis. Monte Carlo parameter samples (alpha, beta of the Beta-Poisson model) can be readily incorporated in risk assessment models built using tools such as S-plus and @ Risk.

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

PubMed

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

2007-06-01

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

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

PubMed Central

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

2007-01-01

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

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

NASA Astrophysics Data System (ADS)

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

2003-12-01

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

Ampicillin levels in sputum, serum, and saliva

PubMed Central

Stewart, Sheila M.; Fisher, Mary; Young, Joy E.; Lutz, W.

1970-01-01

The ampicillin levels in sputum, serum, and saliva from 40 patients receiving a dose of 250 mg., 26 patients receiving a dose of 500 mg., and 11 patients receiving a dose of 1 g. were estimated. The ampicillin was given orally four times daily. The 1-2 hour and 2-3 hour sputum levels were similar in individual patients. There was no difference in the range or mean sputum or saliva levels between specimens from patients receiving 250 mg. and 500 mg., but the levels were significantly higher after the 1 g. dose. The mean serum level showed a small increase after 500 mg. ampicillin as compared with the 250 mg. dose and a big increase after the 1 g. dose: only the latter difference was significant. The sputum levels were approximately 30 to 40 times lower than the corresponding serum levels. There was considerable scatter in the sputum level for any level of ampicillin in the serum: in only two of the 1-2 hour sputum specimens was there no detectable ampicillin. There was no correlation between the sputum levels and either the body weight or the dose in milligrams per kilogram. There was no evidence that corticosteroids or diuretics affected the sputum level. It was not possible to demonstrate any relationship between the purulence of the sputum and the level of ampicillin after doses of 250 mg. or 500 mg., but higher levels were found in the more purulent specimens after 1 g. doses. PMID:4318047

Immunogenicity study to investigate the interchangeability among three different types of polio vaccine: A cohort study in Japan.

PubMed

Ohfuji, Satoko; Ito, Kazuya; Ishibashi, Motoki; Shindo, Shizuo; Takasaki, Yoshio; Yokoyama, Takashi; Yokoyama, Takato; Yamashita, Yuji; Shibao, Keigo; Nakano, Takashi; Tsuru, Tomomi; Irie, Shin; Hirota, Yoshio

2017-06-01

In Japan, the routine immunization program with oral polio vaccine (OPV) has been suspended since September 2012, when a program with 4 doses of inactivated monovalent polio vaccine (IPV) or quadrivalent vaccine against diphtheria, pertussis, and tetanus with IPV (DTaP-IPV) was introduced. The aim of this study was to examine the interchangeability among these 3 types of polio vaccines.We conducted a prospective cohort study at 5 pediatric clinics in Japan. A total of 153 infants were assigned to 1 of the 4 groups by considering the vaccination history of OPV and trivalent vaccine against DTaP. Eleven infants with a history of OPV received 3 doses of DTaP-IPV; 49 infants with a history of OPV and DTaP received 3 doses of IPV; 50 polio vaccine-naïve infants received 2 doses of IPV followed by 2 doses of DTaP-IPV; and 43 polio vaccine-naive infants received 2 doses of DTaP-IPV followed by IPV. The immunogenicity after polio vaccination was evaluated among these 4 groups.After 2 doses of polio vaccination, more than 80% of the infants exhibited a neutralization antibody titer ≥1:8 for all Sabin strains and wild strains in all groups. After the third dose, the seroprotection proportion (i.e., a neutralization antibody titer ≥1:8) reached about 100%. After the fourth dose, a neutralization antibody titer exceeded the required protective levels (i.e., a neutralization antibody titer ≥1:8) considerably in all groups.Four doses of polio vaccines induced a sufficient level of immunity in Japanese infants, irrespective of vaccine combinations or order.

Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.

PubMed

Dósa, Edit; Heltai, Krisztina; Radovits, Tamás; Molnár, Gabriella; Kapocsi, Judit; Merkely, Béla; Fu, Rongwei; Doolittle, Nancy D; Tóth, Gerda B; Urdang, Zachary; Neuwelt, Edward A

2017-10-03

Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy. Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200 mg/kg NAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15 min post NAC. Twenty-eight subjects (15 men; mean age 72.2 ± 6.8 years) received NAC IV (N = 13) or IA (N = 15). The first participant to experience grade 4 toxicity was at the 600 mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450 mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450 mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p < 0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached the 2-3 mM concentration which seemed to be nephroprotective in previous preclinical studies. In adults with kidney impairment, NAC can be safely given both IV and IA at a dose of 450 mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: https://eudract.ema.europa.eu . Unique identifier: 2011-000887-92.

131I-tositumomab myeloablative radioimmunotherapy for non-Hodgkin’s lymphoma: radiation dose to the testes

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

Hattori, Naoya; Gopal, Ajay K.; Shields, Andrew T.

Purpose: To investigate radiation doses to the testes delivered by a radiolabeled anti-CD20 antibody and its effects on male sex hormone levels. Materials and methods: Testicular uptake and retention of 131I-tositumomab were measured, and testicular absorbed doses were calculated for 67 male patients (54+/-11 years of age) with non-Hodgkin's lymphoma who had undergone myeloablative radioimmunotherapy (RIT) using 131I-tositumomab. Time-activity curves for the major organs, testes, and whole body were generated from planar imaging studies. In a subset of patients, male sex hormones were measured before and 1 year after the therapy. Results: The absorbed dose to the testes showed considerablemore » variability (range=4.4-70.2 Gy). Pretherapy levels of total testosterone were below the lower limit of the reference range, and post-therapy evaluation demonstrated further reduction [4.6+/-1.8 nmol/l (pre-RIT) vs. 3.8+/-2.9 nmol/l (post-RIT), P<0.05]. Patients receiving higher radiation doses to the testes (>=25 Gy) showed a greater reduction [4.7+/-1.6 nmol/l (pre-RIT) vs. 3.3+/-2.7 nmol/l (post-RIT), P<0.05] compared with patients receiving lower doses (<25 Gy), who showed no significant change in total testosterone levels. Conclusion: The testicular radiation absorbed dose varied highly among individual patients. Finally, patients receiving higher doses to the testes were more likely to show post-RIT suppression of testosterone levels.« less

Antidiarrheal Activity of Dissotis multiflora (Sm) Triana (Melastomataceae) Leaf Extract in Wistar Rats and Subacute Toxicity Evaluation

PubMed Central

Ndoye Foe, Chantal Florentine; Njankouo Ndam, Youchahou; Njayou, Frédéric Nico; Fonkoua, Marie Christine; Etoa, François-Xavier

2017-01-01

The present work was undertaken to evaluate antidiarrheal activity of ethanolic leaf extract of Dissotis multiflora (Sm) Triana (D. multiflora) on Shigella flexneri-induced diarrhea in Wistar rats and its subacute toxicity. Diarrhea was induced by oral administration of 1.2 × 109 cells/mL S. flexneri to rats. Antidiarrheal activity was investigated in rats with the doses of 111.42 mg/kg, 222.84 mg/kg, and 445.68 mg/kg. The level of biochemical parameters was assessed and organs histology examined by 14 days' subacute toxicity. S. flexneri stool load decreased significantly in dose-dependent manner. The level of ALT increased (p < 0.05) in male rats treated with the dose of 445.68 mg/kg while creatinine level increased in rats treated with both doses. In female rats, a significant decrease (p < 0.05) of the level of AST and creatinine was noted in rats treated with the dose of 222.84 mg/kg of D. multiflora. Histological exams of kidney and liver of treated rats showed architectural modifications at the dose of 445.68 mg/kg. This finding suggests that D. multiflora leaf extract is efficient against diarrhea caused by S. flexneri but the treatment with doses lower than 222.84 mg/kg is recommended while further study is required to define the exact efficient nontoxic dose. PMID:29234391

Phosphoprotein profiles of candidate markers for early cellular responses to low-dose γ-radiation in normal human fibroblast cells

PubMed Central

Yim, Ji-Hye; Yun, Jung Mi; Kim, Ji Young; Lee, In Kyung; Nam, Seon Young

2017-01-01

Abstract Ionizing radiation causes biological damage that leads to severe health effects. However, the effects and subsequent health implications caused by exposure to low-dose radiation are unclear. The objective of this study was to determine phosphoprotein profiles in normal human fibroblast cell lines in response to low-dose and high-dose γ-radiation. We examined the cellular response in MRC-5 cells 0.5 h after exposure to 0.05 or 2 Gy. Using 1318 antibodies by antibody array, we observed ≥1.3-fold increases in a number of identified phosphoproteins in cells subjected to low-dose (0.05 Gy) and high-dose (2 Gy) radiation, suggesting that both radiation levels stimulate distinct signaling pathways. Low-dose radiation induced nucleic acid–binding transcription factor activity, developmental processes, and multicellular organismal processes. By contrast, high-dose radiation stimulated apoptotic processes, cell adhesion and regulation, and cellular organization and biogenesis. We found that phospho-BTK (Tyr550) and phospho-Gab2 (Tyr643) protein levels at 0.5 h after treatment were higher in cells subjected to low-dose radiation than in cells treated with high-dose radiation. We also determined that the phosphorylation of BTK and Gab2 in response to ionizing radiation was regulated in a dose-dependent manner in MRC-5 and NHDF cells. Our study provides new insights into the biological responses to low-dose γ-radiation and identifies potential candidate markers for monitoring exposure to low-dose ionizing radiation. PMID:28122968

TH-AB-207A-12: CT Lung Cancer Screening and the Effects of Further Dose Reduction On CAD Performance

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

Young, S; Lo, P; Hoffman, J

Purpose: CT lung screening is already performed at low doses. In this study, we investigated the effects of further dose reduction on a lung-nodule CAD detection algorithm. Methods: The original raw CT data and images from 348 patients were obtained from our local database of National Lung Screening Trial (NLST) cases. 61 patients (17.5%) had at least one nodule reported on the NLST reader forms. All scans were acquired with fixed mAs (25 for standard-sized patients, 40 for large patients) on a 64-slice scanner (Sensation 64, Siemens Healthcare). All images were reconstructed with 1-mm slice thickness, B50 kernel. Based onmore » a previously-published technique, we added noise to the raw data to simulate reduced-dose versions of each case at 50% and 25% of the original NLST dose (i.e. approximately 1.0 and 0.5 mGy CTDIvol). For each case at each dose level, a CAD detection algorithm was run and nodules greater than 4 mm in diameter were reported. These CAD results were compared to “truth”, defined as the approximate nodule centroids from the NLST forms. Sensitivities and false-positive rates (FPR) were calculated for each dose level, with a sub-analysis by nodule LungRADS category. Results: For larger category 4 nodules, median sensitivities were 100% at all three dose levels, and mean sensitivity decreased with dose. For the more challenging category 2 and 3 nodules, the dose dependence was less obvious. Overall, mean subject-level sensitivity varied from 38.5% at 100% dose to 40.4% at 50% dose, a difference of only 1.9%. However, median FPR quadrupled from 1 per case at 100% dose to 4 per case at 25% dose. Conclusions: Dose reduction affected nodule detectability differently depending on the LungRADS category, and FPR was very sensitive at sub-screening levels. Care should be taken to adapt CAD for the very challenging noise characteristics of screening. Funding support: NIH U01 CA181156; Disclosures (McNitt-Gray): Institutional research agreement, Siemens Healthcare; Past recipient, research grant support, Siemens Healthcare; Consultant, Toshiba America Medical Systems; Consultant, Samsung Electronics.« less

The similia principle: results obtained in a cellular model system.

PubMed

Wiegant, Fred; Van Wijk, Roeland

2010-01-01

This paper describes the results of a research program focused on the beneficial effect of low dose stress conditions that were applied according to the similia principle to cells previously disturbed by more severe stress conditions. In first instance, we discuss criteria for research on the similia principle at the cellular level. Then, the homologous ('isopathic') approach is reviewed, in which the initial (high dose) stress used to disturb cellular physiology and the subsequent (low dose) stress are identical. Beneficial effects of low dose stress are described in terms of increased cellular survival capacity and at the molecular level as an increase in the synthesis of heat shock proteins (hsps). Both phenomena reflect a stimulation of the endogenous cellular self-recovery capacity. Low dose stress conditions applied in a homologous approach stimulate the synthesis of hsps and enhance survival in comparison with stressed cells that were incubated in the absence of low dose stress conditions. Thirdly, the specificity of the low dose stress condition is described where the initial (high dose) stress is different in nature from the subsequently applied (low dose) stress; the heterologous or 'heteropathic' approach. The results support the similia principle at the cellular level and add to understanding of how low dose stress conditions influence the regulatory processes underlying self-recovery. In addition, the phenomenon of 'symptom aggravation' which is also observed at the cellular level, is discussed in the context of self-recovery. Finally, the difference in efficiency between the homologous and the heterologous approach is discussed; a perspective is indicated for further research; and the relationship between studies on the similia principle and the recently introduced concept of 'postconditioning hormesis' is emphasized. Copyright 2009 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.

The Effect of Route, Vehicle, and Divided Doses on the Pharmacokinetics of Chlorpyrifos and its Metabolite Trichloropyridinol in Neonatal Sprague-Dawley Rats

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

Marty, M. S.; Domoradzki, J. Y.; Hansen, S. C.

2007-12-01

There is a paucity of data on neonatal systemic exposure using different dosing paradigms. Male CD (Sprague-Dawley derived) rats at postnatal day (PND) 5 were dosed with chlorpyrifos (CPF, 1 mg/kg) using different routes of exposure, vehicles, and single vs. divided doses. Blood concentrations of CPF and its primary metabolite, trichloropyridinol (TCP), were measured at multiple times through 24 h. Groups included: single gavage bolus vs. divided gavage doses in corn oil (1 vs 3 times in 24 h), single gavage bolus vs. divided gavage doses in rat milk, and subcutaneous administration in DMSO. These data were compared with lactationalmore » exposure of PND 5 pups from dams exposed to CPF in the diet at 5 mg/kg/day for four weeks or published data from dams exposed to daily gavage with CPF at 5 mg/kg/day. Maternal blood CPF levels were an order of magnitude lower from dietary exposure than gavage (1.1 vs 14.8 ng/g), and blood CPF levels in PND 5 pups that nursed dietary-exposed or gavage-exposed dams were below the limit of detection. Single gavage doses of 1 mg/kg CPF in corn oil vehicle in pups resulted in CPF blood levels of 49 ng/g, and in milk vehicle about 9 ng/g. Divided doses led to lower peak CPF levels. A bolus dose of 1 mg/kg CPF in DMSO administered sc appeared to have substantially altered pharmacokinetics from orally administered chlorpyrifos. To be meaningful for risk assessment, neonatal studies require attention to the exposure scenario, since route, vehicle, dose and frequency of administration result in different systemic exposure to the test chemical and its metabolites.« less

Sol-gel derived copper-doped silica glass as a sensitive material for X-ray beam dosimetry

NASA Astrophysics Data System (ADS)

Capoen, Bruno; Hamzaoui, Hicham El; Bouazaoui, Mohamed; Ouerdane, Youcef; Boukenter, Aziz; Girard, Sylvain; Marcandella, Claude; Duhamel, Olivier

2016-01-01

The light emission from a sol-gel-derived Cu-doped silica glass was studied under 10 keV X-ray irradiation using a fibered setup. Both radioluminescence (RL) and optically stimulated luminescence (OSL) were analyzed at different high dose rates up to 50 Gy/s and for different exposure times, yielding accumulated doses up to 50 kGy (in SiO2). Even if a darkening effect appears at this dose level, the material remains X-sensitive after exposure to several kGy. At low dose rate, the scintillation mechanisms are similar to photoluminescence, involving the Cu+ ions electronic levels, contrary to the nonlinear domain (for dose rates higher than 30 Gy/s). This RL, as well as the OSL, could be exploited in their linear domain to measure doses as high as 3 kGy. A thorough study of the OSL signal has shown that it must be employed with caution in order to take the fading phenomenon and the response dependency on stimulation source intensity into consideration.

Effects of medetomidine on serum glucose in cattle calves.

PubMed

Tariq, Muhammad; Kalhoro, Amir Bukhsh; Sarwar, Mian Saeed; Khan, Hamayun; Ahmad, Shakoor; Hassan, Sayed Mubashir; Zahoor, Arshad

2016-05-01

An experimental study was carried out to compare physiological effects (serum glucose level) of medetomidine in Red Sindhi cattle calves at three different doses i.e. 8, 10 and 12µg/kg body weight intravenously. Medetomidine produced a dose dependent significant (P<0.01) increase in serum glucose level with a maximum increase observed at 30 minutes with 8µg/kg, 10μg/kg and 12μg/kg body weight respectively. Start of sedation, degree of sedation and total duration of sedation were all dose dependent and the values obtained were significantly (P<0.01) different from each other. It was observed that the sedation was rapid, deep and longer with the higher doses of medetomidine i.e. 12μg/kg. The results of the present study shows that medetomidine is a very effective and safest drug use as sedative for calves which in lower doses (8μg/kg) can be used as a pre-anesthetic and for restraining of the animal, while higher calculated doses (10μg/kg, 12μg/kg) can be used to execute the minor surgical procedures.

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

PubMed

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

2015-07-31

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

Dose as a Tool for Planning and Implementing Community-Based Health Strategies.

PubMed

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.

Cinnamon extract improves fasting blood glucose and glycosylated hemoglobin level in Chinese patients with type 2 diabetes.

PubMed

Lu, Ting; Sheng, Hongguang; Wu, Johnna; Cheng, Yuan; Zhu, Jianming; Chen, Yan

2012-06-01

For thousands of years, cinnamon has been used as a traditional treatment in China. However, there are no studies to date that investigate whether cinnamon supplements are able to aid in the treatment of type 2 diabetes in Chinese subjects. We hypothesized cinnamon should be effective in improving blood glucose control in Chinese patients with type 2 diabetes. To address this hypothesis, we performed a randomized, double-blinded clinical study to analyze the effect of cinnamon extract on glycosylated hemoglobin A(1c) and fasting blood glucose levels in Chinese patients with type 2 diabetes. A total of 66 patients with type 2 diabetes were recruited and randomly divided into 3 groups: placebo and low-dose and high-dose supplementation with cinnamon extract at 120 and 360 mg/d, respectively. Patients in all 3 groups took gliclazide during the entire 3 months of the study. Both hemoglobin A(1c) and fasting blood glucose levels were significantly reduced in patients in the low- and high-dose groups, whereas they were not changed in the placebo group. The blood triglyceride levels were also significantly reduced in the low-dose group. The blood levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and liver transaminase remained unchanged in the 3 groups. In conclusion, our study indicates that cinnamon supplementation is able to significantly improve blood glucose control in Chinese patients with type 2 diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

Influence of Prostatic Edema on {sup 131}CS Permanent Prostate Seed Implants: A Dosimetric and Radiobiological Study

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

Kehwar, Than S., E-mail: kehwarts@upmc.ed; Jones, Heather A.; Huq, M. Saiful

2011-06-01

Purpose: To study the influence of prostatic edema on postimplant physical and radiobiological parameters using {sup 131}Cs permanent prostate seed implants. Methods and Materials: Thirty-one patients with early prostate cancer who underwent {sup 131}Cs permanent seed implantation were evaluated. Dose-volume histograms were generated for each set of prostate volumes obtained at preimplantation and postimplantion days 0, 14, and 28 to compute quality indices (QIs) and fractional doses at level x (FD{sub x}). A set of equations for QI, FD{sub x}, and biologically effective doses at dose level D{sub x} (BED{sub x}) were defined to account for edema changes with timemore » after implant. Results: There were statistically significant differences found between QIs of pre- and postimplant plans at day 0, except for the overdose index (ODI). QIs correlated with postimplant time, and FD{sub x} was found to increase with increasing postimplant time. With the effect of edema, BED at different dose levels showed less improvement due to the short half-life of {sup 131}Cs, which delivers about 85% of the prescribed dose before the prostate reaches its original volume due to dissipation of edema. Conclusions: Results of the study show that QIs, FD{sub x}, and BEDs at the level of D{sub x} changed from preneedle plans to postimplant plans and have statistically significant differences (p < 0.05), except for the ODI (p = 0.106), which suggests that at the time of {sup 131}C seed implantation, the effect of edema must be accounted for when defining the seed positions, to avoid the possibility of poor dosimetric and radiobiologic results for {sup 131}Cs seed implants.« less

Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats.

PubMed

Rajan, Balan; Sathish, Shanmugam; Balakumar, Subramanian; Devaki, Thiruvengadam

2015-03-01

Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days. Copyright © 2015 Elsevier B.V. All rights reserved.

A randomised, double-blind, placebo-controlled, crossover study to assess the efficacy and safety of three dosing schedules of agalsidase alfa enzyme replacement therapy for Fabry disease.

PubMed

Hughes, D A; Deegan, P B; Milligan, A; Wright, N; Butler, L H; Jacobs, A; Mehta, A B

2013-07-01

Anecdotal reports suggest that the currently approved dosing interval of agalsidase alfa (0.2 mg/kg/2 weeks) for Fabry disease treatment is too long. This randomised, double-blind, placebo-controlled, crossover study investigated three altered dosing intervals. 18 Fabry patients received three agalsidase alfa dosing schedules, each for four weeks (A: 0.2 mg/kg∗2 weeks, B: 0.1 mg/kg/week, C: 0.2 mg/kg/week). Health state, pain levels, sweat volume and latency and plasma and urinary globotriaosylceramide levels were recorded throughout the study. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. A trend toward increased sweat volume on QSART testing, and reduced urine globotriaosylceramide concentration were seen with treatment schedule C. Agalsidase alfa was safe and well tolerated with all schedules. In conclusion, the primary analyses did not find weekly infusions of agalsidase alfa to be statistically better than the approved dosing schedule however the data indicates that further studies with more patients over a longer period are required to more accurately determine the optimum dose and schedule. Copyright © 2013 Elsevier Inc. All rights reserved.

Microstructural characterization and density change of 304 stainless steel reflector blocks after long-term irradiation in EBR-II

NASA Astrophysics Data System (ADS)

Huang, Y.; Wiezorek, J. M. K.; Garner, F. A.; Freyer, P. D.; Okita, T.; Sagisaka, M.; Isobe, Y.; Allen, T. R.

2015-10-01

While thin reactor structural components such as cladding and ducts do not experience significant gradients in dpa rate, gamma heating rate, temperature or stress, thick components can develop strong local variations in void swelling and irradiation creep in response to gradients in these variables. In this study we conducted microstructural investigations by transmission electron microscopy of two 52 mm thick 304-type stainless steel hex-blocks irradiated for 12 years in the EBR-II reactor with accumulated doses ranging from ∼0.4 to 33 dpa. Spatial variations in the populations of voids, precipitates, Frank loops and dislocation lines have been determined for 304 stainless steel sections exposed to different temperatures, different dpa levels and at different dpa rates, demonstrating the existence of spatial gradients in the resulting void swelling. The microstructural measurements compare very well with complementary density change measurements regarding void swelling gradients in the 304 stainless steel hex-block components. The TEM studies revealed that the original cold-worked-state microstructure of the unirradiated blocks was completely erased by irradiation, replaced by high densities of interstitial Frank loops, voids and carbide precipitates at both the lowest and highest doses. At large dose levels the amount of volumetric void swelling correlated directly with the gamma heating gradient-related temperature increase (e.g. for 28 dpa, ∼2% swelling at 418 °C and ∼2.9% swelling at 448 °C). Under approximately iso-thermal local conditions, volumetric void swelling was found to increase with dose level (e.g. ∼0.2% swelling at 0.4 dpa, ∼0.5% swelling at 4 dpa and ∼2% swelling at 28 dpa). Carbide precipitate formation levels were found to be relatively independent of both dpa level and temperature and induced a measurable densification. Void swelling was dominant at the higher dose levels and caused measurable decreases in density. Void swelling at the lowest doses was larger than might be expected based on the dpa level, an observation in agreement with earlier studies showing that the onset of void swelling is accelerated by decreasing dpa rates.

Dose-response studies and 'no-effect-levels' of N-nitroso compounds: some general aspects.

PubMed

Preussmann, R

1980-01-01

One major problem in the evaluation of potential carcinogenic food additives and contaminants is that of thresholds or, better, of 'no-adverse-effect-levels'. Arguments in favor of the postulated 'irreversibility' of carcinogenic effects are based on dose-response studies, single dose and multigeneration experiments as well as on the concept of somatic mutation as the first step in carcinogenesis with subsequent transmittance of induced defects during cell replication. The problem of extrapolation of results of animal experiments using high doses to low exposure and low incidences in man is not yet solved satisfactorily. Possible practical consequences include zero tolerance, acceptable thresholds at low risk and safety factors. Acceptable intakes should never be considered constants but should be changeable as soon as new facts in regard to the safety evaluation are available.

The FLUKA Monte Carlo code coupled with the NIRS approach for clinical dose calculations in carbon ion therapy

NASA Astrophysics Data System (ADS)

Magro, G.; Dahle, T. J.; Molinelli, S.; Ciocca, M.; Fossati, P.; Ferrari, A.; Inaniwa, T.; Matsufuji, N.; Ytre-Hauge, K. S.; Mairani, A.

2017-05-01

Particle therapy facilities often require Monte Carlo (MC) simulations to overcome intrinsic limitations of analytical treatment planning systems (TPS) related to the description of the mixed radiation field and beam interaction with tissue inhomogeneities. Some of these uncertainties may affect the computation of effective dose distributions; therefore, particle therapy dedicated MC codes should provide both absorbed and biological doses. Two biophysical models are currently applied clinically in particle therapy: the local effect model (LEM) and the microdosimetric kinetic model (MKM). In this paper, we describe the coupling of the NIRS (National Institute for Radiological Sciences, Japan) clinical dose to the FLUKA MC code. We moved from the implementation of the model itself to its application in clinical cases, according to the NIRS approach, where a scaling factor is introduced to rescale the (carbon-equivalent) biological dose to a clinical dose level. A high level of agreement was found with published data by exploring a range of values for the MKM input parameters, while some differences were registered in forward recalculations of NIRS patient plans, mainly attributable to differences with the analytical TPS dose engine (taken as reference) in describing the mixed radiation field (lateral spread and fragmentation). We presented a tool which is being used at the Italian National Center for Oncological Hadrontherapy to support the comparison study between the NIRS clinical dose level and the LEM dose specification.

Effect of seabuckthorn leaf extracts on circulating energy fuels, lipid peroxidation and antioxidant parameters in rats during exposure to cold, hypoxia and restraint (C-H-R) stress and post stress recovery.

PubMed

Saggu, Shalini; Kumar, Ratan

2008-06-01

The present study was carried out to study mechanism of adaptogenic activity of seabuckthorn leaf extract, administered orally in rats both in single and five doses at a dose of 100mg/kg body weight 30min prior to C-H-R exposure. The efficacy of the extract was studied on circulating energy fuels, lipid peroxidation and anti-oxidant parameters in rats on attaining the T(rec) 23 degrees C during C-H-R exposure and after recovery (T(rec) 37 degrees C) from C-H-R induced hypothermia. Single dose treatment in rats restricted rise in blood malondialdehyde (MDA) levels and decrease in glutathione (GSH) and catalase (CAT) levels. Both single and five doses also restricted the rise in serum free fatty acids (FFA) and lactate dehydrogenase (LDH) levels on attaining T(rec) 23 degrees C during C-H-R exposure, suggesting more efficient utilization of FFA for energy production and better maintained cell membrane permeability. This suggested that the adaptogenic activity of the extract might be due to its anti-oxidative activity, maintained blood glucose levels, better utilization of FFA and improved cell membrane permeability.

A randomized clinical trial comparing metabolic parameters after 48 weeks of standard- and low-dose stavudine therapy and tenofovir disoproxil fumarate therapy in HIV-infected South African patients.

PubMed

Menezes, C N; Crowther, N J; Duarte, R; Van Amsterdam, D; Evans, D; Dickens, C; Dix-Peek, T; Rassool, M; Prinsloo, A; Raal, F; Sanne, I

2014-01-01

Low-dose stavudine therapy may have a lower toxicity profile compared with standard dose. A randomized controlled trial comparing these two doses of stavudine with tenofovir disoproxil fumarate (tenofovir DF) was performed to assess the effects on anthropometry, markers of inflammation, and lipid and glucose metabolism in Black South African patients. Sixty patients were randomized 1:1:1 to either standard-dose (30-40 mg) or low-dose (20-30 mg) stavudine or tenofovir DF (300 mg), each combined with lamivudine and efavirenz, for 48 weeks. Anthropometry, markers of inflammation, and lipid and glucose metabolism were assessed using standard techniques. In all three treatment arms, there was a significant increase in lipid levels over the study period. At 48 weeks, fasting glucose level (P < 0.005) and homeostasis model assessment (HOMA) score (P < 0.05) increased significantly in the standard-dose stavudine arm, as did insulin and C-peptide levels in both the standard- and low-dose stavudine arms. At week 48, a significant decrease (P < 0.05) in adiponectin was noted in the standard-dose stavudine arm, but there was an increase (P < 0.005) in the tenofovir DF arm. In both the stavudine arms, significant increases in anthropometric measures occurred at 24 weeks but these decreased by week 48. Mitochondrial toxicities occurred in both the stavudine arms. Immunological and virological outcomes were similar for all three arms. This study highlights the occurrence of metabolic abnormalities with both stavudine and tenofovir DF treatment. Awareness of the potential increased cardiovascular risk should be of concern with the use of both these therapies. © 2013 British HIV Association.

Expression of Genes Associated with DNA Damage Sensing in Human Fibroblasts Exposed to Low-dose-rate Gamma Rays

NASA Technical Reports Server (NTRS)

Zhang, Ye; Mehta, Satish; Hammond, Diane; Pierson, Duane; Jeevarajan, Antony; Cucinotta, Francis; Rohde, Larry; Wu, Honglu

2007-01-01

Understanding of the molecular response to low-dose and low-dose-rate radiation exposure is essential for the extrapolation of high-dose radiation risks to those at dose levels relevant to space and other environmental concerns. Most of the reported studies of gene expressions induced by low-dose or low-dose-rate radiation were carried out on exponentially growing cells. In the present study, we analyzed expressions of 84 genes associated with DNA damage sensing using real time PCR in human fibroblasts in mostly G1 phase of the cell cycle. The cells were exposed continuously to gamma rays at a dose rate of 0.8 cGy/hr for 1, 2, 6 or 24 hrs at 37 C throughout the exposure. The total RNA was isolated immediately after the exposure was terminated. Of the 84 genes, only a few showed significant changes of the expression level. Some of the genes (e.g. DDit3 and BTG2) were found to be up or down regulated only after a short period of exposure, while other genes (e.g. PRKDC) displayed a highest expression level at the 24 hr time point. The expression profiles for the exposed cells which had a smaller portion of G1 cells indicated more cell cycle signaling and DNA repair genes either up or down regulated. Interestingly, the panel of genes changed from radiation exposure in G1 cells is different from the panel in cells having less G1 arrest cells. The gene expression profile of the cells responding to low-dose-radiation insult apparently depends on the cell growth stage. The response pathway in G1 cells may differ from that in exponentially growing cells.

Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

NASA Astrophysics Data System (ADS)

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

2014-02-01

Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.

PubMed

Kepka, Lucyna; Tyc-Szczepaniak, Dobromira; Bujko, Krzysztof

2009-07-01

To determine the efficacy of accelerated hypofractionated three-dimensional conformal radiotherapy (3D-CRT) with dose-per-fraction escalation for treatment of stage III non-small cell lung cancer (NSCLC). Between 2001 and 2007, 173 patients with stage III NSCLC were treated using accelerated 3D-CRT and the simultaneous boost technique. Initially, the total dose of 56.7 Gy (including 39.9 Gy to the elective area) was delivered over 4 weeks in fractions of 2.7 Gy (1.9 Gy to the elective area). The dose-per-fraction escalation study commenced after the outcomes of 70 patients had been evaluated. The dose per fraction was increased from 2.7 through 2.8 Gy (level 1 escalation) to 2.9 Gy (level 2 escalation); the total dose increased, respectively, from 56.7 Gy through 58.8 Gy to 60.9 Gy. The dose to the elective area and the overall treatment time remained unchanged. Fit patients received two to three courses of chemotherapy before radiotherapy. The 2- and 3-year overall survival rates were 32 and 19%, respectively (median survival = 17 months). Of the patients, 7% had grade III acute esophageal toxicity and 6% had grade III or greater late pulmonary toxicity. Two of the nine patients who received the level 2 escalation (60.9 Gy) died of pulmonary toxicity. The study was terminated at a dose of 58.8 Gy and this schema was adopted as the institutional policy for treatment of stage III NSCLC. Although dose escalation with accelerated hypofractionated 3D-CRT was limited, the results and toxicity profiles obtained using this technique are promising.

Impact of High-Dose Vitamin D3 Supplementation in Patients with Crohn's Disease in Remission: A Pilot Randomized Double-Blind Controlled Study.

PubMed

Narula, Neeraj; Cooray, Mohan; Anglin, Rebecca; Muqtadir, Zack; Narula, Alisha; Marshall, John K

2017-02-01

To assess the tolerability and efficacy of high-dose vitamin D3 in patients with Crohn's disease (CD). This was a randomized, double-blind placebo-controlled trial of high-dose vitamin D3 at 10,000 IU daily (n = 18) compared to 1000 IU daily (n = 16) for 12 months in patients with CD in remission. The primary outcome was change in serum 25-hydroxy-vitamin D levels. Secondary outcomes included clinical relapse rates and changes in mood scores. High-dose vitamin D3 at 10,000 IU daily significantly improved 25-hydroxy-vitamin D levels from a mean of 73.5 nmol/L [standard deviation (SD) 11.7 nmol/L] to 160.8 nmol/L (SD 43.2 nmol/L) (p = 0.02). On an intention-to-treat basis, the rate of relapse was not significantly different between patients receiving low- and high-dose vitamin D3 (68.8 vs 33.3%, p = 0.0844). In per-protocol analysis, clinical relapse of Crohn's disease was less frequently observed in patients receiving a high dose (0/12 or 0%) compared to those receiving a low dose of 1000 IU daily (3/8 or 37.5%) (p = 0.049). Improvement in anxiety and depression scores and a good safety profile were observed in both groups treated with vitamin D3. Oral supplementation with high-dose vitamin D3 at 10,000 IU daily significantly improved serum 25-hydroxy-vitamin D levels. Rates of clinical relapse were similar between both groups. Larger studies using high-dose vitamin D3 for treatment of inflammatory bowel diseases are warranted. CLINICALTRIALS. NCT02615288.

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

PubMed

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.

Relative sensitivity of developmental and immune parameters in juvenile versus adult male rats after exposure to di(2-ethylhexyl) phthalate

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

Tonk, Elisa C.M., E-mail: ilse.tonk@rivm.nl; Laboratory for Health Protection Research, National Institute for Public Health and the Environment; Verhoef, Aart

The developing immune system displays a relatively high sensitivity as compared to both general toxicity parameters and to the adult immune system. In this study we have performed such comparisons using di(2-ethylhexyl) phthalate (DEHP) as a model compound. DEHP is the most abundant phthalate in the environment and perinatal exposure to DEHP has been shown to disrupt male sexual differentiation. In addition, phthalate exposure has been associated with immune dysfunction as evidenced by effects on the expression of allergy. Male wistar rats were dosed with corn oil or DEHP by gavage from postnatal day (PND) 10–50 or PND 50–90 atmore » doses between 1 and 1000 mg/kg/day. Androgen-dependent organ weights showed effects at lower dose levels in juvenile versus adult animals. Immune parameters affected included TDAR parameters in both age groups, NK activity in juvenile animals and TNF-α production by adherent splenocytes in adult animals. Immune parameters were affected at lower dose levels compared to developmental parameters. Overall, more immune parameters were affected in juvenile animals compared to adult animals and effects were observed at lower dose levels. The results of this study show a relatively higher sensitivity of juvenile versus adult rats. Furthermore, they illustrate the relative sensitivity of the developing immune system in juvenile animals as compared to general toxicity and developmental parameters. This study therefore provides further argumentation for performing dedicated developmental immune toxicity testing as a default in regulatory toxicology. -- Highlights: ► In this study we evaluate the relative sensitivities for DEHP induced effects. ► Results of this study demonstrate the age-dependency of DEHP toxicity. ► Functional immune parameters were more sensitive than structural immune parameters. ► Immune parameters were affected at lower dose levels than developmental parameters. ► Findings demonstrate the susceptibility of the developing immune system for DEHP.« less

[Vaccination against viral hepatitis A and B in adults aged over 40 years--antibody persistence and immune memory].

PubMed

Chlibek, R; Smetana, J; Bostíková, V; Splino, M

2011-09-01

Primary vaccination with combined vaccine against viral hepatitis A (VHA) and viral hepatitis B (VHB) induces higher anti-hepatitis B surface (anti-HBs) antibody responses and similar anti-hepatitis A virus (anti-HAV) antibody responses in adults aged over 40 years in comparison with concomitant monovalent vaccines against VHA and VHB. Th e objectives were to assess, in a clinical study, persistence of anti-HAV and anti-HBs antibodies in adults aged over 40 years four years after primary VHA/VHB vaccination and antibody response following a booster dose of the vaccine. Five hundred and ninety-six subjects aged > 40 years were vaccinated with three doses of the combined VHA/VHB vaccine at Months 0, 1, 6 (HAB group) or with concomitant VHA and VHB vaccines at Months 0, 6 and 0, 1, 6 (ENG+HAV and HBVX+VAQ, respectively). Blood samples were collected one month following primary vaccination (Month 7) and then at one-year intervals for four years after the booster dose with the same vaccine as used for the primary vaccination. The anti-HBs and anti-HAV antibody levels were determined prior to the booster dose and at days 14 and 30 after the booster dose. At Month 7, > 97% of study subjects were seropositive for anti-HAV antibodies in all groups analyzed. Four years after primary vaccination, anti-HAV antibody seropositivity persisted in > 93% of study subjects, increasing to > 99% after the booster dose. At Month 7, the highest proportion of study subjects with anti-HBs antibody levels > or = 10 mIU/ml was found in the HAB group (91.7% versus 79.7% in the ENG+HAV group versus 71.0% in the HBVX+VAQ group). Four years after vaccination, anti-HBs antibody levels of 10 mIU/ml persisted in 57.1% of the HAB study subjects in comparison with 40.1% and 26.6% of the study subjects in the ENG+HAV and HBVX+VAQ groups, respectively. One month after the booster dose, anti-HBs antibody levels increased and antibody levels > or = 10 mIU/ml was achived in 95.2% of study subjects in the HAB group, 90.5% in the ENG+HAV group and 85.3% in the HBVX+VAQ group. In the adults aged over 40 years, an adequate anti-HAV antibody response persisted for at least four years after vaccination and was higher and more sustained in those who received the combined HAB vaccine. A strong antibody response to the booster dose indicative ofthe presence of immune memory was seen in all study groups.

REDUCTION OF DOSES IN DIAGNOSTIC USES OF RADIOISOTOPES

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

Hosain, F.

1960-03-01

> A moderately low-level counting technique with anticoincidence gas- flow counter was developed for use in metabolic and diagnostic tracer studies with radioisotopes. Several important experiments and results were reported which have been carried out with reduced doses of tracer isotopes. A reduction of the tracer dose of ahout 1/30th of the present conventional doses was achieved which helps to minimize the chances of radiation hazards. (auth)

A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio®) in cardiac surgery: the REVAKI‐1 study

PubMed Central

Ring, Arne; Morris, Tom; Wozniak, Marcin; Sullo, Nikol; Dott, William; Verheyden, Veerle; Kumar, Tracy; Brunskill, Nigel; Vaja, Rakesh

2016-01-01

Aims Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre‐clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. Methods We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. Results Thirty‐six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml−1, C max 189.4 ng ml−1 and t 1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post‐surgery nitric oxide bioavailability. Conclusions Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery. PMID:27779776

Immunological Effect of aGV Rabies Vaccine Administered Using the Essen and Zagreb Regimens: A Double-Blind, Randomized Clinical Trial.

PubMed

Miao, Li; Shi, Liwei; Yang, Yi; Yan, Kunming; Sun, Hongliang; Mo, Zhaojun; Li, Li

2018-04-01

This study evaluated the immunological effect of an aGV rabies virus strain using the Essen and Zagreb immunization programs. A total of 1,944 subjects were enrolled and divided into three groups: the Essen test group, Essen control group, and Zagreb test group. Neutralizing antibody levels and antibody seroconversion rates were determined at 7 and 14 days after the initial inoculations and then 14 days after the final inoculation in all of the subjects. The seroconversion rates for the Essen test group, Essen control group, and Zagreb test group, which were assessed 7 days after the first dosing in a susceptible population, were 35.74%, 26.92%, and 45.49%, respectively, and at 14 days, the seroconversion rates in this population were 100%, 100%, and 99.63%, respectively. At 14 days after the final dosing, the seroconversion rates were 100% in all three of the groups. The neutralizing serum antibody levels of the Essen test group, Essen control group, and Zagreb test group at 7 days after the first dosing in the susceptible population were 0.37, 0.26, and 0.56 IU/mL, respectively, and at 14 days after the initial dosing, these levels were 16.71, 13.85, and 16.80 IU/mL. At 14 days after the final dosing, the neutralizing antibody levels were 22.9, 16.3, and 18.62 IU/mL, respectively. The results of this study suggested that the aGV rabies vaccine using the Essen program resulted in a good serum immune response, and the seroconversion rates and the neutralizing antibody levels generated with the Zagreb regimen were higher than those with the Essen regimen when measured 7 days after the first dose.

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

Kathy Held; Kevin Prise; Barry Michael

The management of the risks of exposure of people to ionizing radiation is important in relation to its uses in industry and medicine, also to natural and man-made radiation in the environment. The vase majority of exposures are at a very low level of radiation dose. The risks are of inducing cancer in the exposed individuals and a smaller risk of inducing genetic damage that can be indicate that they are low. As a result, the risks are impossible to detect in population studies with any accuracy above the normal levels of cancer and genetic defects unless the dose levelsmore » are high. In practice, this means that our knowledge depends very largely on the information gained from the follow-up of the survivors of the atomic bombs dropped on Japanese cities. The risks calculated from these high-dose short-duration exposures then have to be projected down to the low-dose long-term exposures that apply generally. Recent research using cells in culture has revealed that the relationship between high- and low-dose biological damage may be much more complex than had previously been thought. The aims of this and other projects in the DOE's Low-Dose Program are to gain an understanding of the biological actions of low-dose radiation, ultimately to provide information that will lead to more accurate quantification of low-dose risk. Our project is based on the concept that the processes by which radiation induces cancer start where the individual tracks of radiation impact on cells and tissues. At the dose levels of most low-dose exposures, these events are rare and any individual cells only ''sees'' radiation tracks at intervals averaging from weeks to years apart. This contrasts with the atomic bomb exposures where, on average, each cell was hit by hundreds of tracks instantaneously. We have therefore developed microbeam techniques that enable us to target cells in culture with any numbers of tracks, from one upwards. This approach enables us to study the biological ha sis of the relationship between high- and low-dose exposures. The targeting approach also allows us to study very clearly a newly recognized effect of radiation, the ''bystander effect'', which appears to dominate some low-dose responses and therefore may have a significant role in low-dose risk mechanisms. Our project also addresses the concept that the background of naturally occurring oxidative damage that takes place continually in cells due to byproducts of metabolism may play a role in low-dose radiation risk. This project therefore also examines how cells are damaged by treatments that modify the levels of oxidative damage, either alone or in combination with low-dose irradiation. In this project, we have used human and rodent cell lines and each set of experiments has been carried out on a single cell type. However, low-dose research has to extend into tissues because signaling between cells of different types is likely to influence the responses. Our studies have therefore also included microbeam experiments using a model tissue system that consists of an explant of a small piece of pig ureter grown in culture. The structure of this tissue is similar to that of epithelium and therefore it relates to the tissues in which carcinoma arises. Our studies have been able to measure bystander-induced changes in the cells growing out from the tissue fragment after it has been targeted with a few radiation tracks to mimic a low-dose exposure.« less

How Does Patient Radiation Exposure Compare With Low-dose O-arm Versus Fluoroscopy for Pedicle Screw Placement in Idiopathic Scoliosis?

PubMed

Su, Alvin W; McIntosh, Amy L; Schueler, Beth A; Milbrandt, Todd A; Winkler, Jennifer A; Stans, Anthony A; Larson, A Noelle

Intraoperative C-arm fluoroscopy and low-dose O-arm are both reasonable means to assist in screw placement for idiopathic scoliosis surgery. Both using pediatric low-dose O-arm settings and minimizing the number of radiographs during C-arm fluoroscopy guidance decrease patient radiation exposure and its deleterious biological effect that may be associated with cancer risk. We hypothesized that the radiation dose for C-arm-guided fluoroscopy is no less than low-dose O-arm scanning for placement of pedicle screws. A multicenter matched-control cohort study of 28 patients in total was conducted. Fourteen patients who underwent O-arm-guided pedicle screw insertion for spinal fusion surgery in 1 institution were matched to another 14 patients who underwent C-arm fluoroscopy guidance in the other institution in terms of the age of surgery, body weight, and number of imaged spine levels. The total effective dose was compared. A low-dose pediatric protocol was used for all O-arm scans with an effective dose of 0.65 mSv per scan. The effective dose of C-arm fluoroscopy was determined using anthropomorphic phantoms that represented the thoracic and lumbar spine in anteroposterior and lateral views, respectively. The clinical outcome and complications of all patients were documented. The mean total effective dose for the O-arm group was approximately 4 times higher than that of the C-arm group (P<0.0001). The effective dose for the C-arm patients had high variability based on fluoroscopy time and did not correlate with the number of imaged spine levels or body weight. The effective dose of 1 low-dose pediatric O-arm scan approximated 85 seconds of the C-arm fluoroscopy time. All patients had satisfactory clinical outcomes without major complications that required returning to the operating room. Radiation exposure required for O-arm scans can be higher than that required for C-arm fluoroscopy, but it depends on fluoroscopy time. Inclusion of more medical centers and surgeons will better account for the variability of C-arm dose due to distinct patient characteristics, surgeon's preference, and individual institution's protocol. Level III-case-control study.

Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial.

PubMed

Bakris, George L; Pitt, Bertram; Weir, Matthew R; Freeman, Mason W; Mayo, Martha R; Garza, Dahlia; Stasiv, Yuri; Zawadzki, Rezi; Berman, Lance; Bushinsky, David A

2015-07-14

Hyperkalemia is a potentially life-threatening condition predominantly seen in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or greater chronic kidney disease (CKD) who may also have diabetes, heart failure, or both. To select starting doses for a phase 3 study and to evaluate the long-term safety and efficacy of a potassium-binding polymer, patiromer, in outpatients with hyperkalemia. Phase 2, multicenter, open-label, dose-ranging, randomized clinical trial (AMETHYST-DN), conducted at 48 sites in Europe from June 2011 to June 2013 evaluating patiromer in 306 outpatients with type 2 diabetes (estimated glomerular filtration rate, 15 to <60 mL/min/1.73 m2 and serum potassium level >5.0 mEq/L). All patients received RAAS inhibitors prior to and during study treatment. Patients were stratified by baseline serum potassium level into mild or moderate hyperkalemia groups and received 1 of 3 randomized starting doses of patiromer (4.2 g [n = 74], 8.4 g [n = 74], or 12.6 g [n = 74] twice daily [mild hyperkalemia] or 8.4 g [n = 26], 12.6 g [n = 28], or 16.8 g [n = 30] twice daily [moderate hyperkalemia]). Patiromer was titrated to achieve and maintain serum potassium level 5.0 mEq/L or lower. The primary efficacy end point was mean change in serum potassium level from baseline to week 4 or prior to initiation of dose titration. The primary safety end point was adverse events through 52 weeks. Secondary efficacy end points included mean change in serum potassium level through 52 weeks. A total of 306 patients were randomized. The least squares mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35 (95% CI, 0.22-0.48) mEq/L for the 4.2 g twice daily starting-dose group, 0.51 (95% CI, 0.38-0.64) mEq/L for the 8.4 g twice daily starting-dose group, and 0.55 (95% CI, 0.42-0.68) mEq/L for the 12.6 g twice daily starting-dose group. In those with moderate hyperkalemia, the reduction was 0.87 (95% CI, 0.60-1.14) mEq/L for the 8.4 g twice daily starting-dose group, 0.97 (95% CI, 0.70-1.23) mEq/L for the 12.6 g twice daily starting-dose group, and 0.92 (95% CI, 0.67-1.17) mEq/L for the 16.8 g twice daily starting-dose group (P < .001 for all changes vs baseline by hyperkalemia starting-dose groups within strata). From week 4 through week 52, statistically significant mean decreases in serum potassium levels were observed at each monthly point in patients with mild and moderate hyperkalemia. Over the 52 weeks, hypomagnesemia (7.2%) was the most common treatment-related adverse event, mild to moderate constipation (6.3%) was the most common gastrointestinal adverse event, and hypokalemia (<3.5 mEq/L) occurred in 5.6% of patients. Among patients with hyperkalemia and diabetic kidney disease, patiromer starting doses of 4.2 to 16.8 g twice daily resulted in statistically significant decreases in serum potassium level after 4 weeks of treatment, lasting through 52 weeks. clinicaltrials.gov Identifier:NCT01371747.

Rotavirus specific maternal antibodies and immune response to RV3-BB neonatal rotavirus vaccine in New Zealand.

PubMed

Chen, Mee-Yew; Kirkwood, Carl D; Bines, Julie; Cowley, Daniel; Pavlic, Daniel; Lee, Katherine J; Orsini, Francesca; Watts, Emma; Barnes, Graeme; Danchin, Margaret

2017-05-04

Maternal antibodies, acquired passively via placenta and/or breast milk, may contribute to the reduced efficacy of oral rotavirus vaccines observed in children in developing countries. This study aimed to investigate the effect of rotavirus specific maternal antibodies on the serum IgA response or stool excretion of vaccine virus after any dose of an oral rotavirus vaccine, RV3-BB, in parallel to a Phase IIa clinical trial conducted at Dunedin Hospital, New Zealand. At the time of the study rotavirus vaccines had not been introduced in New Zealand and the burden of rotavirus disease was evident. Rotavirus specific IgG and serum neutralizing antibody (SNA) levels in cord blood and IgA levels in colostrum and breast milk samples collected ∼4 weeks, ∼20 weeks and ∼28 weeks after birth were measured. Infants were randomized to receive the first dose of vaccine at 0-5 d (neonatal schedule) or 8 weeks (infant schedule). Breast feeding was with-held for 30 minutes before and after vaccine administration. The relationship between rotavirus specific IgG and SNA levels in cord blood and IgA in colostrum and breast milk at the time of first active dose of RV3-BB vaccine and level of IgA response and stool excretion after 3 doses of vaccine was assessed using linear and logistic regression. Forty infants received 3 doses of RV3-BB rotavirus vaccine and were included in the analysis of the neonatal and infant groups. Rotavirus specific IgA in colostrum (neonatal schedule group) and breast milk at 4 weeks (infant schedule group) was identified in 14/21 (67%) and 14/17 (82%) of infants respectively. There was little evidence of an association between IgA in colostrum or breast milk IgA at 4 weeks, or between cord IgG or SNA level, and IgA response or stool excretion after 3 doses of RV3-BB, or after one dose (neonatal schedule) (all p>0.05). The level of IgA in colostrum or breast milk and level of placental IgG and SNA did not impact on the serum IgA response or stool excretion following 3 doses of RV3-BB Rotavirus Vaccine administered using either a neonatal or infant schedule in New Zealand infants.

A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group.

PubMed

Chuk, Meredith K; Widemann, Brigitte C; Minard, Charles G; Liu, Xiaowei; Kim, AeRang; Bernhardt, Melanie Brooke; Kudgus, Rachel A; Reid, Joel M; Voss, Stephan D; Blaney, Susan; Fox, Elizabeth; Weigel, Brenda J

2018-04-25

We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m 2 /day. At 40 mg/m 2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m 2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m 2 /day. A phase 2 study of cabozantinib is being conducted. © 2018 Wiley Periodicals, Inc.

Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients.

PubMed

Kim, In-Wha; Moon, Yoo Jin; Ji, Eunhee; Kim, Kyung Im; Han, Nayoung; Kim, Sung Ju; Shin, Wan Gyoon; Ha, Jongwon; Yoon, Jeong-Hyun; Lee, Hye Suk; Oh, Jung Mi

2012-05-01

The purpose of this study was to characterize the effects of clinical and genetic variables on the pharmacokinetics and complications of tacrolimus during the first year after kidney transplantation. One hundred and thirty-two Korean kidney recipients who received tacrolimus were genotyped for ABCB1 (exons 12, 21, and 26) and CYP3A5 (intron 3). Tacrolimus trough levels, dose, or dose-adjusted trough levels and complications were compared among patients during the early stage (3, 7, 14, 30, and 90 days) and up to 1 year according to the genotypes. A donor source-adjusted linear mixed model with multilevel analysis adjusting for age, body weight, hematocrit, and serum creatinine showed that CYP3A5 genotype is associated with dose-adjusted level of tacrolimus (p < 0.001). The influence of ABCB1 polymorphisms on the pharmacokinetics or complications of tacrolimus was less certain in our study. The incidence of acute rejections was significantly higher in recipients of cadaveric donor kidney (p < 0.05). A generalized estimating equation model analysis showed that alopecia and hyperlipidemia were associated with dose-adjusted level of tacrolimus (p < 0.001). Genotype of CYP3A5 variants along with significant clinical covariates may be useful in individualizing tacrolimus therapy in kidney transplantation patients.

Effect of oral administration of bark extracts of Pterocarpus santalinus L. on blood glucose level in experimental animals.

PubMed

Kameswara Rao, B; Giri, R; Kesavulu, M M; Apparao, C

2001-01-01

The effect of administration of different doses of Pterocarpus santalinus L. bark extracts in normal and diabetic rats, on blood glucose levels was evaluated in this study. Among the three fractions (aqueous, ethanol and hexane), ethanolic fraction at the dose of 0.25 g/kg body weight showed maximum antihyperglycemic activity. The same dose did not cause any hypoglycemic activity in normal rats. The results were compared with the diabetic rats treated with glibenclamide and the antihyperglycemic activity of ethanolic extract of PS bark at the dose of 0.25 g/kg b.w. was found to be more effective than that of glibenclamide.

Risk Assessment Study of Fluoride Salts: Probability-Impact Matrix of Renal and Hepatic Toxicity Markers.

PubMed

Usuda, Kan; Ueno, Takaaki; Ito, Yuichi; Dote, Tomotaro; Yokoyama, Hirotaka; Kono, Koichi; Tamaki, Junko

2016-09-01

The present risk assessment study of fluoride salts was conducted by oral administration of three different doses of sodium and potassium fluorides (NaF, KF) and zinc fluoride tetrahydrate (ZnF2 •4H2O) to male Wistar rats. The rats were divided into control and nine experimental groups, to which oral injections of 0.5 mL distilled water and 0.5 mL of fluoride solutions, respectively, were given. The dosage of fluoride compounds was adjusted to contain 2.1 mg (low-dose group, LG), 4.3 mg (mid-dose group, MG), and 5.4 mg fluoride per 200 g rat body weight (high-dose group, HG) corresponding to 5, 10, and 12.5 % of LD50 values for NaF. The 24-h urine volume, N-acetyl-β-D-glucosaminidase (NAG) and creatinine clearance (Ccr) were measured as markers of possible acute renal impact. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined in serum samples as markers of acute hepatic impact. The levels of serum and urinary fluoride were determined to evaluate fluoride bioavailability. The results reveal that higher doses of NaF, KF, and ZnF2 induced renal damage as indicated by higher urinary NAG (p < 0.05 with ≥90th percentile of control). High doses of ZnF2 also induced a significant Ccr decrease (p < 0.05 with ≤10th percentile of control). Low doses of NaF and mid-doses of ZnF2 induced polyuria (p < 0.05 with ≥90th percentile of control) while medium doses of NaF and low doses of KF also induced liver damage, as indicated by a high level of AST (p < 0.05 with ≥90th percentile of control). These findings suggest that oral administration of fluoride is a potential, dose-dependent risk factor of renal tubular damage.

Triiodothyronine modulates the expression of leptin and adiponectin in 3T3-L1 adipocytes

PubMed Central

de Oliveira, Miriane; Síbio, Maria Teresa De; Olimpio, Regiane Marques Castro; Moretto, Fernanda Cristina Fontes; Luvizotto, Renata de Azevedo Melo; Nogueira, Celia Regina

2015-01-01

Objective To study the effect of different doses of triiodothyronine on gene expression of the adipokines leptin and adiponectin, at different times, and to evaluate the difference in expression between the two adipokines in each group. Methods 3T3-L1 adipocytes were incubated with triiodothyronine at physiological dose (10nM) and supraphysiological doses (100nM or 1,000nM), or without triiodothyronine (control, C) for 0.5, 6, or 24 hours. Leptin and adiponectin mRNA was detected using real-time polymerase chain reaction (RT-PCR). One-way analyses of variance, Tukey’s test or Student’s t test, were used to analyze data, and significance level was set at 5%. Results Leptin levels decreased in the 1,000nM-dose group after 0.5 hour. Adiponectin levels dropped in the 10nM-dose group, but increased at the 100nM dose. After 6 hours, both genes were suppressed in all hormone concentrations. After 24 hours, leptin levels increased at 10, 100 and 1,000nM groups as compared to the control group; and adiponectin levels increased only in the 100nM group as compared to the control group. Conclusion These results demonstrated fast actions of triiodothyronine on the leptin and adiponectin expression, starting at 0.5 hour, at a dose of 1,000nM for leptin and 100nM for adiponectin. Triiodothyronine stimulated or inhibited the expression of adipokines in adipocytes at different times and doses which may be useful to assist in the treatment of obesity, assuming that leptin is increased and adiponectin is decreased, in obesity cases. PMID:25993072

Triiodothyronine modulates the expression of leptin and adiponectin in 3T3-L1 adipocytes.

PubMed

Oliveira, Miriane de; de Síbio, Maria Teresa; Olimpio, Regiane Marques Castro; Moretto, Fernanda Cristina Fontes; Luvizotto, Renata de Azevedo Melo; Nogueira, Celia Regina

2015-01-01

To study the effect of different doses of triiodothyronine on gene expression of the adipokines leptin and adiponectin, at different times, and to evaluate the difference in expression between the two adipokines in each group. 3T3-L1 adipocytes were incubated with triiodothyronine at physiological dose (10nM) and supraphysiological doses (100nM or 1,000nM), or without triiodothyronine (control, C) for 0.5, 6, or 24 hours. Leptin and adiponectin mRNA was detected using real-time polymerase chain reaction (RT-PCR). One-way analyses of variance, Tukey's test or Student's t test, were used to analyze data, and significance level was set at 5%. Leptin levels decreased in the 1,000nM-dose group after 0.5 hour. Adiponectin levels dropped in the 10nM-dose group, but increased at the 100nM dose. After 6 hours, both genes were suppressed in all hormone concentrations. After 24 hours, leptin levels increased at 10, 100 and 1,000nM groups as compared to the control group; and adiponectin levels increased only in the 100nM group as compared to the control group. These results demonstrated fast actions of triiodothyronine on the leptin and adiponectin expression, starting at 0.5 hour, at a dose of 1,000nM for leptin and 100nM for adiponectin. Triiodothyronine stimulated or inhibited the expression of adipokines in adipocytes at different times and doses which may be useful to assist in the treatment of obesity, assuming that leptin is increased and adiponectin is decreased, in obesity cases.

AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

PubMed

Rangarajan, Savita; Walsh, Liron; Lester, Will; Perry, David; Madan, Bella; Laffan, Michael; Yu, Hua; Vettermann, Christian; Pierce, Glenn F; Wong, Wing Y; Pasi, K John

2017-12-28

Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected. The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with stabilization of hemostasis and a profound reduction in factor VIII use in all seven participants. In this small study, no safety events were noted, but no safety conclusions can be drawn. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795 ; EudraCT number, 2014-003880-38 .).

Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

PubMed Central

2011-01-01

Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p.) 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.). IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v.) prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical) given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA. PMID:22114930

Digoxin: placental transfer, effects on the fetus, and therapeutic use in the newborn.

PubMed

Soyka, L F

1975-03-01

Digoxin rapidly crosses the placenta and reaches equilibrium, with maternal and fetal sera having equal concentrations. Virtually nothing is known about the effects of transplacentally administered digoxin on the fetus. Toxicity has been reported in the fetus of a woman ingesting a huge overdose of digitoxin; the same result would be anticipated with digoxin poisoning. Serum levels in pregnant women receiving the standard dose of 0.25 mg tend to be subnormal and certain patients may require a small increase in dose during the last trimester. While the full-term neonate appears to tolerate relatively high doses and the resultant high serum levels, there is no compelling evidence that such doses are necessary or even useful. Since toxicity can and does occur in neonates, especially during administration of loading (digitalizing) doses, it is recommended that maintenance doses of 0.01 mg per kg per day be used routinely. If the full inotropic effect is needed immediately, a loading dose of 0.03 mg per kg may be employed. Maintenance therapy is then begun on the following day. Without a loading dose cumulation occurs for about 3 days; after 5 or so days, serum levels will equal those found after use of a loading dose followed by maintenance therapy. Results of a single study suggest that the daily dose should be divided and given every 12 hours. After about 1 week of therapy, the serum level should be determined and the dose modified to maintain a serum level of 1 to 2 ng per ml. If the therapeutic effect is less than desired, a cautions increase in dose to as high as 0.02 mg per kg per day or to that dose which produces serum levels up to 3 ng per ml can be tried. Certain infants appear to tolerate serum levels of 3.5 to 4 ng per ml but such infants must be closely monitored. There are no data which indicate that a greater inotropic response will occur at these high serum levels, though this point has not been definitively investigated, and is the highest priority question for research. The intramuscular route should be researved for the unusual situation. Vomiting should be considered an early sign of toxicity and may act as a "safety valve." When adminstered in solution (as in the elixir or solution for intravenous use), oral digoxin is rapidly absorbed an an inotropic response is found within minutes, reaching a peak within hours, so that little is gained by parenteral administration. If an inotropic effect is urgently needed, intravenous administration of ouabain will give an immediate response.

Rumen modulatory effect of thyme, clove and peppermint oils in vitro using buffalo rumen liquor.

PubMed

Roy, Debashis; Tomar, S K; Kumar, Vinod

2015-02-01

The present study was conducted to examine the rumen modulatory effect of thyme, clove and peppermint oils on rumen fermentation pattern in vitro using roughage based diet. Thyme, clove and peppermint oils were tested at concentration of 0, 30, 300 and 600 mg/l (ppm) of total culture fluid using in vitro gas production technique in wheat straw based diet (concentrate: Wheat straw 50:50). Different in vitro parameters e.g., total gas production, methane production, nutrient degradability, volatile fatty acid (VFA) production and ammonia nitrogen concentration were studied using buffalo rumen liquor. Thyme oil at higher dose level (600 ppm) reduced (p<0.05) total gas production, feed degradability and ammonia nitrogen (NH3-N) concentration whereas total VFA concentration was significantly lower (p>0.05) in 300 and 600 ppm dose levels. 600 ppm dose level of clove oil reduced (p<0.05) total gas production, feed degradability, total VFA and acetate to propionate ratio. Methane production was significantly reduced (p<0.05) in 300 and 600 ppm dose levels of clove and peppermint oil. Right combination of these essential oils may prove to enhance performance of animals by reducing methane production and inhibiting protein degradation in rumen.

The effect of intraoperative administration of dexamethasone for PONV prophylaxis on perioperative blood glucose level in obese and normal weight children.

PubMed

Gnatzy, Richard; Hempel, Gunther; Kaisers, Udo X; Höhne, Claudia

2015-11-01

The incidence of postoperative nausea and vomiting (PONV) can be reduced by dexamethasone. Single-dose administration may cause elevated blood glucose levels in obese adults. No data are available for children. The aim was to evaluate perioperative blood glucose changes related to body weight in children who received dexamethasone. This prospective observational study included 62 children. All patients received total intravenous anesthesia and a single dose of dexamethasone (0.15 mg/kg, maximum 8 mg). Blood glucose levels were measured up to 6 h. Standard deviation scores (SDS) were calculated using age- and gender-specific body mass index (BMI) percentiles, p<0.05. A total of 62 children (11.5±2.9 years, median SDS 0.43, 29% overweight/obese) were included. Blood glucose levels increased from 5.52±0.52 to 6.74±0.84 mmol/L 6 h after dexamethasone without correlation to the BMI-SDS. This study showed an increase of perioperative blood glucose (normoglycemic ranges) after single dose of dexamethasone, but no BMI-dependent effect was observed in children. Therefore, low-dose dexamethasone may be used in obese children for PONV prophylaxis.

Effects of Three Low-Doses of D-Tagatose on Glycemic Control Over Six Months in Subjects with Mild Type 2 Diabetes Mellitus Under Control with Diet and Exercise.

PubMed

Ensor, Mark; Williams, Jarrod; Smith, Rebecca; Banfield, Amy; Lodder, Robert A

2014-10-01

The primary objective of this study was to evaluate the safety and the effect of D-tagatose on the glycemic control of subjects with type 2 diabetes as determined by HbA 1c levels at the end of 6 months of therapy using the subject's own baseline HbA 1c level as a comparator. The determination of the minimal dose required to cause a statistically significant reduction in HbA 1c was of particular interest. Eight weeks after screening, the qualifying subjects were randomized to receive one of three doses of D-tagatose: 2.5 g TID, 5.0 g TID or 7.5 g TID. Blood levels of HbA 1c , fasting blood glucose concentrations, plasma lipids, changes in body weight, changes in body mass index, and change in insulin levels were checked at each study visit and at the end of the study. Treatment success, as measured by the reduction of HbA 1c , was greatest for the 7.5 g D-tagatose dose group, although the difference between the treatments was not statistically significant. For fasting glucose, only the 7.5 g dosage group exhibited reductions from baseline at the 3- and 6-month time points. Mean body weights reduced in a dose-response fashion, with the 5.0 g and the 7.5 g D-tagatose doses providing the greatest reductions. D-tagatose at dosages of 2.5 g, 5.0 g, and 7.5 g TID for six months were well tolerated by this subject population. D-tagatose at 5.0 g TID was the minimal dose required to reduce HbA 1c . D-tagatose at 7.5 g TID provided the greatest effect in most measured efficacy parameters.

Effects of Three Low-Doses of D-Tagatose on Glycemic Control Over Six Months in Subjects with Mild Type 2 Diabetes Mellitus Under Control with Diet and Exercise

PubMed Central

Ensor, Mark; Williams, Jarrod; Smith, Rebecca; Banfield, Amy; Lodder, Robert A.

2014-01-01

The primary objective of this study was to evaluate the safety and the effect of D-tagatose on the glycemic control of subjects with type 2 diabetes as determined by HbA1c levels at the end of 6 months of therapy using the subject’s own baseline HbA1c level as a comparator. The determination of the minimal dose required to cause a statistically significant reduction in HbA1c was of particular interest. Eight weeks after screening, the qualifying subjects were randomized to receive one of three doses of D-tagatose: 2.5 g TID, 5.0 g TID or 7.5 g TID. Blood levels of HbA1c, fasting blood glucose concentrations, plasma lipids, changes in body weight, changes in body mass index, and change in insulin levels were checked at each study visit and at the end of the study. Treatment success, as measured by the reduction of HbA1c, was greatest for the 7.5 g D-tagatose dose group, although the difference between the treatments was not statistically significant. For fasting glucose, only the 7.5 g dosage group exhibited reductions from baseline at the 3- and 6-month time points. Mean body weights reduced in a dose-response fashion, with the 5.0 g and the 7.5 g D-tagatose doses providing the greatest reductions. D-tagatose at dosages of 2.5 g, 5.0 g, and 7.5 g TID for six months were well tolerated by this subject population. D-tagatose at 5.0 g TID was the minimal dose required to reduce HbA1c. D-tagatose at 7.5 g TID provided the greatest effect in most measured efficacy parameters. PMID:25580449

The effect of grape seed extract on estrogen levels of postmenopausal women: a pilot study.

PubMed

Wahner-Roedler, Dietlind L; Bauer, Brent A; Loehrer, Laura L; Cha, Stephen S; Hoskin, Tanya L; Olson, Janet E

2014-06-01

The role of estrogens in breast cancer (BC) development is widely accepted, leading to the development of selective estrogen receptor modulators and aromatase inhibitors for BC treatment and prevention. However, because of potential adverse effects, healthy women with high risk of BC are hesitant to take them. Preliminary evidence from animal studies shows that grapes may have an aromatase-inhibiting effect, decreasing estrogen synthesis and increasing androgen precursors. We conducted a randomized, double-blind, dose-finding early-phase trial on the effect of grape seed extract (GSE) on estrogen levels. Postmenopausal women who met study inclusion criteria (N = 46) were randomly assigned to daily GSE at a dose of 200, 400, 600, or 800 mg for 12 weeks. Primary outcome was change in plasma levels of estrogen conjugates from baseline to 12 weeks posttreatment. Thirty-nine participants (84.8%) completed the study. GSE in the 4 daily doses did not significantly decrease estrogen or increase androgen precursors.

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

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.

First month prednisone dose predicts prednisone burden during the following 11 months: an observational study from the RELES cohort

PubMed Central

Ruiz-Irastorza, G; Garcia, M; Espinosa, G; Caminal, L; Mitjavila, F; González-León, R; Sopeña, B; Canora, J; Villalba, M V; Rodríguez-Carballeira, M; López-Dupla, J M; Callejas, J L; Castro, A; Tolosa, C; Sánchez-García, M E; Pérez-Conesa, M; Navarrete-Navarrete, N; Rodríguez, A P; Herranz, M T; Pallarés, L

2016-01-01

Aim To study the influence of prednisone dose during the first month after systemic lupus erythematosus (SLE) diagnosis (prednisone-1) on glucocorticoid burden during the subsequent 11 months (prednisone-2–12). Methods 223 patients from the Registro Español de Lupus Eritematoso Sistémico inception cohort were studied. The cumulative dose of prednisone-1 and prednisone-2–12 were calculated and recoded into a four-level categorical variable: no prednisone, low dose (up to 7.5 mg/day), medium dose (up to 30 mg/day) and high dose (over 30 mg/day). The association between the cumulative prednisone-1 and prednisone-2–12 doses was tested. We analysed whether the four-level prednisone-1 categorical variable was an independent predictor of an average dose >7.5 mg/day of prednisone-2–12. Adjusting variables included age, immunosuppressives, antimalarials, methyl-prednisolone pulses, lupus nephritis and baseline SLE Disease Activity Index (SLEDAI). Results Within the first month, 113 patients (51%) did not receive any prednisone, 24 patients (11%) received average low doses, 46 patients (21%) received medium doses and 40 patients (18%) received high doses. There was a strong association between prednisone-1 and prednisone-2–12 dose categories (p<0.001). The cumulative prednisone-1 dose was directly associated with the cumulative prednisone-2–12 dose (p<0.001). Compared with patients on no prednisone, patients taking medium (adjusted OR 5.27, 95% CI 2.18 to 12.73) or high-dose prednisone-1 (adjusted OR 10.5, 95% CI 3.8 to 29.17) were more likely to receive prednisone-2–12 doses of >7.5 mg/day, while patients receiving low-dose prednisone-1 were not (adjusted OR 1.4, 95% CI 0. 0.38 to 5.2). If the analysis was restricted to the 158 patients with a baseline SLEDAI of ≥6, the model did not change. Conclusion The dose of prednisone during the first month after the diagnosis of SLE is an independent predictor of prednisone burden during the following 11 months. PMID:27547439

Effect of GABA on oxidative stress in the skeletal muscles and plasma free amino acids in mice fed high-fat diet.

PubMed

Xie, Z X; Xia, S F; Qiao, Y; Shi, Y H; Le, G W

2015-06-01

Increased levels of plasma free amino acids (pFAAs) can disturb the blood glucose levels in patients with obesity, diabetes mellitus and metabolic syndrome (MS) and are associated with enhanced protein oxidation. Oxidation of proteins, especially in the muscles, can promote protein degradation and elevate the levels of pFAAs. Gamma-aminobutyric acid (GABA), a food additive, can reduce high-fat diet (HFD)-induced hyperglycaemia; however, the mechanisms remain unclear. The aim of this study was to evaluate the effects of GABA on protein oxidation and pFAAs changes. One hundred male C57BL/6 mice were randomly divided into five groups that were fed with control diet, HFD and HFD supplied with 0.2%, 0.12% and 0.06% GABA in drinking water for 20 weeks respectively. HFD feeding led to muscular oxidative stress, protein oxidation, pFAA disorders, hyperglycaemia and augmented plasma GABA levels. Treatment with GABA restored normally fasting blood glucose level and dose-dependently inhibited body weight gains, muscular oxidation and protein degradation. While medium and low doses of GABA mitigated HFD-induced pFAA disorders, the high dose of GABA deteriorated the pFAA disorders. Medium dose of GABA increased the levels of GABA, but high dose of GABA reduced the levels of plasma GABA and increased the activity of succinic semialdehyde dehydrogenase in the liver. Therefore, treatment with GABA mitigated HFD-induced hyperglycaemia probably by repairing HFD-induced muscular oxidative stress and pFAA disorders in mice. Our data also suggest that an optimal dose of GABA is crucial for the prevention of excess GABA-related decrease in the levels of pFAA and GABA as well as obesity. Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH.

RhBMP-2-induced radiculitis in patients undergoing transforaminal lumbar interbody fusion: relationship to dose.

PubMed

Villavicencio, Alan T; Burneikiene, Sigita

2016-10-01

Recombinant human bone morphogenetic protein-2 (rhBMP-2) remains the primary synthetic osteoinductive material used in spinal fusion surgery today. The early inflammation reaction to rhBMP-2 manifesting with radicular symptoms has been previously reported in patients undergoing transforaminal lumbar interbody fusion (TLIF). There is a disagreement with regard to the factors affecting its occurrence and whether such symptoms are dose dependent. The purpose of this analysis was to determine the incidence of rhBMP-2-induced radiculitis and its relationship to dose. A retrospective cohort analysis was performed of the prospectively collected data. All consecutive patients (n=204) who underwent one- or two-level TLIF and instrumented posterolateral fusion with an off-label rhBMP-2 use were included in this analysis. The patients who developed new radicular symptoms after initial improvement postoperatively and had sterile fluid collections indicative of inflammatory process, or in the absence of any structural abnormalities that would explain these symptoms on imaging studies, were deemed to have rhBMP-2-induced radiculitis. Magnetic resonance imaging (MRI) scans were obtained for all patients who developed postoperative radicular symptoms. Correlations between the total rhBMP-2 dose, dose per spinal level, and incidence of radiculitis were evaluated while controlling for age, sex, number of TLIF levels, and surgeon. The incidence of postoperative radiculitis was 11.3% (23 out of 204). The average total rhBMP-2 dose was 4.9 mg (range=2.1-12) and the average dose per spinal level was 3.8 mg (range=1.05-12). Logistic regression analysis did not identify any significant correlations between the rhBMP-2 doses and the incidence of radiculitis (p=.6). The incidence of rhBMP-2-induced radiculitis in patients undergoing TLIF is quite high, but there were no dose-related correlations found. The study, however, cannot rule out a possibility that a larger variation in bone morphogenetic protein (BMP) doses could still be a factor in the development of rhBMP-2-associated radiculitis. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of 3-methylcholanthrene-induced increases in ascorbic acid levels on tissue. beta. -glucuronidase activity in rats

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

Calabrese, E.J.; Barrett, T.J.; Leonard, D.A.

1988-01-01

The interrelationship between tissue ascorbic acid levels and tissue ..beta..-glucuronidase activity was examined in rats injected with 3-methylcholanthrene, an agent which induces ascorbic acid synthesis in rats. Six Fisher 344 rats were dosed intraperitoneally (IP) with 30 mg/kg of 3-methylcholanthrene. Ascorbic acid levels and ..beta..-glucuronidase (..beta..-G) activity were determined for lung, liver and kidney tissues. In a follow-up study, rats were dosed for three consecutive days with 3-methylcholanthrene. Controls in both groups were dosed IP with Emulphor (EL-620). Animals were sacrificed one week after the final dosage and lung, liver and kidney tissues were examined.

Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study.

PubMed

Schulz, Craig A; Mehta, Minesh P; Badie, Benham; McGinn, Cornelius J; Robins, H Ian; Hayes, Lori; Chappell, Rick; Volkman, Jen; Binger, Kim; Arzoomanian, Rhoda; Simon, Kris; Alberti, Dona; Feierabend, Christine; Tutsch, Kendra D; Kunugi, Keith A; Wilding, George; Kinsella, Timothy J

2004-07-15

To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma. Patients were required to have biopsy-proven malignant glioma. Patients received 100 (n = 4), 200 (n = 3), 300 (n = 3), 400 (n = 6), 500 (n = 4), 625 (n = 5), or 781 (n = 6) mg/m(2)/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost [2.0 Gy for 5 Saturdays]). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used. Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (n = 3), thrombocytopenia (n = 3), and elevated liver function studies (n = 3). The maximal tolerated dose was 625 mg/m(2)/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 microM). In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m(2)/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.

Oral hypoglycemic activity of culinary-medicinal mushrooms Pleurotus ostreatus and P. cystidiosus (higher basidiomycetes) in normal and alloxan-induced diabetic Wistar rats.

PubMed

Jayasuriya, W J A B; Suresh, T S; Abeytunga, D; Fernando, G H; Wanigatunga, C A

2012-01-01

This study investigates the oral hypoglycemic activity of Pleurotus ostreatus (P.o.) and P. cystidiosus (P.c.) mushrooms on normal and alloxan-induced diabetic Wistar rats. Different doses (250, 500, 750, 1000, and 1250 mg/kg/body weight) of suspensions of freeze-dried and powdered (SFDP) P.o. and P.c. were administered to normal rats, and postprandial serum glucose levels were measured. Optimal time of activity was investigated using the dose 500 mg/kg. Hypoglycemic effect of a single dose of SFDP P.o. and P.c. (500 mg/kg) were investigated using diabetic male and female rats at different stages of estrous cycle and compared with metformin and glibenclamide. Chronic hypoglycemic activity of SFDP P.o. and P.c. (500 mg/kg) was studied using serum glucose levels and glycosylated hemoglobin levels. Maximally effective dose of SFDP P.o. and P.c. was 500 mg/kg. The highest reduction in the serum glucose level was observed 120 minutes after administration of mushrooms. A single dose of P.o. and P.c. significantly (P < 0.05) reduced the serum glucose levels of male diabetic rats. The hypoglycemic activity in female rats was highest in proestrous stage. The hypoglycemic effect of P.o. and P.c. is comparable with metformin and glibenclamide. Daily single administrations of P.o. and P.c. to diabetic rats exert apparent control on the homeostasis of blood glucose. SFDP P.o. and P.c. possessed marked and significant oral hypoglycemic activity. This study suggests the consumption of P.o. and P.c. mushrooms might bring health benefits to mankind as it shows hypoglycemic activity in rats.

Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support.

PubMed

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.

A dose-up of ursodeoxycholic acid decreases transaminases in hepatitis C patients

PubMed Central

Sato, Shuichi; Miyake, Tatsuya; Tobita, Hiroshi; Oshima, Naoki; Ishine, Junichi; Hanaoka, Takuya; Amano, Yuji; Kinoshita, Yoshikazu

2009-01-01

AIM: To examine whether a dose-up to 900 mg of ursodeoxycholic acid (UDCA) decreases transaminases in hepatitis C patients. METHODS: From January to December 2007, patients with chronic hepatitis C or compensated liver cirrhosis with hepatitis C virus (HCV) (43-80 years old) showing positive serum HCV-RNA who had already taken 600 mg/d of UDCA were recruited into this study. Blood parameters were examined at 4, 8 and 24 wk after increasing the dose of oral UDCA from 600 to 900 mg/d. RESULTS: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) levels were significantly decreased following the administration of 900 mg/d as compared to 600 mg/d. The decrease in ALT from immediately before the dose-up of UDCA to 8 wk after the dose-up was 14.3 IU/L, while that for AST was 10.5 IU/L and for GGT was 9.8 IU/L. Platelet count tended to increase after the dose-up of UDCA, although it did not show a statistically significant level (P = 0.05). Minor adverse events were observed in 3 cases, although no drop-outs from the study occurred. CONCLUSION: Oral administration of 900 mg/d of UDCA was more effective than 600 mg/d for reducing ALT, AST, and GGT levels in patients with HCV-related chronic liver disease. PMID:19522030

Boosting effect of a second dose of measles vaccine given to 12-year-old children.

PubMed

Böttiger, M

1993-01-01

In Sweden, a two-dose programme of vaccination against measles, mumps and rubella (MMR) was introduced in 1982 and the target groups were children aged 18 months and 12 years. In 1993 the first age group of 12-year-olds that were vaccinated with MMR at 18 months will appear. The majority of the 12-year-old vaccines for many years, however, had already been vaccinated against measles and the MMR measles component was thus a booster dose. As the benefit of a booster dose against measles has been questioned, this was studied in a group of 163 12-year-old children, 122 of whom had been vaccinated against measles as young children. Of the 41 unvaccinated children, 23 had a history of clinical measles. The mean neutralizing titre level of the earlier vaccinated children, prior to the booster, was lower than that of the naturally immune children (reciprocal titre level 8 versus 20). After the booster the corresponding titre levels were 13 and 23. Among the seronegative children receiving their first dose, this figure amounted to 14. A moderate rise in titre was seen in those with low prevaccination titres. As the antibody protection afforded by vaccination was slightly lower than that of natural infection, even after a booster, follow-up studies must be recommended to evaluate the long-term protection of both a single and a two-dose programme.

Low-dose testosterone alleviates vascular damage caused by castration in male rats in puberty via modulation of the PI3K/AKT signaling pathway.

PubMed

Zhao, Jing; Liu, Ge-Li; Wei, Ying; Jiang, Li-Hong; Bao, Peng-Li; Yang, Qing-Yan

2016-09-01

The aim of the present study was to investigate the effect of testosterone on glucolipid metabolism and vascular injury in male rats, and examine the underlying molecular mechanisms. A total of 40 male Sprague-Dawley rats were divided into a control group (n=10), high-fat-diet + castration group (n=10), high‑fat‑diet + castration + low dose testosterone group (n=10), and high-fat-diet + castration + high dose testosterone group (n=10). Hematoxylin and eosin staining was performed to evaluate the morphology of the thoracic aortic tissues. Immunohistochemical staining was used to detect biomarkers of the phosphoinositide 3‑kinase (PI3K) signaling pathway. The mRNA and protein expression levels of PI3K, AKT, insulin receptor substrate‑1 (IRS‑1), glucose transporter type 4 (GLUT‑4), nuclear factor (NF)‑κB and tumor necrosis factor (TNF)‑α in the aortas were determined using quantitative polymerase chain reaction and Western blot analyses, respectively. Apoptosis in the aortic tissues was detected using a TUNEL assay. Castration induced apoptosis in the animals fed a high‑fat‑diet, whereas low dose testosterone replacement ameliorated the apoptosis in the aorta. However, the levels of apoptosis was more severe following high‑dose testosterone treatment. Low‑dose testosterone induced upregulation in the levels of IRS‑1, AKT, GLUT‑4 protein, NF‑κB, TNF‑α and PI3K, compared with those in the animals fed a high‑fat diet following castration. A high dose of testosterone resulted in a significant decrease in the levels of IRS‑1, AKT, GLUT‑4, NF‑κB, TNF‑α and PI3K. Compared with the rats in the high‑fat diet + castration group, a low dose of testosterone induced upregulation in the mRNA levels of IRS‑1, AKT and GLUT‑4, and downregulation of the mRNA levels of NF‑κB, TNF‑α and PI3K. A high dose of testosterone resulted in a significant decrease in the levels of IRS‑1, AKT and GLUT‑4, and marked increases in the mRNA levels of NF‑κB, TNF‑α and PI3K, compared with the low dose group. Castration induced marked disorders of glucolipid metabolism and vascular injuries in the pubescent male rats. Low‑dose testosterone treatment was found to ameliorate the vascular damage caused by castration via the PI3K/AKT signaling pathway.

Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia.

PubMed

Akdim, Fatima; Tribble, Diane L; Flaim, JoAnn D; Yu, Rosie; Su, John; Geary, Richard S; Baker, Brenda F; Fuhr, Rainard; Wedel, Mark K; Kastelein, John J P

2011-11-01

Mipomersen, an apolipoprotein (apo) B synthesis inhibitor, has been shown to produce potent reductions in apoB and LDL-cholesterol levels in animal models as well as healthy human volunteers. A randomized, double-blind, placebo-controlled, dose-escalation study was designed to evaluate the efficacy and safety of mipomersen monotherapy with or without dose loading in subjects with mild-to-moderate hyperlipidaemia. Fifty subjects with LDL-cholesterol levels between 119 and 266 mg/dL were enrolled into five cohorts at a 4:1 randomization ratio of active to placebo. Two 13-week dose regimens were evaluated at doses ranging from 50 to 400 mg/week. Mipomersen produced dose-dependent reductions in all apoB containing lipoproteins. In the 200 and 300 mg/week dose cohorts, mean reductions from baseline in LDL cholesterol were -45 ± 10% (P= 0.000) and -61 ± 8% (P= 0.000), corresponding to a -46 ± 11% (P= 0.000) and -61 ± 7% (P= 0.000) decrease in apoB levels. Triglyceride levels were also lowered with median reductions up to 53% (P= 0.021). The most common adverse events were injection site reactions. Seven of 40 subjects (18%) showed consecutive transaminase elevations >3× upper limit of normal. Five of these subjects received 400 mg/week, four of whom had apoB levels below the limit of detection. As a consequence, the 400 mg/week cohort was discontinued. Mipomersen administered as monotherapy in subjects with mild-to-moderate hyperlipidaemia produced potent reductions in all apoB-containing lipoproteins. Higher doses were associated with hepatic transaminase increases.

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

PubMed

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

2017-04-13

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

Low-dose factor VIII infusion in Chinese adult haemophilia A patients: pharmacokinetics evidence that daily infusion results in higher trough level than with every-other-day infusion with similar factor VIII consumption.

PubMed

Hua, B; Lee, A; Fan, L; Li, K; Zhang, Y; Poon, M-C; Zhao, Y

2017-05-01

Pharmacokinetics (PK) modelling suggests improvement of trough levels are achieved by using more frequent infusion strategy. However, no clinical study data exists to confirm or quantify improvement in trough level, particularly for low-dose prophylaxis in patients with haemophilia A. To provide evidence that low dose daily (ED) prophylaxis can increase trough levels without increasing FVIII consumption compared to every-other-day (EOD) infusion. A cross-over study on 5 IU kg -1 FVIII daily vs. 10 IU kg -1 EOD infusions, each for 14 days was conducted at the PUMCH-HTC. On the ED schedule, trough (immediate prior to infusion), and peak FVIII:C levels (30 min after infusion) were measured on days 1-5; and trough levels alone on days 7, 9, 11 and 13. For the EOD schedule, troughs, peaks and 4-h postinfusion were measured on day 1; troughs and peaks on days 3, 5, and 7; troughs alone on days 9, 11 and 13 and 24-h postinfusion on days 2, 4 and 6. FVIII inhibitors were assessed on days 0 and 14 during both infusion schedules. Six patients were enrolled. PK evidence showed that daily prophylaxis achieved higher (~2 times) steady-state FVIII trough levels compared to EOD with the same total factor consumption. The daily prophylaxis had good acceptability among patients and reduced chronic pain in the joints in some patients. Our PK study shows low-dose factor VIII daily infusion results in higher trough level than with EOD infusion with similar factor VIII consumption in Chinese adult haemophilia A patients. © 2017 John Wiley & Sons Ltd.

A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients.

PubMed

Davis, Gary L; Nelson, David R; Terrault, Norah; Pruett, Timothy L; Schiano, Thomas D; Fletcher, Courtney V; Sapan, Christine V; Riser, Laura N; Li, Yufeng; Whitley, Richard J; Gnann, John W

2005-08-01

Chronic hepatitis C is the most common indication for liver transplantation, but viral recurrence is universal and progressive graft injury occurs in most recipients. Our aim was to assess the safety, pharmacokinetics (PK), and antiviral effects of high doses of a human hepatitis C antibody enriched immune globulin product (HCIG) in patients undergoing liver transplantation for chronic hepatitis C. This was a multicenter, randomized, open-label, controlled trial conducted at 4 transplant centers in the United States. A total of 18 patients with chronic hepatitis C, who underwent liver transplantation, were randomized to receive low-dose HCIG (75 mg/kg) or high-dose HCIG (200 mg/kg), or no treatment. A total of 17 infusions of HCIG were administered in each treated patient over 14 weeks using a time-dependent dosing strategy based on the PK of anti-hepatitis B immune globulin in liver transplant recipients. Hepatitis C virus levels, liver enzymes, and liver biopsies were obtained serially throughout the study period. PK profiles of HCV antibodies were determined on days 4, 10, and 98. HCIG infusions were safe and tolerated. The infusion rate could not be maximized because of symptoms for 18% to 30% of the doses. The half-life of HCIG was extremely short immediately after transplantation but was gradually prolonged. In the high-dose group, serum alanine aminotransferase (ALT) levels normalized in most subjects and no patient developed hepatic fibrosis. However, serum HCV RNA levels were not suppressed at either dose. In conclusion, HCIG, an anti-HCV enriched immune globulin product, appears to be safe in patients with chronic hepatitis C undergoing liver transplantation. Further studies are required to determine whether the drug has beneficial effects in this group of patients.

A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations.

PubMed

Fiedler, Walter; Kayser, Sabine; Kebenko, Maxim; Janning, Melanie; Krauter, Jürgen; Schittenhelm, Marcus; Götze, Katharina; Weber, Daniela; Göhring, Gudrun; Teleanu, Veronica; Thol, Felicitas; Heuser, Michael; Döhner, Konstanze; Ganser, Arnold; Döhner, Hartmut; Schlenk, Richard F

2015-06-01

Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara-C)/daunorubicin induction (7+3) followed by three cycles of intermediate-dose Ara-C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose-limiting toxicity (DLT), prolonged haemotoxicity and hand-foot syndrome. At dose level -1, sunitinib 25 mg was restricted to days 1-7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3-internal tandem duplication and 5/8 with FLT3-tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse-free and event-free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild-type subclones. © 2015 John Wiley & Sons Ltd.

Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.

PubMed

Maráz, Anikó; Cserháti, Adrienn; Uhercsák, Gabriella; Szilágyi, Éva; Varga, Zoltán; Révész, János; Kószó, Renáta; Varga, Linda; Kahán, Zsuzsanna

2018-03-15

In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.

A pilot study: dose adaptation of capecitabine using mobile phone toxicity monitoring - supporting patients in their homes.

PubMed

Weaver, Andrew; Love, Sharon B; Larsen, Mark; Shanyinde, Milensu; Waters, Rachel; Grainger, Lisa; Shearwood, Vanessa; Brooks, Claire; Gibson, Oliver; Young, Annie M; Tarassenko, Lionel

2014-10-01

Real-time symptom monitoring using a mobile phone is potentially advantageous for patients receiving oral chemotherapy. We therefore conducted a pilot study of patient dose adaptation using mobile phone monitoring of specific symptoms to investigate relative dose intensity of capecitabine, level of toxicity and perceived supportive care. Patients with breast or colorectal cancer receiving capecitabine completed a symptom, temperature and dose diary twice a day using a mobile phone application. This information was encrypted and automatically transmitted in real time to a secure server, with moderate levels of toxicity automatically prompting self-care symptom management messages on the screen of the patient's mobile phone or in severe cases, a call from a specialist nurse to advise on care according to an agreed protocol. Patients (n = 26) completed the mobile phone diary on 92.6 % of occasions. Twelve patients had a maximum toxicity grade of 3 (46.2 %). The average dose intensity for all patients as a percentage of standard dose was 90 %. In eight patients, the dose of capecitabine was reduced, and in eight patients, the dose of capecitabine was increased. Patients and healthcare professionals involved felt reassured by the novel monitoring system, in particular, during out of hours. It is possible to optimise the individual dose of oral chemotherapy safely including dose increase and to manage chemotherapy side effects effectively using real-time mobile phone monitoring of toxicity parameters entered by the patient.

Association between water fluoride and the level of children's intelligence: a dose-response meta-analysis.

PubMed

Duan, Q; Jiao, J; Chen, X; Wang, X

2018-01-01

Higher fluoride concentrations in water have inconsistently been associated with the levels of intelligence in children. The following study summarizes the available evidence regarding the strength of association between fluoridated water and children's intelligence. Meta-analysis. PubMed, Embase, and Cochrane Library databases were systematically analyzed from November 2016. Observational studies that have reported on intelligence levels in relation to high and low water fluoride contents, with 95% confidence intervals (CIs) were included. Further, the results were pooled using inverse variance methods. The correlation between water fluoride concentration and intelligence level was assessed by a dose-response meta-analysis. Twenty-six studies reporting data on 7258 children were included. The summary results indicated that high water fluoride exposure was associated with lower intelligence levels (standardized mean difference : -0.52; 95% CI: -0.62 to -0.42; P < 0.001). The findings from subgroup analyses were consistent with those from overall analysis. The dose-response meta-analysis suggested a significant association between water fluoride dosage and intelligence (P < 0.001), while increased water fluoride exposure was associated with reduced intelligence levels. Greater exposure to high levels of fluoride in water was significantly associated with reduced levels of intelligence in children. Therefore, water quality and exposure to fluoride in water should be controlled in areas with high fluoride levels in water. Copyright © 2017. Published by Elsevier Ltd.

Survey of computed tomography scanners in Taiwan: Dose descriptors, dose guidance levels, and effective doses

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

Tsai, H. Y.; Tung, C. J.; Yu, C. C.

2007-04-15

The IAEA and the ICRP recommended dose guidance levels for the most frequent computed tomography (CT) examinations to promote strategies for the optimization of radiation dose to CT patients. A national survey, including on-site measurements and questionnaires, was conducted in Taiwan in order to establish dose guidance levels and evaluate effective doses for CT. The beam quality and output and the phantom doses were measured for nine representative CT scanners. Questionnaire forms were completed by respondents from facilities of 146 CT scanners out of 285 total scanners. Information on patient, procedure, scanner, and technique for the head and body examinationsmore » was provided. The weighted computed tomography dose index (CTDI{sub w}), the dose length product (DLP), organ doses and effective dose were calculated using measured data, questionnaire information and Monte Carlo simulation results. A cost-effective analysis was applied to derive the dose guidance levels on CTDI{sub w} and DLP for several CT examinations. The mean effective dose{+-}standard deviation distributes from 1.6{+-}0.9 mSv for the routine head examination to 13{+-}11 mSv for the examination of liver, spleen, and pancreas. The surveyed results and the dose guidance levels were provided to the national authorities to develop quality control standards and protocols for CT examinations.« less

Dose and Fractionation in Radiation Therapy of Curative Intent for Non-Small Cell Lung Cancer: Meta-Analysis of Randomized Trials

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

Ramroth, Johanna; Cutter, David J.; Darby, Sarah C.

Purpose: The optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy. Methods and Materials: Eligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled. Results: 3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, highermore » versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2). Conclusions: In trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no upper dose level was found above which there was no further benefit. These findings support the consideration of further radiation therapy dose escalation trials, making use of modern treatment methods to reduce toxicity.« less

Protocol for a multicentred randomised controlled trial investigating the use of personalised golimumab dosing tailored to inflammatory load in ulcerative colitis: the GOAL-ARC study (GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis) led by the INITIAtive group (NCT 0268772)

PubMed Central

Sheridan, Juliette; Coe, Carol Ann; Doran, Peter; Egan, Laurence; Cullen, Garret; Kevans, David; Leyden, Jan; Galligan, Marie; O’Toole, Aoibhlinn; McCarthy, Jane; Doherty, Glen

2018-01-01

Introduction Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), often leading to an impaired quality of life in affected patients. Current treatment modalities include antitumour necrosis factor (anti-TNF) monoclonal antibodies (mABs) including infliximab, adalimumab and golimumab (GLM). Several recent retrospective and prospective studies have demonstrated that fixed dosing schedules of anti-TNF agents often fails to consistently achieve adequate circulating therapeutic drug levels (DL) with consequent risk of immunogenicity treatment failure and potential risk of hospitalisation and colectomy in patients with UC. The design of GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis aims to address the impact of dose escalation of GLM immediately following induction and during the subsequent maintenance phase in response to suboptimal DL or persisting inflammatory burden as represented by raised faecal calprotectin (FCP). Aim The primary aim of the study is to ascertain if monitoring of FCP and DL of GLM to guide dose optimisation (during maintenance) improves rates of patient continuous clinical response and reduces disease activity in UC. Methods and analysis A randomised, multicentred two-arm trial studying the effect of dose optimisation of GLM based on FCP and DL versus treatment as per SMPC. Eligible patients will be randomised in a 1:1 ratio to 1 of 2 treatment groups and shall be treated over a period of 46 weeks. Ethics and dissemination The study protocol was approved by the Research Ethics committee of St. Vincent’s University Hospital. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. Trial registration numbers EudraCT number: 2015-004724-62; Clinicaltrials.gov Identifier: NCT0268772; Pre-results. PMID:29379609

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

Folate intake, serum folate levels and esophageal cancer risk: an overall and dose-response meta-analysis.

PubMed

Zhao, Yan; Guo, Chenyang; Hu, Hongtao; Zheng, Lin; Ma, Junli; Jiang, Li; Zhao, Erjiang; Li, Hailiang

2017-02-07

Previously reported findings on the association between folate intake or serum folate levels and esophageal cancer risk have been inconsistent. This study aims to summarize the evidence regarding these relationships using a dose-response meta-analysis approach. We performed electronic searches of the Pubmed, Medline and Cochrane Library electronic databases to identify studies examining the effect of folate on the risk of esophageal cancer. Ultimately, 19 studies were included in the meta-analysis. Summary odds ratios (ORs) were estimated using a random effects model. A linear regression analysis of the natural logarithm of the OR was carried out to assess the possible dose-response relationship between folate intake and esophageal cancer risk. The pooled ORs for esophageal cancer in the highest vs. lowest levels of dietary folate intake and serum folate were 0.63 (95% CI: 0.56-0.71) and 0.71 (95% CI: 0.55-0.92), respectively. The dose-response meta-analysis indicated that a 100 μg/day increment in dietary folate intake reduced the estimate risk of esophageal cancer by 12%. These findings suggest that dietary and serum folate exert a protective effect against esophageal carcinogenesis.

A random walk rule for phase I clinical trials.

PubMed

Durham, S D; Flournoy, N; Rosenberger, W F

1997-06-01

We describe a family of random walk rules for the sequential allocation of dose levels to patients in a dose-response study, or phase I clinical trial. Patients are sequentially assigned the next higher, same, or next lower dose level according to some probability distribution, which may be determined by ethical considerations as well as the patient's response. It is shown that one can choose these probabilities in order to center dose level assignments unimodally around any target quantile of interest. Estimation of the quantile is discussed; the maximum likelihood estimator and its variance are derived under a two-parameter logistic distribution, and the maximum likelihood estimator is compared with other nonparametric estimators. Random walk rules have clear advantages: they are simple to implement, and finite and asymptotic distribution theory is completely worked out. For a specific random walk rule, we compute finite and asymptotic properties and give examples of its use in planning studies. Having the finite distribution theory available and tractable obviates the need for elaborate simulation studies to analyze the properties of the design. The small sample properties of our rule, as determined by exact theory, compare favorably to those of the continual reassessment method, determined by simulation.

Effects of Aroclor 1254 reg sign on hydrocortisone levels in adult Rhesus monkeys (Macaca mulatta)

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

Loo, J.C.K.; Tryphonas, H.; Jordan, N.

Researchers, using female Sprague Dawley rats, reported the effects of chronic (5-7 months) oral dosing with Aroclor 1254{reg sign} (Polychlorinated biphenyls-PCB) on the serum levels of corticosterone, the principle glucocorticoid in rats. Their findings indicated that corticosterone levels were significantly depressed at dose levels of 479 {mu}g/kg bw/day and above. The objective of the present study was to determine the effects of PCB on the hydrocortisone levels in Rhesus monkey (Macaca mulatta) serum. In the monkey the controlling hormone is hydrocortisone which is identical to that of humans.

TU-G-204-09: The Effects of Reduced- Dose Lung Cancer Screening CT On Lung Nodule Detection Using a CAD Algorithm

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

Young, S; Lo, P; Kim, G

2015-06-15

Purpose: While Lung Cancer Screening CT is being performed at low doses, the purpose of this study was to investigate the effects of further reducing dose on the performance of a CAD nodule-detection algorithm. Methods: We selected 50 cases from our local database of National Lung Screening Trial (NLST) patients for which we had both the image series and the raw CT data from the original scans. All scans were acquired with fixed mAs (25 for standard-sized patients, 40 for large patients) on a 64-slice scanner (Sensation 64, Siemens Healthcare). All images were reconstructed with 1-mm slice thickness, B50 kernel.more » 10 of the cases had at least one nodule reported on the NLST reader forms. Based on a previously-published technique, we added noise to the raw data to simulate reduced-dose versions of each case at 50% and 25% of the original NLST dose (i.e. approximately 1.0 and 0.5 mGy CTDIvol). For each case at each dose level, the CAD detection algorithm was run and nodules greater than 4 mm in diameter were reported. These CAD results were compared to “truth”, defined as the approximate nodule centroids from the NLST reports. Subject-level mean sensitivities and false-positive rates were calculated for each dose level. Results: The mean sensitivities of the CAD algorithm were 35% at the original dose, 20% at 50% dose, and 42.5% at 25% dose. The false-positive rates, in decreasing-dose order, were 3.7, 2.9, and 10 per case. In certain cases, particularly in larger patients, there were severe photon-starvation artifacts, especially in the apical region due to the high-attenuating shoulders. Conclusion: The detection task was challenging for the CAD algorithm at all dose levels, including the original NLST dose. However, the false-positive rate at 25% dose approximately tripled, suggesting a loss of CAD robustness somewhere between 0.5 and 1.0 mGy. NCI grant U01 CA181156 (Quantitative Imaging Network); Tobacco Related Disease Research Project grant 22RT-0131.« less

Clinical Experience and Evaluation of Patient Treatment Verification With a Transit Dosimeter

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

Ricketts, Kate, E-mail: k.ricketts@ucl.ac.uk; Department of Radiotherapy Physics, Royal Berkshire NHS Foundation Trust, Reading; Navarro, Clara

2016-08-01

Purpose: To prospectively evaluate a protocol for transit dosimetry on a patient population undergoing intensity modulated radiation therapy (IMRT) and to assess the issues in clinical implementation of electronic portal imaging devices (EPIDs) for treatment verification. Methods and Materials: Fifty-eight patients were enrolled in the study. Amorphous silicon EPIDs were calibrated for dose and used to acquire images of delivered fields. Measured EPID dose maps were back-projected using the planning computed tomographic (CT) images to calculate dose at prespecified points within the patient and compared with treatment planning system dose offline using point dose difference and point γ analysis. Themore » deviation of the results was used to inform future action levels. Results: Two hundred twenty-five transit images were analyzed, composed of breast, prostate, and head and neck IMRT fields. Patient measurements demonstrated the potential of the dose verification protocol to model dose well under complex conditions: 83.8% of all delivered beams achieved the initial set tolerance level of Δ{sub D} of 0 ± 5 cGy or %Δ{sub D} of 0% ± 5%. Importantly, the protocol was also sensitive to anatomic changes and spotted that 3 patients from 20 measured prostate patients had undergone anatomic change in comparison with the planning CT. Patient data suggested an EPID-reconstructed versus treatment planning system dose difference action level of 0% ± 7% for breast fields. Asymmetric action levels were more appropriate for inversed IMRT fields, using absolute dose difference (−2 ± 5 cGy) or summed field percentage dose difference (−6% ± 7%). Conclusions: The in vivo dose verification method was easy to use and simple to implement, and it could detect patient anatomic changes that impacted dose delivery. The system required no extra dose to the patient or treatment time delay and so could be used throughout the course of treatment to identify and limit systematic and random errors in dose delivery for patient groups.« less

Clinical Experience and Evaluation of Patient Treatment Verification With a Transit Dosimeter.

PubMed

Ricketts, Kate; Navarro, Clara; Lane, Katherine; Blowfield, Claire; Cotten, Gary; Tomala, Dee; Lord, Christine; Jones, Joanne; Adeyemi, Abiodun

2016-08-01

To prospectively evaluate a protocol for transit dosimetry on a patient population undergoing intensity modulated radiation therapy (IMRT) and to assess the issues in clinical implementation of electronic portal imaging devices (EPIDs) for treatment verification. Fifty-eight patients were enrolled in the study. Amorphous silicon EPIDs were calibrated for dose and used to acquire images of delivered fields. Measured EPID dose maps were back-projected using the planning computed tomographic (CT) images to calculate dose at prespecified points within the patient and compared with treatment planning system dose offline using point dose difference and point γ analysis. The deviation of the results was used to inform future action levels. Two hundred twenty-five transit images were analyzed, composed of breast, prostate, and head and neck IMRT fields. Patient measurements demonstrated the potential of the dose verification protocol to model dose well under complex conditions: 83.8% of all delivered beams achieved the initial set tolerance level of ΔD of 0 ± 5 cGy or %ΔD of 0% ± 5%. Importantly, the protocol was also sensitive to anatomic changes and spotted that 3 patients from 20 measured prostate patients had undergone anatomic change in comparison with the planning CT. Patient data suggested an EPID-reconstructed versus treatment planning system dose difference action level of 0% ± 7% for breast fields. Asymmetric action levels were more appropriate for inversed IMRT fields, using absolute dose difference (-2 ± 5 cGy) or summed field percentage dose difference (-6% ± 7%). The in vivo dose verification method was easy to use and simple to implement, and it could detect patient anatomic changes that impacted dose delivery. The system required no extra dose to the patient or treatment time delay and so could be used throughout the course of treatment to identify and limit systematic and random errors in dose delivery for patient groups. Copyright © 2016 Elsevier Inc. All rights reserved.

Paclitaxel and carboplatin in early phase studies: Roswell Park Cancer Institute experience in the subset of patients with lung cancer.

PubMed

Creaven, P J; Raghavan, D; Pendyala, L; Loewen, G; Kindler, H L; Berghorn, E J

1997-08-01

The combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion followed by carboplatin infused over 30 minutes has been evaluated in a series of phase I studies and is currently being explored in a phase II study in patients with limited- and extensive-stage small cell lung cancer. Pharmacokinetic measurements were performed at all dose levels in the phase I studies, in which the use of granulocyte colony-stimulating factor in previously treated patients enabled more than twice the dose of paclitaxel to be given with low to moderate doses of carboplatin (dosed to a target area under the concentration-time curve of 4.0 mg x min x mL[-1]). Treatment-naive patients tolerated high paclitaxel doses (270 mg/m2) with carboplatin (dosed to a target area under the curve of 4.5 mg x min x mL[-1]) without granulocyte colony-stimulating factor support. Twenty-three patients (including previously treated and untreated) with non-small cell lung cancer were entered at a variety of paclitaxel doses in the phase I studies. At 100 to 205 mg/m2 paclitaxel, none of nine treated patients responded; at 230 to 290 mg/m2, four (29%) of 14 responded. In the phase II study of paclitaxel 250 mg/m2 in previously untreated patients with small cell lung cancer, two of five evaluable patients with extensive-stage disease have shown a partial response. In a preliminary analysis of the pharmacodynamics of paclitaxel in relation to neurotoxicity (dose limiting in two of three phase I studies), neurotoxicity correlated with the total dose of paclitaxel, the area under the curve, and the peak paclitaxel concentration, but not with the length of time plasma paclitaxel levels remained above 0.05 micromol/L. These correlations were not strong, however, and analysis of these data is ongoing.

Dose-response effects of Lepidium meyenii (Maca) aqueous extract on testicular function and weight of different organs in adult rats.

PubMed

Chung, Francisco; Rubio, Julio; Gonzales, Carla; Gasco, Manuel; Gonzales, Gustavo F

2005-04-08

Lepidium meyenii (Brassicaceae) known as Maca grows exclusively between 4000 and 4500 m over the sea level in the Peruvian central Andes. The dried hypocotyls of Maca are traditionally used as food and for its supposed fertility-enhancing properties. A dose-response study was performed to determine the effect of 7 days oral administration of an aqueous lyophilized extract of Maca at 0.01-5 g/kg (corresponding to 0.022-11 g dry hypocotyls of Maca/kg) on body and different organ weights, stages of the seminiferous tubules, epididymal sperm count and motility, and serum testosterone and estradiol levels in rats. In doses up to 5 g extract/kg, no toxicity was observed. Almost all organ weights were similar in controls and in the Maca extract-treated groups. Seminal vesicles weight was significantly reduced at 0.01 and 0.10 g extract/kg. Maca increased in length of stages VII-VIII of the seminiferous tubules in a dose-response fashion, with highest response at 1.0 g/kg, while caput/corpus epididymal sperm count increased at the 1.0 g dose. Cauda epididymal sperm count, sperm motility, and serum estradiol level were not affected at any of the doses studied. Serum testosterone was lower at 0.10 g extract/kg. Low-seminal vesicle weights correlated with low-serum testosterone levels (R2=0.33; P<0.0001) and low-testosterone/estradiol ratio (R2=0.35; P<0.0001). Increase in epididymal sperm count was related to lengths of stages VII-VIII. Highest effect on stages VII-VIII of the seminiferous tubules was observed at 1.0 g Maca aqueous extract/kg. The present study demonstrated that Maca extract in doses up to 5 g/kg (equivalent to the intake of 770 g hypocotyls in a man of 70 kg) was safe and that higher effect on reproductive parameters was elicited with a dose of 1 g extract/kg corresponding to 2.2 g dry Maca hypocotyls/kg.

Very low-dose (0.15 mGy) chest CT protocols using the COPDGene 2 test object and a third-generation dual-source CT scanner with corresponding third-generation iterative reconstruction software.

PubMed

Newell, John D; Fuld, Matthew K; Allmendinger, Thomas; Sieren, Jered P; Chan, Kung-Sik; Guo, Junfeng; Hoffman, Eric A

2015-01-01

The purpose of this study was to evaluate the impact of ultralow radiation dose single-energy computed tomographic (CT) acquisitions with Sn prefiltration and third-generation iterative reconstruction on density-based quantitative measures of growing interest in phenotyping pulmonary disease. The effects of both decreasing dose and different body habitus on the accuracy of the mean CT attenuation measurements and the level of image noise (SD) were evaluated using the COPDGene 2 test object, containing 8 different materials of interest ranging from air to acrylic and including various density foams. A third-generation dual-source multidetector CT scanner (Siemens SOMATOM FORCE; Siemens Healthcare AG, Erlangen, Germany) running advanced modeled iterative reconstruction (ADMIRE) software (Siemens Healthcare AG) was used.We used normal and very large body habitus rings at dose levels varying from 1.5 to 0.15 mGy using a spectral-shaped (0.6-mm Sn) tube output of 100 kV(p). Three CT scans were obtained at each dose level using both rings. Regions of interest for each material in the test object scans were automatically extracted. The Hounsfield unit values of each material using weighted filtered back projection (WFBP) at 1.5 mGy was used as the reference value to evaluate shifts in CT attenuation at lower dose levels using either WFBP or ADMIRE. Statistical analysis included basic statistics, Welch t tests, multivariable covariant model using the F test to assess the significance of the explanatory (independent) variables on the response (dependent) variable, and CT mean attenuation, in the multivariable covariant model including reconstruction method. Multivariable regression analysis of the mean CT attenuation values showed a significant difference with decreasing dose between ADMIRE and WFBP. The ADMIRE has reduced noise and more stable CT attenuation compared with WFBP. There was a strong effect on the mean CT attenuation values of the scanned materials for ring size (P < 0.0001) and dose level (P < 0.0001). The number of voxels in the region of interest for the particular material studied did not demonstrate a significant effect (P > 0.05). The SD was lower with ADMIRE compared with WFBP at all dose levels and ring sizes (P < 0.05). The third-generation dual-source CT scanners using third-generation iterative reconstruction methods can acquire accurate quantitative CT images with acceptable image noise at very low-dose levels (0.15 mGy). This opens up new diagnostic and research opportunities in CT phenotyping of the lung for developing new treatments and increased understanding of pulmonary disease.

Studies on toxicity, anti-stress and hepato-protective properties of Kombucha tea.

PubMed

Pauline, T; Dipti, P; Anju, B; Kavimani, S; Sharma, S K; Kain, A K; Sarada, S K; Sairam, M; Ilavazhagan, G; Devendra, K; Selvamurthy, W

2001-09-01

The objective of the study was to evaluate toxicity, anti-stress activity and hepato-protective properties of Kombucha tea. Kombucha tea was fed orally for 15 days using three different doses i.e. normal dose, five and ten times the dose. Rats were then sacrificed and various biochemical, and histological parameters were estimated. Anti-stress activity was evaluated either by 1) by exposing animals to cold and hypoxia and estimating the levels of malondialdehyde and reduced glutathione in plasma/blood or 2) by subjecting the animals to restraint stress and recording faecal output. Hepato-toxicity was induced by challenging the animals to an acute dose of paracetamol (1 gm/kg) orally and determining the plasma levels of SGPT, SGOT and MDA. The effect of oral administration of different doses of K-tea to albino rats was examined and the results indicate that K-tea has no significant toxicity as revealed by various biochemical and histopathological parameters. K-tea has been found to prevent lipid peroxidation and fall in reduced glutathione level when rats were exposed to cold and hypoxia in simulated chamber. Further, K-tea has also been found to decrease the Wrap-restraint faecal pellet output in rats. K-tea has also been found to decrease paracetamol induced hepatotoxicity significantly. The study shows that K-tea has anti-stress and hepato-protective activities.

THYROID INSUFFICIENCY AND GENE EXPRESSION IN DEVELOPING RAT BRAIN: A DOSE RESPONSE STUDY.

EPA Science Inventory

Thyroid Insufficiency and Gene Expression in Developing Rat Brain: A Dose Response Study. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption is an area of major concern in environmental neurotoxicity. Deficits in thyroid hormone (TH) levels h...

Effect of High-Dose vs Standard-Dose Multivitamin Supplementation at the Initiation of HAART on HIV Disease Progression and Mortality in Tanzania

PubMed Central

Isanaka, Sheila; Mugusi, Ferdinand; Hawkins, Claudia; Spiegelman, Donna; Okuma, James; Aboud, Said; Guerino, Chalamilla; Fawzi, Wafaie W.

2013-01-01

Context Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. Objective To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. Design, Setting, and Participants A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. Intervention The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. Main Outcome Measure The composite of HIV disease progression or death from any cause. Results The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96–1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11–1.87) vs standard-dose supplementation. Conclusion In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. Trial Registration clinicaltrials.gov Identifier: NCT00383669 PMID:23073950

Prenatal tolerance induction: relationship between cell dose, marrow T-cells, chimerism, and tolerance.

PubMed

Chen, Jeng-Chang; Chang, Ming-Ling; Huang, Shiu-Feng; Chang, Pei-Yeh; Muench, Marcus O; Fu, Ren-Huei; Ou, Liang-Shiou; Kuo, Ming-Ling

2008-01-01

It was reported that the dose of self-antigens can determine the consequence of deletional tolerance and donor T cells are critical for tolerance induction in mixed chimeras. This study aimed at assessing the effect of cell doses and marrow T cells on engraftment and tolerance induction after prenatal bone marrow transplantation. Intraperitoneal cell transplantation was performed in FVB/N (H-2K(q)) mice at gestational day 14 with escalating doses of adult C57BL/6 (H-2K(b)) marrows. Peripheral chimerism was examined postnatally by flow cytometry and tolerance was tested by skin transplantation. Transplantation of light-density marrow cells showed a dose response. High-level chimerism emerged with a threshold dose of 5.0 x 10(6) and host leukocytes could be nearly replaced at a dose of 7.5-10.0 x 10(6). High-dose transplants conferred a steady long-lasting donor-specific tolerance but were accompanied by >50% incidence of graft-versus-host disease. Depletion of marrow T cells lessened graft-versus-host disease to the detriment of engraftment. With low-level chimerism, tolerance was a graded phenomenon dependent upon the level of chimerism. Durable chimerism within 6 months required a threshold of > or = 2% chimerism at 1 month of age and predicted a 50% chance of long-term tolerance, whereas transient chimerism (<2%) only caused hyporesponsiveness to the donor. Tolerance induction did not succeed without peripheral chimerism even if a large amount of injected donor cells persisted in the peritoneum. Neither did an increase in cell doses or donor T-cell contents benefit skin graft survivals unless it had substantially improved peripheral chimerism. Thus, peripheral chimerism level can be a simple and straightforward test to predict the degree of prenatal immune tolerance.

Individual external doses below the lowest reference level of 1 mSv per year five years after the 2011 Fukushima nuclear accident among all children in Soma City, Fukushima: A retrospective observational study.

PubMed

Tsubokura, Masaharu; Murakami, Michio; Nomura, Shuhei; Morita, Tomohiro; Nishikawa, Yoshitaka; Leppold, Claire; Kato, Shigeaki; Kami, Masahiro

2017-01-01

After the 2011 Fukushima Daiichi nuclear power plant accident, little information has been available on individual doses from external exposure among residents living in radioactively contaminated areas near the nuclear plant; in the present study we evaluated yearly changes in the doses from external exposure after the accident and the effects of decontamination on external exposure. This study considered all children less than 16 years of age in Soma City, Fukushima who participated in annual voluntary external exposure screening programs during the five years after the accident (n = 5,363). In total, 14,405 screening results were collected. The median participant age was eight years. The geometric mean levels of annual additional doses from external exposure attributable to the Fukushima accident, decreased each year: 0.60 mSv (range: not detectable (ND)-4.29 mSv), 0.37 mSv (range: ND-3.61 mSv), 0.22 mSv (range: ND-1.44 mSv), 0.20 mSv (range: ND-1.87 mSv), and 0.17 mSv (range: ND-0.85 mSv) in 2011, 2012, 2013, 2014, and 2015, respectively. The proportion of residents with annual additional doses from external exposure of more than 1 mSv dropped from 15.6% in 2011 to zero in 2015. Doses from external exposure decreased more rapidly than those estimated from only physical decay, even in areas without decontamination (which were halved in 395 days from November 15, 2011), presumably due to the weathering effects. While the ratios of geometric mean doses immediately after decontamination to before were slightly lower than those during the same time in areas without decontamination, annual additional doses reduced by decontamination were small (0.04-0.24 mSv in the year of immediately after decontamination was completed). The results of this study showed that the levels of external exposure among Soma residents less than 16 years of age decreased during the five years after the Fukushima Daiichi nuclear power plant accident. Decontamination had only limited and temporal effects on reducing individual external doses.

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

PubMed

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.

Metformin as an initial adjunct to low-dose liraglutide enhances the weight-decreasing potential of liraglutide in obese polycystic ovary syndrome: Randomized control study.

PubMed

Jensterle, Mojca; Goricar, Katja; Janez, Andrej

2016-04-01

Liraglutide (LIRA) treatment is associated with the dose-dependent reduction of weight. Higher doses are more effective than lower doses, although higher doses are also more poorly tolerated. Metformin may enhance the weight-lowering potential of LIRA via the stimulatory modulation of incretin in addition to its direct beneficial effects in PCOS. The aim of the present study was to evaluate whether metformin as an adjunct to low-dose LIRA affects body weight with increased efficacy compared with low-dose LIRA alone in obese patients with PCOS. In a 12-week study, 44 obese women with PCOS were randomly offered either combined treatment (COMBO) with 1,000 mg metformin twice a day and 1.2 mg LIRA once a day, or treatment with 1.2 mg LIRA alone. The primary outcome of treatment was an alteration in the levels of obesity. A total of 43 patients [aged 30.3±4.4 years; body mass index (BMI) 37.2±4.5 kg/m 2 ; mean ± standard deviation] completed the study. The subjects treated with COMBO lost on average 6.2±2.4 kg compared with a 3.8±3.5 kg weight loss in the patients treated with LIRA alone (P=0.024). The BMI decreased by 2.2±0.8 kg/m 2 in patients treated with COMBO and by 1.4±1.2 kg/m 2 in patients treated with LIRA alone (P=0.024). A clinically significant ≥5% weight reduction was achieved in 59.1% of patients treated with COMBO and 42.9% of patients treated with LIRA alone. Reductions in glucose levels following oral glucose tolerance testing, as well as in androstenedione levels in the COMBO group were significantly greater compared with those in the LIRA group. The side effects were mild and transient in the two treatment groups. A combination of metformin and low-dose LIRA was more effective than low-dose LIRA alone in reducing body weight in obese patients with PCOS.

Effects of pre- and postnatal exposure to the UV-filter Octyl Methoxycinnamate (OMC) on the reproductive, auditory and neurological development of rat offspring

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

Axelstad, Marta, E-mail: maap@food.dtu.dk; Boberg, Julie; Hougaard, Karin Sorig

Octyl Methoxycinnamate (OMC) is a frequently used UV-filter in sunscreens and other cosmetics. The aim of the present study was to address the potential endocrine disrupting properties of OMC, and to investigate how OMC induced changes in thyroid hormone levels would be related to the neurological development of treated offspring. Groups of 14-18 pregnant Wistar rats were dosed with 0, 500, 750 or 1000 mg OMC/kg bw/day during gestation and lactation. Serum thyroxine (T{sub 4}), testosterone, estradiol and progesterone levels were measured in dams and offspring. Anogenital distance, nipple retention, postnatal growth and timing of sexual maturation were assessed. Onmore » postnatal day 16, gene expression in prostate and testes, and weight and histopathology of the thyroid gland, liver, adrenals, prostate, testes, epididymis and ovaries were measured. After weaning, offspring were evaluated in a battery of behavioral and neurophysiological tests, including tests of activity, startle response, cognitive and auditory function. In adult animals, reproductive organ weights and semen quality were investigated. Thyroxine (T{sub 4}) levels showed a very marked decrease during the dosing period in all dosed dams, but were less severely affected in the offspring. On postnatal day 16, high dose male offspring showed reduced relative prostate and testis weights, and a dose-dependent decrease in testosterone levels. In OMC exposed female offspring, motor activity levels were decreased, while low and high dose males showed improved spatial learning abilities. The observed behavioral changes were probably not mediated solely by early T{sub 4} deficiencies, as the observed effects differed from those seen in other studies of developmental hypothyroxinemia. At eight months of age, sperm counts were reduced in all three OMC-dosed groups, and prostate weights were reduced in the highest dose group. Taken together, these results indicate that perinatal OMC-exposure can affect both the reproductive and neurological development of rat offspring, which may be a cause of concern, as humans are systematically exposed to the compound through usage of sunscreens and other cosmetics.« less

Subchronic chloroform priming protects mice from a subsequently administered lethal dose of chloroform

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

Philip, Binu K.; Anand, Sathanandam S.; Palkar, Prajakta S.

2006-10-01

Protection offered by pre-exposure priming with a small dose of a toxicant against the toxic and lethal effects of a subsequently administered high dose of the same toxicant is autoprotection. Although autoprotection has been extensively studied with diverse toxicants in acute exposure regimen, not much is known about autoprotection after priming with repeated exposure. The objective of this study was to investigate this concept following repeated exposure to a common water contaminant, chloroform. Swiss Webster (SW) mice, exposed continuously to either vehicle (5% Emulphor, unprimed) or chloroform (150 mg/kg/day po, primed) for 30 days, were challenged with a normally lethalmore » dose of chloroform (750 mg chloroform/kg po) 24 h after the last exposure. As expected, 90% of the unprimed mice died between 48 and 96 h after administration of the lethal dose in contrast to 100% survival of mice primed with chloroform. Time course studies indicated lower hepato- and nephrotoxicity in primed mice as compared to unprimed mice. Hepatic CYP2E1, glutathione levels (GSH), and covalent binding of {sup 14}C-chloroform-derived radiolabel did not differ between livers of unprimed and primed mice after lethal dose exposure, indicating that protection in liver is neither due to decreased bioactivation nor increased detoxification. Kidney GSH and glutathione reductase activity were upregulated, with a concomitant reduction in oxidized glutathione in the primed mice following lethal dose challenge, leading to decreased renal covalent binding of {sup 14}C-chloroform-derived radiolabel, in the absence of any change in CYP2E1 levels. Buthionine sulfoximine (BSO) intervention led to 70% mortality in primed mice challenged with lethal dose. These data suggest that higher detoxification may play a role in the lower initiation of kidney injury observed in primed mice. Exposure of primed mice to a lethal dose of chloroform led to 40% lower chloroform levels (AUC{sub 15-360min}) in the systemic circulation. Exhalation of {sup 14}C-chloroform was unchanged in primed as compared to unprimed mice (AUC{sub 1-6h}). Urinary excretion of {sup 14}C-chloroform was higher in primed mice after administration of the lethal dose. However, neither slightly higher urinary elimination nor unchanged expiration can account for the difference in systemic levels of chloroform. Liver and kidney regeneration was inhibited by the lethal dose in unprimed mice leading to progressive injury, organ failure, and 90% mortality. In contrast, sustained and highly stimulated compensatory hepato- and nephrogenic repair prevented the progression of injury resulting in 100% survival of primed mice challenged with the lethal dose. These findings affirm the critical role of tissue regeneration and favorable detoxification (only in kidney) of the lethal dose of chloroform in subchronic chloroform priming-induced autoprotection.« less

Solar Modulation of Atmospheric Cosmic Radiation:. Comparison Between In-Flight and Ground-Level Measurements

NASA Astrophysics Data System (ADS)

Iles, R. H. A.; Taylor, G. C.; Jones, J. B. L.

January 2000 saw the start of a collaborative study involving the Mullard Space Science Laboratory, Virgin Atlantic Airways, the Civil Aviation Authority and the National Physical Laboratory in a program to investigate the cosmic radiation exposure to aircrew. The study has been undertaken in view of EU Directive 96/291 (May 2000) which requires the assessment of the level of radiation exposure to aircrew. The project's aims include validation of radiation dose models and evaluation of space weather effects on atmospheric cosmic radiation levels, in particular those effects not accounted for by the models. Ground level measurements are often used as a proxy for variations in cosmic radiation dose levels at aircraft altitudes, especially during Forbush Decreases (FDs) and Solar Energetic Particle (SEP) events. Is this estimation realistic and does the ground level data accurately represent what is happening at altitude? We have investigated the effect of a FD during a flight from Hong Kong to London Heathrow on the 15th July 2000 and compared count rate and dose measurements with simultaneous variations measured at ground level. We have also compared the results with model outputs.

A New Dual-purpose Quality Control Dosimetry Protocol for Diagnostic Reference-level Determination in Computed Tomography.

PubMed

Sohrabi, Mehdi; Parsi, Masoumeh; Sina, Sedigheh

2018-05-17

A diagnostic reference level is an advisory dose level set by a regulatory authority in a country as an efficient criterion for protection of patients from unwanted medical exposure. In computed tomography, the direct dose measurement and data collection methods are commonly applied for determination of diagnostic reference levels. Recently, a new quality-control-based dose survey method was proposed by the authors to simplify the diagnostic reference-level determination using a retrospective quality control database usually available at a regulatory authority in a country. In line with such a development, a prospective dual-purpose quality control dosimetry protocol is proposed for determination of diagnostic reference levels in a country, which can be simply applied by quality control service providers. This new proposed method was applied to five computed tomography scanners in Shiraz, Iran, and diagnostic reference levels for head, abdomen/pelvis, sinus, chest, and lumbar spine examinations were determined. The results were compared to those obtained by the data collection and quality-control-based dose survey methods, carried out in parallel in this study, and were found to agree well within approximately 6%. This is highly acceptable for quality-control-based methods according to International Atomic Energy Agency tolerance levels (±20%).

Effect of somatostatin on meal-induced gastric secretion in duodenal ulcer patients.

PubMed

Konturek, S J; Swierczek, J; Kwiecień, N; Mikoś, E; Oleksy, J; Wierzbicki, Z

1977-11-01

The effect of somatostatin, a growth hormone releasing-inhibiting hormone (GH-RIH) on basal and meal-, pentagastrin-, or histamine-stimulated gastric acid and pepsin secretion was studied in six duodenal ulcer patients. Intravenous GH-RIH infused in graded doses ranging from 0.62 to 5.0 microgram/kg/hr produced a dose-related inhibition of pentagastrin-induced acid secretion reaching about 15% of control level at the dose of 5.0 microgram/kg/hr. Acid inhibition was paralleled by a decrease in the pepsin output and accompanied by a dose-dependent reduction in serum growth hormone and insulin levels measured by radioimmunoassay. GH-RIH used in a single dose of 2.5 microgram/kg/hr produced about 85% inhibition of acid secretion induced by a meal (measured by intragastric titration) accompanied by a significant decrease in serum gastrin and insulin levels. The effect of GH-RIH on histamine-stimulated secretion was very modest and observed only after stopping the GH-RIH infusion. Thus GH-RIH suppressed acid and pepsin secretion induced by pentagastrin and a meal, and this effect was accompanied by a suppression of serum growth hormone and gastrin levels which may contribute to the inhibition of gastric secretion observed.

Improving spot-scanning proton therapy patient specific quality assurance with HPlusQA, a second-check dose calculation engine

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

Mackin, Dennis; Li, Yupeng; Taylor, Michael B.

Purpose: The purpose of this study was to validate the use of HPlusQA, spot-scanning proton therapy (SSPT) dose calculation software developed at The University of Texas MD Anderson Cancer Center, as second-check dose calculation software for patient-specific quality assurance (PSQA). The authors also showed how HPlusQA can be used within the current PSQA framework.Methods: The authors compared the dose calculations of HPlusQA and the Eclipse treatment planning system with 106 planar dose measurements made as part of PSQA. To determine the relative performance and the degree of correlation between HPlusQA and Eclipse, the authors compared calculated with measured point doses.more » Then, to determine how well HPlusQA can predict when the comparisons between Eclipse calculations and the measured dose will exceed tolerance levels, the authors compared gamma index scores for HPlusQA versus Eclipse with those of measured doses versus Eclipse. The authors introduce the αβγ transformation as a way to more easily compare gamma scores.Results: The authors compared measured and calculated dose planes using the relative depth, z/R × 100%, where z is the depth of the measurement and R is the proton beam range. For relative depths than less than 80%, both Eclipse and HPlusQA calculations were within 2 cGy of dose measurements on average. When the relative depth was greater than 80%, the agreement between the calculations and measurements fell to 4 cGy. For relative depths less than 10%, the Eclipse and HPlusQA dose discrepancies showed a negative correlation, −0.21. Otherwise, the correlation between the dose discrepancies was positive and as large as 0.6. For the dose planes in this study, HPlusQA correctly predicted when Eclipse had and had not calculated the dose to within tolerance 92% and 79% of the time, respectively. In 4 of 106 cases, HPlusQA failed to predict when the comparison between measurement and Eclipse's calculation had exceeded the tolerance levels of 3% for dose and 3 mm for distance-to-agreement.Conclusions: The authors found HPlusQA to be reasonably effective (79%± 10%) in determining when the comparison between measured dose planes and the dose planes calculated by the Eclipse treatment planning system had exceeded the acceptable tolerance levels. When used as described in this study, HPlusQA can reduce the need for patient specific quality assurance measurements by 64%. The authors believe that the use of HPlusQA as a dose calculation second check can increase the efficiency and effectiveness of the QA process.« less

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

PubMed

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

2017-03-01

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

PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE AND ITS METABOLITE O-DESMETHYLTRAMADOL FOLLOWING A SINGLE, ORALLY ADMINISTERED DOSE IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

PubMed

Boonstra, Jennifer L; Barbosa, Lorraine; Van Bonn, William G; Johnson, Shawn P; Gulland, Frances M D; Cox, Sherry K; Martin-Jimenez, Tomas

2015-09-01

Tramadol is a synthetic, centrally acting, opiate-like analgesic that is structurally related to codeine and morphine. The objective of this study was to determine the pharmacokinetics of tramadol hydrochloride and its major active metabolite O-desmethyltramadol (M1) in the California sea lion (Zalophus californianus). A single dose of tramadol was administered orally in fish at 2 mg/kg to a total of 15 wild California sea lions admitted for rehabilitation. Twenty-four total blood samples were collected post drug administration at 10, 20, 30, and 45 min and at 1, 3, 5, 6, 8, 12, and 24 hr. Blood plasma was separated and stored at -80°C until analysis with high-performance liquid chromatography was performed to determine levels of tramadol and M1, the major active metabolite. The results indicate that the plasma levels of parent tramadol are low or negligible during the first 30-45 min and then reach the predicted mean maximum plasma concentration of 358 ng/ml at 1.52 hr. The M1 metabolite was not detectable in 21 of 24 plasma samples, below the level of quantification of 5 ng/ml in one sample, and detectable at 11 and 17 ng/ml in two of the samples. This study suggests that a 2 mg/kg dose would need to be administered every 6-8 hr to maintain concentrations of tramadol above the minimum human analgesic level for mild to moderate pain. Based on dosing simulations, a dose of 4 mg/kg q8 hr or q12 hr, on average, may represent an adequate compromise, but further studies are needed using a larger sample size. Pharmacodynamic studies are warranted to determine if tramadol provides analgesic effects in this species. The potential for tramadol toxicosis at any dose also has not been determined in this species.

Estimation of skin entrance doses (SEDs) for common medical X-ray diagnostic examinations in India and proposed diagnostic reference levels (DRLs).

PubMed

Sonawane, A U; Shirva, V K; Pradhan, A S

2010-02-01

Skin entrance doses (SEDs) were estimated by carrying out measurements of air kerma from 101 X-ray machines installed in 45 major and selected hospitals in the country by using a silicon detector-based dose Test-O-Meter. 1209 number of air kerma measurements of diagnostic projections for adults have been analysed for seven types of common diagnostic examinations, viz. chest (AP, PA, LAT), lumbar spine (AP, LAT), thoracic spine (AP, LAT), abdomen (AP), pelvis (AP), hip joints (AP) and skull (PA, LAT) for different film-screen combinations. The values of estimated diagnostic reference levels (DRLs) (third quartile values of SEDs) were compared with guidance levels/DRLs of doses published by the IAEA-BSS-Safety Series No. 115, 1996; HPA (NRPB) (2000 and 2005), UK; CRCPD/CDRH (USA), European Commission and other national values. The values of DRLs obtained in this study are comparable with the values published by the IAEA-BSS-115 (1996); HPA (NRPB) (2000 and 2005) UK; EC and CRCPD/CDRH, USA including values obtained in previous studies in India.

Micro-Dose Calibrator for Pre-clinical Radiotracer Assays | NCI Technology Transfer Center | TTC

Cancer.gov

Pre-clinical radiotracer biomedical research involves the use of compounds labeled with radioisotopes, including cell binding studies, immune cell labeling techniques, and radio-ligand bio-distribution studies. Before this Micro-Dose Calibrator, measurement of pre-clinical level dosage for small animal studies was inaccurate and unreliable. This dose calibrator is a prototype ready for manufacturing. It is designed to accurately measure radioactive doses in the range of 50 nCi (1.8 kBq) to 100 µCi (3.7 MBq) with 1% precision. The NCI seeks co-development or licensing to commercialize it. Alternative uses will be considered.

Prescribing patterns and the use of therapeutic drug monitoring of psychotropic medication in a psychiatric high-security unit.

PubMed

Castberg, Ingrid; Spigset, Olav

2008-10-01

The aim of this study was to investigate the use of psychotropic medication and therapeutic drug monitoring in a high-security psychiatric unit and to compare the doses and serum concentrations both with the recommended intervals and with the doses and serum concentrations in a control group. One hundred thirty-two patients were admitted in the period from January 2000 to December 2005. All available samples were used when comparing serum concentrations and doses with the recommended ranges. For the comparison of doses and serum concentration-to-dose (C:D) ratios with the control group only 1 sample from each patient was used. A total of 459 analyses of 27 different drugs in samples from 8 women and 73 men were included. The median number of therapeutic drug monitoring analyses per patient was 4 (range 1-29). Thirty-seven of the 81 patients (46%) used 2 or more antipsychotics at the same time. Clozapine, lamotrigine, olanzapine, quetiapine, ziprasidone, and zuclopenthixol were often given in doses above the recommended. The serum levels were frequently above those recommended for clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zuclopenthixol. The serum levels were significantly higher in the study group than in the control group for clozapine, lamotrigine, quetiapine, and zuclopenthixol. The given dose was significantly higher in the study group than in the control group for clozapine, lamotrigine and zuclopenthixol. The C:D ratio was significantly lower in the study group than in the control group for olanzapine but higher for quetiapine. The non-evidence based practice of high-dose polypharmacy with several antipsychotics is widely used in this unit. The use of higher doses in the study group than in the control group was not due to differences in metabolism or adherence to treatment between the 2 groups. The frequent use of therapeutic drug monitoring did not seem to have a great impact on the prescribed doses.

Decorporation Approach after Rat Lung Contamination with Plutonium: Evaluation of the Key Parameters Influencing the Efficacy of a Protracted Chelation Treatment.

PubMed

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.

In vitro activity and human pharmacokinetics of teicoplanin.

PubMed Central

Verbist, L; Tjandramaga, B; Hendrickx, B; Van Hecken, A; Van Melle, P; Verbesselt, R; Verhaegen, J; De Schepper, P J

1984-01-01

The in vitro activity of teicoplanin, a new antibiotic related to vancomycin, was determined against 456 gram-positive cocci. The activity of teicoplanin in comparison with that of vancomycin was similar against staphylococci but 4 to 40 times higher against enterococci and beta-hemolytic and viridans streptococci. The single-dose pharmacokinetics of teicoplanin were studied in six healthy volunteers after administration of 3 and 6 mg/kg intravenously and of 3 mg/kg intramuscularly. The kinetic parameters after both intravenous doses were very similar. The curves for concentration in plasma for the 3- and 6-mg/kg intravenous doses showed a triexponential decline with elimination half-lives of 47.3 and 44.1 h, respectively. The percentages of the doses recovered in urine (0 to 102 h) were 43.2 and 44.1%, respectively. The areas under the plasma curves were dose related: 256.5 and 520.9 micrograms/h per ml, respectively. The bioavailability of teicoplanin after injection of 3 mg/kg intramuscularly was 90%, and the peak level was 7.1 micrograms/ml. The mean levels in plasma 24 h after the 3-mg/kg doses were 2.1 and 2.3 micrograms/ml, respectively, and the mean level in plasma 24 h after the 6-mg/kg intravenous dose was 4.2 micrograms/ml. PMID:6240962

Locomotor activity and tissue levels following acute ...

EPA Pesticide Factsheets

Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metrics. Products of cyhalothrin, a type II pyrethroid, include mixtures of isomers (e.g., λ-cyhalothrin) as well as enriched active isomers (e.g., γ-cyhalothrin). We measured acute changes in locomotor activity in adult male rats and directly correlated these changes to peak brain and plasma concentrations of λ- and γ-cyhalothrin using a within-subject design. One-hour locomotor activity studies were conducted 1.5 h after oral gavage dosing, and immediately thereafter plasma and brains were collected for analyzing tissue levels using LC/MS/MS methods. Both isomers produced dose-related decreases in activity counts, and the effective dose range for γ-cyhalothrin was lower than for λ-cyhalothrin. Doses calculated to decrease activity by 50% were 2-fold lower for the γ-isomer (1.29 mg/kg) compared to λ-cyhalothrin (2.65 mg/kg). Salivation, typical of type II pyrethroids, was also observed at lower doses of γ-cyhalothrin. Administered dose correlated well with brain and plasma concentrations, which furthermore showed good correlations with activity changes. Brain and plasma levels were tightly correlated across doses. While γ-cyhalothrin was 2-fold more potent based on administ

C.E.R.A. administered once monthly corrects and maintains stable hemoglobin levels in chronic kidney disease patients not on dialysis: the observational study MICENAS II.

PubMed

Martínez-Castelao, Alberto; Cases, Aleix; Coll, Elisabeth; Bonal, Jordi; Galceran, Josep M; Fort, Joan; Moreso, Francesc; Torregrosa, Vicente; Guirado, Lluís; Ruiz, Pilar

2015-01-01

C.E.R.A. (continuous erythropoietin receptor activator, pegilated-rHuEPO ß) corrects and maintains stable hemoglobin levels in once-monthly administration in chronic kidney disease (CKD) patients. The aim of this study was to evaluate the management of anemia with C.E.R.A. in CKD patients not on dialysis in the clinical setting. Two hundred seventy two anemic CKD patients not on dialysis treated with C.E.R.A. were included in this retrospective, observational, multicentric study during 2010. Demographical characteristics, analytical parameters concerning anemia, treatment data and iron status were recorded. C.E.R.A. achieved a good control of anemia in both naïve patients (mean Hemoglobin 11.6g/dL) and patients converted from a previous ESA (mean Hemoglobin 11.7g/dL). Most naïve patients received C.E.R.A. once monthly during the correction phase and required a low monthly dose (median dose 75 µg/month). The same median dose was required in patients converted from a previous ESA, and it was lower than recommended in the Summary of Product Characteristics (SPC). Iron status was adequate in 75% of anemic CKD patients, but only 50% of anemic patients with iron deficiency received iron supplementation. C.E.R.A. corrects and maintains stable hemoglobin levels in anemic CKD patients not on dialysis, requiring conversion doses lower than those recommended by the SPC, and achieving target hemoglobin levels with once-monthly dosing frequency both in naïve and converted patients.

The effect of low dose rate on metabolomic response to radiation in mice

PubMed Central

Goudarzi, Maryam; Mak, Tytus D.; Chen, Congju; Smilenov, Lubomir B.; Brenner, David J.

2014-01-01

Metabolomics has been shown to have utility in assessing responses to exposure by ionizing radiation (IR) in easily accessible biofluids such as urine. Most studies to date from our laboratory and others have employed γ-irradiation at relatively high dose rates (HDR), but many environmental exposure scenarios will probably be at relatively low dose rates (LDR). There are well-documented differences in the biologic responses to LDR compared to HDR, so an important question is to assess LDR effects at the metabolomics level. Our study took advantage of a modern mass spectrometry approach in exploring the effects of dose rate on the urinary excretion levels of metabolites 2 days after IR in mice. A wide variety of statistical tools were employed to further focus on metabolites, which showed responses to LDR IR exposure (0.00309 Gy/min) distinguishable from those of HDR. From a total of 709 detected spectral features, more than 100 were determined to be statistically significant when comparing urine from mice irradiated with 1.1 or 4.45 Gy to that of sham-irradiated mice 2 days post-exposure. The results of this study show that LDR and HDR exposures perturb many of the same pathways such as TCA cycle and fatty acid metabolism, which also have been implicated in our previous IR studies. However, it is important to note that dose rate did affect the levels of particular metabolites. Differences in urinary excretion levels of such metabolites could potentially be used to assess an individual's exposure in a radiobiological event and thus would have utility for both triage and injury assessment. PMID:25047638

Reproducibility of three-dimensional cephalometric landmarks in cone-beam and low-dose computed tomography.

PubMed

Olszewski, R; Frison, L; Wisniewski, M; Denis, J M; Vynckier, S; Cosnard, G; Zech, F; Reychler, H

2013-01-01

The purpose of this study is to compare the reproducibility of three-dimensional cephalometric landmarks on three-dimensional computed tomography (3D-CT) surface rendering using clinical protocols based on low-dose (35-mAs) spiral CT and cone-beam CT (I-CAT). The absorbed dose levels for radiosensitive organs in the maxillofacial region during exposure in both 3D-CT protocols were also assessed. The study population consisted of ten human dry skulls examined with low-dose CT and cone-beam CT. Two independent observers identified 24 cephalometric anatomic landmarks at 13 sites on the 3D-CT surface renderings using both protocols, with each observer repeating the identification 1 month later. A total of 1,920 imaging measurements were performed. Thermoluminescent dosimeters were placed at six sites around the thyroid gland, the submandibular glands, and the eyes in an Alderson phantom to measure the absorbed dose levels. When comparing low-dose CT and cone-beam CT protocols, the cone-beam CT protocol proved to be significantly more reproducible for four of the 13 anatomical sites. There was no significant difference between the protocols for the other nine anatomical sites. Both low-dose and cone-beam CT protocols were equivalent in dose absorption to the eyes and submandibular glands. However, thyroid glands were more irradiated with low-dose CT. Cone-beam CT was more reproducible and procured less irradiation to the thyroid gland than low-dose CT. Cone-beam CT should be preferred over low-dose CT for developing three-dimensional bony cephalometric analyses.

Inhibition effects of chlorogenic acid on benign prostatic hyperplasia in mice.

PubMed

Huang, Ya; Chen, Huaguo; Zhou, Xin; Wu, Xingdong; Hu, Enming; Jiang, Zhengmeng

2017-08-15

This study aimed to evaluate the inhibitory effects and explore mechanisms of chlorogenic acid against testosterone-induced benign prostatic hyperplasia (BPH) in mice. Benign prostatic hyperplasia model was induced in experimental groups by daily subcutaneous injections of testosterone propionate (7.5mg/kg/d) consecutively for 14 d. A total of 60 mice were randomly divided into six groups: (Group 1) normal control group, (Group 2) benign prostatic hyperplasia model control group, (Group 3) benign prostatic hyperplasia mice treated with finasteride at a dose of 1mg/kg, (Group 4) benign prostatic hyperplasia mice treated with chlorogenic acid at dose levels of 0.8mg/kg (low dose group), (Group 5) benign prostatic hyperplasia mice treated with chlorogenic acid at dose levels of 1.6mg/kg (medium dose group) and (Group 6) benign prostatic hyperplasia mice treated with chlorogenic acid at dose levels of 3.2mg/kg (high dose group). Animals were sacrificed on the scheduled termination, pick out the eyeball to get blood, then prostates were weighed and prostatic index were determined. Then the serum acid phosphatase (ACP), prostatic acid phosphatase (PACP) and typeⅡ5-alpha-reductase (SRD5A2) levels were measured and observed morphological changes of the prostate. Comparing with benign prostatic hyperplasia model group, the high and medium dose of chlorogenic acid could significantly reduce prostate index and levels of acid phosphatase, prostatic acid phosphatase and typeⅡ5-alpha-reductase (P<0.05 or P<0.01). These findings were supported by histopathological observations of prostate tissues. Histopathological examination also indicated that chlorogenic acid treatment at the high and medium doses inhibited testosterone-induced prostatic hyperplasia. The results indicated that chlorogenic acid exhibited restraining effect on benign prostatic hyperplasia model animals, and its mechanism might be related to inhibit typeⅡ5-alpha reductase activity. Copyright © 2017. Published by Elsevier B.V.

RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

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

Chinnaiyan, Prakash, E-mail: prakash.chinnaiyan@moffitt.org; Won, Minhee; Wen, Patrick Y.

Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m{sup 2} per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m{sup 2} on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established dailymore » dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.« less

Quantitative Image Quality and Histogram-Based Evaluations of an Iterative Reconstruction Algorithm at Low-to-Ultralow Radiation Dose Levels: A Phantom Study in Chest CT

PubMed Central

Lee, Ki Baek

2018-01-01

Objective To describe the quantitative image quality and histogram-based evaluation of an iterative reconstruction (IR) algorithm in chest computed tomography (CT) scans at low-to-ultralow CT radiation dose levels. Materials and Methods In an adult anthropomorphic phantom, chest CT scans were performed with 128-section dual-source CT at 70, 80, 100, 120, and 140 kVp, and the reference (3.4 mGy in volume CT Dose Index [CTDIvol]), 30%-, 60%-, and 90%-reduced radiation dose levels (2.4, 1.4, and 0.3 mGy). The CT images were reconstructed by using filtered back projection (FBP) algorithms and IR algorithm with strengths 1, 3, and 5. Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were statistically compared between different dose levels, tube voltages, and reconstruction algorithms. Moreover, histograms of subtraction images before and after standardization in x- and y-axes were visually compared. Results Compared with FBP images, IR images with strengths 1, 3, and 5 demonstrated image noise reduction up to 49.1%, SNR increase up to 100.7%, and CNR increase up to 67.3%. Noteworthy image quality degradations on IR images including a 184.9% increase in image noise, 63.0% decrease in SNR, and 51.3% decrease in CNR, and were shown between 60% and 90% reduced levels of radiation dose (p < 0.0001). Subtraction histograms between FBP and IR images showed progressively increased dispersion with increased IR strength and increased dose reduction. After standardization, the histograms appeared deviated and ragged between FBP images and IR images with strength 3 or 5, but almost normally-distributed between FBP images and IR images with strength 1. Conclusion The IR algorithm may be used to save radiation doses without substantial image quality degradation in chest CT scanning of the adult anthropomorphic phantom, down to approximately 1.4 mGy in CTDIvol (60% reduced dose). PMID:29354008

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

Quantification of the Glycemic Response to Microdoses of Subcutaneous Glucagon at Varying Insulin Levels

PubMed Central

Castle, Jessica R.; Bakhtiani, Parkash A.; Haidar, Ahmad; Branigan, Deborah L.; Breen, Matthew; Ward, W. Kenneth

2014-01-01

OBJECTIVE Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. RESEARCH DESIGN AND METHODS Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 μg) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. RESULTS At low insulin levels, EGP rose proportionately with glucagon dose, from 5 ± 68 to 112 ± 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 ± 53 to 26 ± 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P < 0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P < 0.001). CONCLUSIONS EGP increases steeply with glucagon doses between 25 and 175 μg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas. PMID:25139882

Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels.

PubMed

El Youssef, Joseph; Castle, Jessica R; Bakhtiani, Parkash A; Haidar, Ahmad; Branigan, Deborah L; Breen, Matthew; Ward, W Kenneth

2014-11-01

Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 μg) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. At low insulin levels, EGP rose proportionately with glucagon dose, from 5 ± 68 to 112 ± 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 ± 53 to 26 ± 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P < 0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P < 0.001). EGP increases steeply with glucagon doses between 25 and 175 μg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Effects of crude kerosene on testosterone levels, aggression and toxicity in rat.

PubMed

Njoroge, Rachel W; Macharia, Benson N; Sawe, Dinah J; Maiyoh, Geoffrey K

2015-01-01

The use of crude kerosene as a dietary supplement in boarding schools has been a common practice in east Africa and other countries for many years, with the belief of it reducing the sex drive (libido) at the pubertal stage. There is however no scientific basis for this belief. The present study aimed at using a rat animal model to investigate the effects of crude kerosene on serum testosterone levels, aggression and its possible toxic effects. Fifteen male albino rats of approximately similar age and average weights were put into three groups of five animals each; the control group (placebo), low kerosene dose (10 μl/day) group and high kerosene dose (300 μl/day) group. ELISA was used to determine the serum testosterone levels. During treatment, changes in aggression were observed and noted. Liver toxicity was determined using enzyme assays, total protein and albumin while renal toxicity was monitored using serum creatinine levels. A full hemogram was conducted to determine hematological effects. Various tissue biopsies were obtained and examined using histopathological techniques for evidence of toxicity. Contrary to the common belief, our findings showed an overall increase of serum testosterone levels of up to 66% in the low dose and 75% in the high dose groups, with an increasing trend by the end of the study. The high dose group showed significantly increased levels of white blood cells (WBC) ( p  = 0.036), red blood cells (RBC) ( p  = 0.025), hematocrit (HCT) ( p  = 0.03), red cell distribution width ( p  = 0.028) and platelets ( p  = 0.017). The histological results of the stomach indicated chronic gastritis.

Dynamic changes in metabolic profiles of rats subchronically exposed to mequindox.

PubMed

Jiang, Limiao; Zhao, Xiuju; Huang, Chongyang; Lei, Hehua; Tang, Huiru; Wang, Yulan

2014-11-01

Mequindox is widely used as an antibacterial veterinary drug and a feeding additive for farm animals in China. Although its toxicity has been widely studied, little is known regarding the metabolic effects of subchronic exposure to mequindox, which is vital for the health of meat producing livestock. Here, we characterized the dose- and time-dependent metabolic alterations in female Wistar rats subchronically exposed to mequindox through dietary supplementation at the level of 40, 110 and 280 mg kg(-1) for 13 weeks, employing a NMR based metabonomics approach with supplementary information from serum clinical chemistry. We found that urinary metabolic profiles were significantly affected in all dosed groups during the supplementation period; plasma and hepatic metabolic profiles were significantly affected only in rats dosed with moderate and high levels of mequindox. We also observed a return to control levels, for the profiles of urine and liver, at all dose levels after a two weeks washout period. However, this was not the case for the metabolic profiles of plasma from rats dosed at high levels. At the molecular level, we showed that subchronic exposure to mequindox resulted in tricarboxylic acid cycle (TCA cycle) stimulation, suppression of glycolysis, and promotion of gluconeogenesis and lipid oxidation in rats. In addition, subchronic exposure to mequindox induced oxidative stress in rats. Furthermore, a disturbance of gut microbiota, manifested by alterations in the urinary excretion of hippurate, phenylacetylglycine, 3-(3-hydroxyphenyl)propionate, p-cresol glucuronide, methylamine, dimethylamine, and formate, was associated with mequindox exposure. The present study provided important holistic metabolic information on the effects of subchronic dosage of mequindox on rats, which is useful for evaluating the safety of mequindox usage in meat producing animals.

NovaSil clay intervention in Ghanaians at high risk for aflatoxicosis: II. Reduction in biomarkers of aflatoxin exposure in blood and urine.

PubMed

Wang, P; Afriyie-Gyawu, E; Tang, Y; Johnson, N M; Xu, L; Tang, L; Huebner, H J; Ankrah, N-A; Ofori-Adjei, D; Ellis, W; Jolly, P E; Williams, J H; Wang, J-S; Phillips, T D

2008-05-01

The efficacy of NovaSil clay (NS) to reduce aflatoxin (AF) biomarkers of exposure was evaluated in 656 blood samples and 624 urine samples collected from study participants during a 3-month phase IIa clinical intervention trial in Ghana. NS was delivered before meals via capsules. Serum AFB (1)-albumin adduct was measured by radioimmunoassay and urinary AFM (1) metabolites were quantified by immunoaffinity-high-performance liquid chromatography (HPLC)-fluorescence methods. Levels of AFB (1) -albumin adduct in serum samples collected at baseline and at 1 month were similar (p = 0.2354 and p = 0.3645, respectively) among the placebo (PL), low dose (LD, 1.5 g NS day (-1)), and high dose (HD, 3.0 g NS day (-1)) groups. However, the levels of AFB (1)-albumin adduct at 3 months were significantly decreased in both the LD group (p < 0.0001) and the HD group (p < 0.0001) compared with levels in the PL group. Levels of AFM(1) in urine samples collected at baseline and at 1 month were not statistically different among the three study groups. However, a significant decrease (up to 58%) in the median level of AFM (1) in samples collected at 3 months was found in the HD group when compared with the median level in the PL group (p < 0.0391). In addition, significant effects were found for dose, time, and dose-time interaction with serum AFB(1)-albumin adduct and dose-time interaction with urinary AFM (1) metabolites. The results suggest that capsules containing NS clay can be used to reduce effectively the bioavailability of dietary AF based on a reduction of AF-specific biomarkers.

Irradiation doses on thyroid gland during the postoperative irradiation for breast cancer.

PubMed

Akın, Mustafa; Ergen, Arzu; Unal, Aysegul; Bese, Nuran

2014-01-01

Thyroid gland is one of the radiosensitive endocrine organs in the body. It has been shown that direct irradiation of thyroid with total doses of 26 to 30 Gy can lead to functional abnormalities. In this study, irradiation doses on thyroid gland of the patients who received postoperative chest-wall/breast and regional nodal irradiation were assessed. Retrospective analyses of treatment plans from 122 breast cancer patients who were treated with 3D conformal radiotherapy (3D CRT) planning was performed. All patients received irradiation to supraclavicular/level III lymph nodes in addition to chest-wall/breast. A total dose of 46 Gy was delivered in 25 days to supraclavicular/level III lymph node region while a total dose of 50 Gy was delivered to whole breast/chest-wall. Thyroid gland was contoured on 2-5 mm thickness of computed tomography scans. Absolute thyroid volume, mean thyroid doses were calculated. The mean thyroid volume of all patients was 16.7 cc (min: 1.9 cc, max: 41.6 cc). The mean irradiation dose on was 22.5 Gy (0.32 Gy-46.5 Gy). The level of dose was higher than 26 Gy in 44% of the patients. In majority of the node-positive breast cancer patients treated with 3D CRT, the thyroid gland was exposed to considerable doses. On the other hand, for 44% of the patients are at risk for developing thyroid function abnormalities which should be considered during the routine follow-up.

Dietary Aloe Vera Supplementation Improves Facial Wrinkles and Elasticity and It Increases the Type I Procollagen Gene Expression in Human Skin in vivo

PubMed Central

Cho, Soyun; Lee, Serah; Lee, Min-Jung; Lee, Dong Hun; Won, Chong-Hyun; Kim, Sang Min

2009-01-01

Background No studies have yet been undertaken to determine the effect of aloe gel on the clinical signs and biochemical changes of aging skin. Objective We wanted to determine whether dietary aloe vera gel has anti-aging properties on the skin. Methods Thirty healthy female subjects over the age of 45 were recruited and they received 2 different doses (low-dose: 1,200 mg/d, high-dose: 3,600 mg/d) of aloe vera gel supplementation for 90 days. Their baseline status was used as a control. At baseline and at completion of the study, facial wrinkles were measured using a skin replica, and facial elasticity was measured by an in vivo suction skin elasticity meter. Skin samples were taken before and after aloe intake to compare the type I procollagen and matrix metalloproteinase 1 (MMP-1) mRNA levels by performing real-time RT-PCR. Results After aloe gel intake, the facial wrinkles improved significantly (p<0.05) in both groups, and facial elasticity improved in the lower-dose group. In the photoprotected skin, the type I procollagen mRNA levels were increased in both groups, albeit without significance; the MMP-1 mRNA levels were significantly decreased in the higher-dose group. Type I procollagen immunostaining was substantially increased throughout the dermis in both groups. Conclusion Aloe gel significantly improves wrinkles and elasticity in photoaged human skin, with an increase in collagen production in the photoprotected skin and a decrease in the collagen-degrading MMP-1 gene expression. However, no dose-response relationship was found between the low-dose and high-dose groups. PMID:20548848

Renal Insufficiency in Concert with Renin-angiotensin-aldosterone Inhibition Is a Major Risk Factor for Hyperkalemia Associated with Low-dose Trimethoprim-sulfamethoxazole in Adults.

PubMed

Higashioka, Kazuhiko; Niiro, Hiroaki; Yoshida, Kenji; Oryoji, Kensuke; Kamada, Kazuo; Mizuki, Shinichi; Yokota, Eisuke

2016-01-01

Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used to prevent pneumocystis pneumonia in daily practice. Previous reports have shown a relationship between high- or standard-dose of TMP-SMX and hyperkalemia, however it remains unclear whether this is true for low-dose TMP-SMX. In this study we sought to determine the risk factors for hyperkalemia associated with low-dose TMP-SMX. In this retrospective cohort study, 186 consecutive adult patients who received TMP-SMX as prophylaxis for pneumocystis pneumonia from January 2014 to January 2015 were evaluated. Data on the patients' age, gender, baseline estimated glomerular filtration rate (eGFR), baseline serum potassium, maximum serum potassium, duration reaching the maximal serum potassium level, dosage, and concomitant use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), β-blockers, non-steroidal anti-inflammatory drugs and potassium-sparing diuretics were retrospectively collected. Hyperkalemia was defined as a serum potassium level ≥5 mEq/L. Univariate and multivariate analyses were performed. The median age of the patients was 66 years and 51.1% were men. Hyperkalemia associated with low-dose TMP-SMX was observed in 32 patients (17.2%). The median duration to reach the maximal serum potassium level was 12 days. The multivariate logistic regression analysis identified renal insufficiency to be a major risk factor for hyperkalemia associated with low-dose TMP-SMX (eGFR <60 mL/min/1.73 m(2), adjusted OR 4.62). Moreover, in the subpopulation of patients with renal insufficiency, ACEi/ARB use was considered to be a major risk factor for hyperkalemia (adjusted OR 3.96). Renal insufficiency in concert with ACEi/ARB use is a major risk factor for hyperkalemia induced by low-dose TMP-SMX.

Comparison of low-dose spinal anesthesia and single-shot femoral block combination with conventional dose spinal anesthesia in outpatient arthroscopic meniscus repair.

PubMed

Turhan, K S Cakar; Akmese, R; Ozkan, F; Okten, F F

2015-04-01

In the current prospective, randomized study, we aimed to compare the effects of low dose selective spinal anesthesia with 5 mg of hyperbaric bupivacaine and single-shot femoral nerve block combination with conventional dose selective spinal anesthesia in terms of intraoperative anesthesia characteristics, block recovery characteristics, and postoperative analgesic consumption. After obtaining institutional Ethics Committee approval, 52 ASA I-II patients aged 25-65, undergoing arthroscopic meniscus repair were randomly assigned to Group S (conventional dose selective spinal anesthesia with 10 mg bupivacaine) and Group FS (low-dose selective spinal anesthesia with 5mg bupivacaine +single-shot femoral block with 0.25% bupivacaine). Primary endpoints were time to reach T12 sensory block level, L2 regression, and complete motor block regression. Secondary endpoints were maximum sensory block level (MSBL); time to reach MSBL, time to first urination, time to first analgesic consumption and pain severity at the time of first mobilization. Demographic characteristics were similar in both groups (p > 0.05). MSBL and time to reach T12 sensory level were similar in both groups (p > 0.05). Time to reach L2 regression, complete motor block regression, and time to first micturition were significantly shorter; time to first analgesic consumption was significantly longer; and total analgesic consumption and severity of pain at time of first mobilization were significantly lower in Group FS (p < 0.05). The findings of the current study suggest that addition of single-shot femoral block to low dose spinal anesthesia could be an alternative to conventional dose spinal anesthesia in outpatient arthroscopic meniscus repair. NCT02322372.

Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe).

PubMed

Kim, Kyung-Jin; Kim, Sang-Hyun; Yoon, Young Won; Rha, Seung-Woon; Hong, Soon-Jun; Kwak, Choong-Hwan; Kim, Weon; Nam, Chang-Wook; Rhee, Moo-Yong; Park, Tae-Ho; Hong, Taek-Jong; Park, Sungha; Ahn, Youngkeun; Lee, Namho; Jeon, Hui-Kyung; Jeon, Dong-Woon; Han, Kyoo-Rok; Moon, Keon-Woong; Chae, In-Ho; Kim, Hyo-Soo

2016-10-01

We aimed to compare the effects of fixed-dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS). This multicenter eight-week randomized double-blind phase III study evaluated the safety and efficacy of fixed-dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid-lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed-dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily). Fixed-dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed-dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%-63%, 37%-43%, and 19%-24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non-DM or non-MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non-DM or MetS vs non-MetS patients. Fixed-dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS. © 2016 The Authors Cardiovascular Therapeutics Published by John Wiley & Sons Ltd.

Phase I study of neoadjuvant accelerated short course radiation therapy with photons and capecitabine for resectable pancreatic cancer.

PubMed

Wo, Jennifer Y; Mamon, Harvey J; Ferrone, Cristina R; Ryan, David P; Blaszkowsky, Lawrence S; Kwak, Eunice L; Tseng, Yolanda D; Napolitano, Brian N; Ancukiewicz, Marek; Swanson, Richard S; Lillemoe, Keith D; Fernandez-del Castillo, Carlos; Hong, Theodore S

2014-01-01

In this phase I study, we sought to determine the feasibility and tolerability of neoadjuvant short course radiotherapy (SC-CRT) delivered with photon RT with concurrent capecitabine for resectable pancreatic adenocarcinoma. Ten patients with localized, resectable pancreatic adenocarcinoma were enrolled from December 2009 to August 2011. In dose level I, patients received 3 Gy × 10. In dose level 2, patients received 5 Gy × 5 (every other day). In dose level 3, patients received 5 Gy × 5 (consecutive days). Capecitabine was given during weeks 1 and 2. Surgery was performed 1-3 weeks after completion of chemotherapy. With an intended accrual of 12 patients, the study was closed early due to unexpected intraoperative complications. Compared to the companion phase I proton study, patients treated with photons had increased intraoperative RT fibrosis reported by surgeons (27% vs. 63%). Among those undergoing a Whipple resection, increased RT fibrosis translated to an increased mean OR time of 69 min. Dosimetric comparison revealed significantly increased low dose exposure to organs at risk for patients treated with photon RT. This phase I experience evaluating the tolerability of neoadjuvant SC-CRT with photon RT closed early due to unexpected intraoperative complications. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Effects of hydroalcoholic extract of Rhus coriaria seed on glucose and insulin related biomarkers, lipid profile, and hepatic enzymes in nicotinamide-streptozotocin-induced type II diabetic male mice.

PubMed

Ahangarpour, Akram; Heidari, Hamid; Junghani, Majid Salehizade; Absari, Reza; Khoogar, Mehdi; Ghaedi, Ehsan

2017-10-01

Type 2 diabetes often leads to dislipidemia and abnormal activity of hepatic enzymes. The purpose of this study was to evaluate the antidiabetic and hypolipidemic properties of Rhus coriaria ( R. coriaria ) seed extrac on nicotinamide-streptozotocin induced type 2 diabetic mice. In this experimental study, 56 male Naval Medical Research Institute mice (30-35 g) were randomly separated into seven groups: control, diabetic group, diabetic mice treated with glibenclamide (0.25 mg/kg, as standard antidiabetic drug) or R. coriaria seed extract in doses of 200 and 300 mg/kg, and control groups received these two doses of extract orally for 28 days. Induction of diabetes was done by intraperitoneal injection of nicotinamide and streptozotocin. Ultimately, body weight of mice, blood levels of glucose, insulin, hepatic enzymes, leptin, and lipid profile were assayed. After induction of type 2 diabetes, level of glucose, cholesterol, low density lipoprotein, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase increased and level of insulin and high density lipoprotein decreased remarkably. Administration of both doses of extract decreased level of glucose and cholesterol significantly in diabetic mice. LDL level decreased in treated group with dose of 300 mg/kg of the extract. Although usage of the extract improved level of other lipid profiles, insulin and hepatic enzymes, changes weren't significant. This study showed R. coriaria seeds administration has a favorable effect in controlling some blood parameters in type 2 diabetes. Therefore it may be beneficial in the treatment of diabetes.

Using Population Dose to Evaluate Community-level Health Initiatives.

PubMed

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.

Reduction of spermatogenesis in mice after tributyltin administration.

PubMed

Chen, Yufang; Zuo, Zhenghong; Chen, Shuzhen; Yan, Feihuang; Chen, Yixin; Yang, Zengming; Wang, Chonggang

2008-09-29

Organotin compounds, such as tributyltin (TBT) used as an antifouling biocide, can induce masculinization in female mollusks. However, few studies addressing the effect of TBT on spermatogenesis in mammalian have been reported. This study was conducted to investigate the effects of TBT at low doses (0.5, 5, and 50 microg/kg, respectively) on spermatogenesis in mice as exposed from puberty and gave insight into the mechanism. After exposure for 30 days, the gonadosomatic index (GSI) was significantly decreased. The testosterone levels in the testes were not altered and the 17beta-estradiol levels were significantly decreased in a dose-dependent manner, spermatogenesis of the testis was significantly inhibited. Estrogen receptor (ER-alpha and ER-beta) levels in testes of the mice exposed to TBT were decreased in a dose-dependent manner. The results suggest that ER play an important role in TBT-mediated inhibition of spermatogenesis.

[Personal dose monitoring of radiation workers in medical institutions at the municipal level and below in a city from 2011 to 2014].

PubMed

Wang, C; Mo, S F; Zhang, J B; Li, J R; Huang, R L; Tan, H Y

2017-08-20

Objective: To determine the personal dose level of radiation workers in medical institutions at the municipal level and below in a city, and to provide a scientific support for strengthening the radiation protection in the city's medical institutions. Methods: Information of the successful applicants for the "Radiation Worker Permit" from 174 medical institutions at the municipal level and below was collected from October 1, 2011 to December 31, 2014. The annual effective dose was calculated based on the personal dose monitoring report, and indicators including sex, permit application time, hospital level, type of occupational radiation, length of radiation work, blood test, and micronucleated lymphocyte rate were analyzed. Results: Of the 1 143 radiation worker permit applications submitted by medical institutions the municipal level and below in this city from 2011 to 2014, 1 123 provided at least one personal dose monitoring report. The annual effective dose of the radiation workers was 0-4.76 mSv (mean 0.31±0.40 mSv) , and the collective annual effective dose was 351.96 mSv. The annual effective dose was significantly different between radiation workers with different times of permit application, hospital levels, and types of occupational radiation ( P <0.05) . Interventional radiology workers had the highest annual effective dose (0.63 mSv) , and annual effective dose was significantly different between interventional radiology workers with different lengths of radiation work ( H =10.812, P <0.05) . Conclusion: The personal radiation dose of radiation workers in medical institutions at the municipal level and below in this city is maintained at a relatively low level, suggesting that the occupational environment is relatively safe for these workers. However, more focus should be placed on clinical interventional radiology workers.

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

PubMed

Miyauchi, Katsumi; Kimura, Takeshi; Shimokawa, Hiroaki; Daida, Hiroyuki; Iimuro, Satoshi; Iwata, Hiroshi; Ozaki, Yukio; Sakuma, Ichiro; Nakagawa, Yoshihisa; Hibi, Kiyoshi; Hiro, Takafumi; Fukumoto, Yoshihiro; Hokimoto, Seiji; Ohashi, Yasuo; Ohtsu, Hiroshi; Saito, Yasushi; Matsuzaki, Masunori; Nagai, Ryozo

2018-03-30

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.

PubMed

Shimizu, Toshio; Fukuoka, Kazuya; Takeda, Masayuki; Iwasa, Tutomu; Yoshida, Takeshi; Horobin, Joanna; Keegan, Mitchell; Vaickus, Lou; Chavan, Ajit; Padval, Mahesh; Nakagawa, Kazuhiko

2016-05-01

VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

[131I]FIAU labeling of genetically transduced, tumor-reactive lymphocytes: cell-level dosimetry and dose-dependent toxicity.

PubMed

Zanzonico, Pat; Koehne, Guenther; Gallardo, Humilidad F; Doubrovin, Mikhail; Doubrovina, Ekaterina; Finn, Ronald; Blasberg, Ronald G; Riviere, Isabelle; O'Reilly, Richard J; Sadelain, Michel; Larson, Steven M

2006-09-01

Donor T cells have been shown to be reactive against and effective in adoptive immunotherapy of Epstein-Barr virus (EBV) lymphomas which develop in some leukemia patients post marrow transplantation. These T cells may be genetically modified by incorporation of a replication-incompetent viral vector (NIT) encoding both an inactive mutant nerve growth factor receptor (LNGFR), as an immunoselectable surface marker, and a herpes simplex virus thymidine kinase (HSV-TK), rendering the cells sensitive to ganciclovir. The current studies are based on the selective HSV-TK-catalyzed trapping (phosphorylation) of the thymidine analog [(131)I]-2'-fluoro-2'-deoxy-1-beta-D-arabinofuransyl-5-iodo-uracil (FIAU) as a means of stably labeling such T cells for in vivo trafficking (including tumor targeting) studies. Because of the radiosensitivity of lymphocytes and the potentially high absorbed dose to the nucleus from intracellular (131)I (even at tracer levels), the nucleus absorbed dose (D ( n )) and dose-dependent immune functionality were evaluated for NIT(+) T cells labeled ex vivo in [(131)I]FIAU-containing medium. Based on in vitro kinetic studies of [(131)I]FIAU uptake by NIT(+) T cells, D ( n ) was calculated using an adaptation of the MIRD formalism and the recently published MIRD cellular S factors. Immune cytotoxicity of [(131)I]FIAU-labeled cells was assayed against (51)Cr-labeled target cells [B-lymphoblastoid cells (BLCLs)] in a standard 4-h release assay. At median nuclear absorbed doses up to 830 cGy, a (51)Cr-release assay against BLCLs showed no loss of immune cytotoxicity, thus demonstrating the functional integrity of genetically transduced, tumor-reactive T cells labeled at this dose level for in vivo cell trafficking and tumor targeting studies.

Acute and subchronic toxicity study of Tamra Bhasma (incinerated copper) prepared with and without Amritikarana.

PubMed

Chaudhari, Swapnil Y; Nariya, Mukesh B; Galib, R; Prajapati, Pradeep K

2016-03-01

Tamra Bhasma (TB) is one among herbo-metallic preparations extensively used in routine ayurvedic practice. In the present era, Bhasma preparations used in ayurvedic system of medicines are always under stern observations for containing heavy metals which may raise the question of safety aspect. In the present study, TB prepared with and without Amritikarana was subjected to toxicity study to ascertain the role of Amritikarana on safety profile of TB in rats. Both the samples of TB were administered to rats for 28 consecutive days at the doses of 5.5, 27.5, and 55 mg/kg. The effects of both drugs were assessed on ponderal changes, hematological, serum biochemical, and histopathology of various organs. Results showed that both the samples of TB did not produce any sign and symptoms of toxicity at therapeutic dose level (5.5 mg/kg) and therapeutic equivalent dose (TED) × 5 (27.5 mg/kg) while at higher dose of TED × 10 (55 mg/kg) TB has mild toxicity in liver, kidney, heart, and thymus on repeated administration for 28 days in rats. The sample without Amritikarana has more magnitude of toxicity than the sample with Amritikarana. From the present study, it is concluded that TB with Amritikarana was found to be relatively safer than TB without Amritikarana at different dose levels in rats and hence suggest for safely use in humans at therapeutic dose level. It proves the role of Amritikarana in the preparation of TB. Copyright © 2016 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

Ergothioneine prevents endothelial dysfunction induced by mercury chloride.

PubMed

Gökçe, Göksel; Arun, Mehmet Zuhuri; Ertuna, Elif

2018-06-01

Exposure to mercury has detrimental effects on the cardiovascular system, particularly the vascular endothelium. The present study aimed to investigate the effects of ergothioneine (EGT) on endothelial dysfunction induced by low-dose mercury chloride (HgCl 2 ). Agonist-induced contractions and relaxations were evaluated in isolated aortic rings from 3-month-old male Wistar rats treated by intra-muscular injection to caudal hind leg muscle with HgCl 2 (first dose, 4.6 µg/kg; subsequent doses, 0.07 µg/kg/day for 15 days) and optionally with EGT (2 µg/kg for 30 days). Reactive oxygen species (ROS) in aortic rings were measured by means of lucigenin- and luminol-enhanced chemiluminescence. The protein level of endothelial nitric oxide synthase was evaluated by ELISA. Blood glutathione (GSH) and catalase levels, lipid peroxidation and total nitrite were measured spectrophotometrically. The results indicated that low-dose HgCl 2 administration impaired acetylcholine (ACh)-induced relaxation and potentiated phenylephrine- and serotonin-induced contractions in rat aortas. In addition, HgCl 2 significantly increased the levels of ROS in the aortic tissue. EGT prevented the loss of ACh-induced relaxations and the increase in contractile responses. These effects were accompanied by a significant decrease in ROS levels. EGT also improved the ratio of reduced GSH to oxidized GSH and catalase levels with a concomitant decrease in lipid peroxidation. In conclusion, to the best of our knowledge, the present study was the first to report that EGT prevents endothelial dysfunction induced by low-dose HgCl 2 administration. EGT may serve as a therapeutic tool to reduce mercury-associated cardiovascular complications via improving the antioxidant status.

Estimating the dose response relationship for occupational radiation exposure measured with minimum detection level.

PubMed

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.

Radiation exposure levels within timber industries in Calabar, Nigeria

PubMed Central

Inyang, S. O.; Inyang, I. S.; Egbe, N. O.

2009-01-01

The UNSCEAR (2000) observed that there could be some exposure at work which would require regulatory control but is not really considered. This study was, therefore, set up to evaluate the effective dose in timber industries in Calabar, Nigeria to determine if the evaluated dose levels could lead to any radiological health effect in the workers, and also determine if the industries require regulatory control. The gamma ray exposure at four timber industries measured using an exposure meter were converted to effective dose and compared with the public and occupational values. The evaluated effective dose values in the timber industries were below public and occupational exposure limits and may not necessarily result in any radiological health hazard. Therefore, they may not require regulatory control. PMID:20098544

Intradermal inactivated poliovirus vaccine: a preclinical dose-finding study.

PubMed

Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

2015-05-01

Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

A systematic review of Bisphenol A "low dose" studies in the context of human exposure: a case for establishing standards for reporting "low-dose" effects of chemicals.

PubMed

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.

Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a phase I trial (NWCOG-2).

PubMed

Gollins, S W; Myint, S; Susnerwala, S; Haylock, B; Wise, M; Topham, C; Samuel, L; Swindell, R; Morris, J; Mason, L; Levine, E

2009-09-15

The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery. Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (< or =1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m(-2) b.i.d. and irinotecan 50 mg m(-2); Dose level 2: capecitabine 650 mg m(-2) b.i.d. and irinotecan 60 mg m(-2); Dose level 3: capecitabine 825 mg m(-2) b.i.d. and irinotecan 60 mg m(2); Dose level 4: capecitabine 825 mg m(-2) b.i.d. and irinotecan 70 mg m(-2). Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as < or =1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%. In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m(-2) b.i.d. days 1-35 and weekly IV irinotecan at 60 mg m(-2) weeks 1-4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.

Performance of toxicity probability interval based designs in contrast to the continual reassessment method

PubMed Central

Horton, Bethany Jablonski; Wages, Nolan A.; Conaway, Mark R.

2016-01-01

Toxicity probability interval designs have received increasing attention as a dose-finding method in recent years. In this study, we compared the two-stage, likelihood-based continual reassessment method (CRM), modified toxicity probability interval (mTPI), and the Bayesian optimal interval design (BOIN) in order to evaluate each method's performance in dose selection for Phase I trials. We use several summary measures to compare the performance of these methods, including percentage of correct selection (PCS) of the true maximum tolerable dose (MTD), allocation of patients to doses at and around the true MTD, and an accuracy index. This index is an efficiency measure that describes the entire distribution of MTD selection and patient allocation by taking into account the distance between the true probability of toxicity at each dose level and the target toxicity rate. The simulation study considered a broad range of toxicity curves and various sample sizes. When considering PCS, we found that CRM outperformed the two competing methods in most scenarios, followed by BOIN, then mTPI. We observed a similar trend when considering the accuracy index for dose allocation, where CRM most often outperformed both the mTPI and BOIN. These trends were more pronounced with increasing number of dose levels. PMID:27435150

Direct Measurement of Perchlorate Exposure Biomarkers in a Highly Exposed Population: A Pilot Study

PubMed Central

Wong, Michelle; Copan, Lori; Olmedo, Luis; Patton, Sharyle; Haas, Robert; Atencio, Ryan; Xu, Juhua; Valentin-Blasini, Liza

2011-01-01

Exposure to perchlorate is ubiquitous in the United States and has been found to be widespread in food and drinking water. People living in the lower Colorado River region may have perchlorate exposure because of perchlorate in ground water and locally-grown produce. Relatively high doses of perchlorate can inhibit iodine uptake and impair thyroid function, and thus could impair neurological development in utero. We examined human exposures to perchlorate in the Imperial Valley among individuals consuming locally grown produce and compared perchlorate exposure doses to state and federal reference doses. We collected 24-hour urine specimen from a convenience sample of 31 individuals and measured urinary excretion rates of perchlorate, thiocyanate, nitrate, and iodide. In addition, drinking water and local produce were also sampled for perchlorate. All but two of the water samples tested negative for perchlorate. Perchlorate levels in 79 produce samples ranged from non-detect to 1816 ppb. Estimated perchlorate doses ranged from 0.02 to 0.51 µg/kg of body weight/day. Perchlorate dose increased with the number of servings of dairy products consumed and with estimated perchlorate levels in produce consumed. The geometric mean perchlorate dose was 70% higher than for the NHANES reference population. Our sample of 31 Imperial Valley residents had higher perchlorate dose levels compared with national reference ranges. Although none of our exposure estimates exceeded the U. S. EPA reference dose, three participants exceeded the acceptable daily dose as defined by bench mark dose methods used by the California Office of Environmental Health Hazard Assessment. PMID:21394205

Investigation of dose characteristics in three-dimensional MAGAT-type polymer gel dosimetry with MSE MR imaging

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.

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

PubMed

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

2015-01-01

To study the short-term response and tolerance of different doses of amino acids in parenteral nutrition among preterm infants. This study included 86 preterm infants who had a birth weight between 1 000 to 2 000 g and were admitted to the hospital within 24 hours of birth between March 2013 and June 2014. According to the early application of different doses of amino acids, they were randomized into low-dose group (n=29, 1.0 g/kg per day with an increase of 1.0 g/kg daily and a maximum of 3.5 g/kg per day), medium-dose group (n=28, 2.0 g/kg per day with an increase of 1.0 g/kg daily and a maximum of 3.7 g/kg per day), and high-dose group (n=29, 3.0 g/kg per day with an increase of 0.5-1.0 g/kg daily and a maximum of 4.0 g/kg per day). Other routine parenteral nutrition and enteral nutrition support were also applied. The maximum weight loss was lower and the growth rate of head circumference was greater in the high-dose group than in the low-dose group (P<0.05). The infants in the medium- and high-dose groups had faster recovery of birth weight, earlier attainment of 100 kcal/(kg·d) of enteral nutrition, shorter duration of hospital stay, and less hospital cost than those in the low-dose group (P<0.05). Blood urea nitrogen (BUN) levels in the high-dose group increased compared with the other two groups 7 days after birth (P<0.05). The levels of creatinine, pH, bicarbonate, bilirubin, and transaminase and the incidence of complications showed no significant differences between groups (P>0.05). Parenteral administration of high-dose amino acids in preterm infants within 24 hours after birth can improve the short-term nutritional status of preterm infants, but there is a transient increase in BUN level.

Phase II trial of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer.

PubMed

Trump, Donald L; Potter, Douglas M; Muindi, Josephia; Brufsky, Adam; Johnson, Candace S

2006-05-15

Data suggest that vitamin D plays a role in the treatment and prevention of prostate cancer. The combination of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) plus dexamethasone was studied based on evidence that dexamethasone potentiates the antitumor effects of calcitriol and ameliorates hypercalcemia. Oral calcitriol was administered weekly, Monday, Tuesday, and Wednesday (MTW), at a dose of 8 microg, for 1 month, at a dose of 10 microg every MTW for 1 month, and at a dose of 12 microg every MTW thereafter. Dexamethasone at a dose of 4 mg was administered each Sunday, and MTW weekly. Calcium and creatinine were determined weekly and radiographs of the urinary tract were performed every 3 months. All patients were considered evaluable for toxicity. Forty-three men with androgen-independent prostate cancer were entered; 37 received at least 1 month of calcitriol given at a dose of 12 microg every day x 3 per week. The majority of patients had bone metastases and rising prostate-specific antigen (PSA) levels. All had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eight patients (19%) experienced partial responses by PSA criterion (PSA decline of > or =50%, persisting for > or = 28 days). Subjective clinical improvement occurred in some patients. Toxicity was minimal: urinary tract stones in 2 patients; and a readily reversible, CTC (v.3.0) Grade <2 creatinine increase in 4 patients. Throughout the study only 4 patients ever had a serum calcium level >11.0 mg/dL and no patient had a calcium level >12.0 mg/dL. The response rate reported in the current study (19%) was not found to be clearly higher than expected with dexamethasone alone. High-dose intermittent calcitriol plus dexamethasone appears to be safe, feasible, and has antitumor activity. Copyright 2006 American Cancer Society

Lack of Response in an Autistic Population to a Low Dose Clinical Trial of Pyridoxine Plus Magnesium.

ERIC Educational Resources Information Center

Tolbert, Lelland; And Others

1993-01-01

As some therapeutic benefits for autistic persons have been reported from combined high doses of pyridoxine and magnesium, this study evaluated long-term administration of low doses (to minimize adverse effects) to 15 subjects with autism. Findings indicated that, at this dosage level, pyridoxine and magnesium had no effect on the severity of…

Transfer of Low Dose Aspirin Into Human Milk.

PubMed

Datta, Palika; Rewers-Felkins, Kathleen; Kallem, Raja Reddy; Baker, Teresa; Hale, Thomas W

2017-05-01

Aspirin has antipyretic and anti-inflammatory properties and is frequently used by pregnant and lactating women. However, its transfer in human milk when administered at low dose has not been reported. Research aim: This study aimed to evaluate the transfer of acetylsalicylic acid and its metabolite, salicylic acid, into human milk following the use of low dose aspirin. In this study, milk samples were collected at 0, 1, 2, 4, 8, 12, and 24 hours from seven breastfeeding women after a steady-state daily dose of 81 mg of aspirin. Milk levels of acetylsalicylic acid and salicylic acid were determined by liquid chromatography-tandem mass spectrometry. Acetylsalicylic acid levels were below the limit of quantification (0.61 ng/ml) in all the milk samples, whereas salicylic acid was detected at very low concentrations. The average concentration of salicylic acid observed was 24 ng/ml and the estimated relative infant dose was 0.4%. Acetylsalicylic acid transfer into milk is so low that it is undetectable even by highly sophisticated methodology. Salicylic acid does appear in the human milk in comparatively low amounts, which are probably subclinical in infants. Thus, the daily use of an 81-mg dose of aspirin should be considered safe during lactation.

Subchronic toxicity studies of t-butyl alcohol in rats and mice.

PubMed

Lindamood, C; Farnell, D R; Giles, H D; Prejean, J D; Collins, J J; Takahashi, K; Maronpot, R R

1992-07-01

The purpose of this study was to evaluate the toxicity of t-butyl alcohol, an important commodity chemical, an additive to unleaded gasoline, and a contaminant of drinking water. Ninety-day toxicity studies were conducted in B6C3F1 mice and Fischer 344 (F344) rats of both sexes using dosed water. Dose levels of t-butyl alcohol were 0, 0.25, 0.5, 1, 2, and 4% (w/v). Lethality was observed at the 4% level of both sexes and species. Weight-gain depression was present in all dose levels of male rats; 4% female rats; 1, 2, and 4% male mice; and 2 and 4% female mice. Water consumption was increased at lower dose levels in male rats and decreased in the higher dose levels of both sexes of rats and female mice. Clinical signs in rats were ataxia in both sexes and hypoactivity in males. Clinical signs in mice were ataxia, abnormal posture, and hypoactivity. In rats, urine volumes were reduced, in association with crystalluria. Gross lesions at necropsy were urinary tract calculi, renal pelvic and ureteral dilatation, and thickening of the urinary bladder mucosa. Microscopic lesions were hyperplasia of transitional epithelia and inflammation of the urinary bladder. In male rats treated with t-butyl alcohol, microscopic renal changes were suggestive of alpha-2 mu-globulin nephropathy. No-effect levels for the urinary tract lesions were 1% in male rats and mice (803.7 mg/kg/day for the male rats and 1565.8 mg/kg/day for the male mice) and 2% in female rats and mice (1451.5 mg/kg/day for the female rats and 4362.9 mg/kg/day for the female mice). The results indicate that in rodents the urinary tract is the target organ for t-butyl alcohol toxicity, and males are more sensitive to t-butyl alcohol toxicity than females.

Detection of pulmonary nodule growth with dose reduced chest tomosynthesis: a human observer study using simulated nodules

NASA Astrophysics Data System (ADS)

Söderman, Christina; Johnsson, Ã. se; Vikgren, Jenny; Rossi Norrlund, Rauni; Molnar, David; Mirzai, Maral; Svalkvist, Angelica; Mânsson, Lars Gunnar; Bâth, Magnus

2016-03-01

Chest tomosynthesis may be a suitable alternative to computed tomography for the clinical task of follow up of pulmonary nodules. The aim of the present study was to investigate the detection of pulmonary nodule growth suggestive of malignancy using chest tomosynthesis. Previous studies have indicated remained levels of detection of pulmonary nodules at dose levels corresponding to that of a conventional lateral radiograph, approximately 0.04 mSv, which motivated to perform the present study this dose level. Pairs of chest tomosynthesis image sets, where the image sets in each pair were acquired of the same patient at two separate occasions, were included in the study. Simulated nodules with original diameters of approximately 8 mm were inserted in the pairs of image sets, simulating situations where the nodule had remained stable in size or increased isotropically in size between the two different imaging occasions. Four different categories of nodule growth were included, corresponding to a volume increase of approximately 21 %, 68 %, 108 % and 250 %. All nodules were centered in the depth direction in the tomosynthesis images. All images were subjected to a simulated dose reduction, resulting in images corresponding to an effective dose of 0.04 mSv. Four observers were given the task of rating their confidence that the nodule was stable in size or not on a five-level rating scale. This was done both before any size measurements were made of the nodule as well as after measurements were performed. Using Receiver operating characteristic analysis, the rating data for the nodules that were stable in size was compared to the rating data for the nodules simulated to have increased in size. Statistically significant differences between the rating distributions for the stable nodules and all of the four nodule growth categories were found. For the three largest nodule growths, nearly perfect detection of nodule growth was seen. In conclusion, the present study indicates that during optimal imaging conditions and for nodules with diameters of approximately 8 mm that grow fairly symmetrically, chest tomosynthesis performed at a dose level corresponding to that of a lateral chest radiograph can, with high sensitivity, differentiate nodules stable in size from nodules growing at rates associated with fast growing malignant nodules.

Range and trend of expected toxicity level (ETL) in standard A + B designs: a report from the Children's Oncology Group.

PubMed

Chen, Zhengjia; Krailo, Mark D; Sun, Junfeng; Azen, Stanley P

2009-03-01

The traditional algorithm-based 3+3 designs are most widely used for their practical simplicity in phase I clinical trials. At early stage, a common belief was that the expected toxicity level (ETL) at the maximum tolerated dose (MTD) should be 33% [Storer, B. Design and analysis of phase I clinical trials. Biometrics 1989;45;925-937, Gorden, N., Willson, J. Using toxicity grades in the design and analysis of cancer phase I clinical trials. Statistics in Medicine 1992; 11: 2063-2075, Mick, R. Phase I Clinical Trial Design. In Schilsky, R., Milano, G., Ratain, M., eds. Principles of Antineoplastic Drug Development and Pharmacology New York, NY: Marcel Dekker, 1996; 29-36]. Recently, Kang and Ahn [Kang, S., Ahn, C. The expected toxicity rate at the maximum tolerated dose in the standard phase I cancer clinical trial design. Drug Information Journal 2001; 35:1189-1199, Kang, S., Ahn, C. An investigation of the traditional algorithm-based designs for phase I cancer clinical trials. Drug Information Journal 2002; 36:865-873] found that the ETL is between 17% and 21% and He et al [He, W., Liu, J., Binkowitz, B., Quan, H. A model-based approach in the estimation of the maximum tolerated dose in phase I cancer clinical trials. Statistics in Medicine 2006; 25(12):2027-42] further reported that the ETL ranges from 19% to 24%. However they only investigated designs where the number of dose levels was at most 20. It has practical significance in designing and conducting phase I clinical trial to definitely assess the full range and trend of ETL by all possible number of tested dose levels in traditional algorithm-based A+B designs, especially 3+3 designs. In this simulation study, we originally find that the ETL decreases monotonically from about 30% to 0% as the number of dose levels increase from 3 to infinity, which will correct the inaccuracy in the common belief among phase I trial investigators. To help better design and conduct phase I trials, we create a table as a reference for the association between ETL and number of dose levels considered in a design when the exact shape of the dose-toxicity relationship is not well understood. We conclude that the number of specified dose levels is an important factor affecting substantially the ETL at MTD and recommend that fewer than 20 dose levels be designated.

Effects of ursolic acid on glucose metabolism, the polyol pathway and dyslipidemia in non-obese type 2 diabetic mice.

PubMed

Lee, Jin; Lee, Hae-In; Seo, Kown-Il; Cho, Hyun Wook; Kim, Myung-Joo; Park, Eun-Mi; Lee, Mi-Kyung

2014-07-01

Ursolic acid (UA) is a pentacyclic triterpenoid compound that naturally occurs in fruits, leaves and flowers of medicinal herbs. This study investigated the dose-response efficacy of UA (0.01 and 0.05%) on glucose metabolism, the polyol pathway and dyslipidemia in streptozotocin/nicotinamide-induced diabetic mice. Supplement with both UA doses reduced fasting blood glucose and plasma triglyceride levels in non-obese type 2 diabetic mice. High-dose UA significantly lowered plasma free fatty acid, total cholesterol and VLDL-cholesterol levels compared with the diabetic control mice, while LDL-cholesterol levels were reduced with both doses. UA supplement effectively decreased hepatic glucose-6-phosphatase activity and increased glucokinase activity, the glucokinase/glucose-6-phosphatase ratio, GLUT2 mRNA levels and glycogen content compared with the diabetic control mice. UA supplement attenuated hyperglycemia-induced renal hypertrophy and histological changes. Renal aldose reductase activity was higher, whereas sorbitol dehydrogenase activity was lower in the diabetic control group than in the non-diabetic group. However, UA supplement reversed the biochemical changes in polyol pathway to normal values. These results demonstrated that low-dose UA had preventive potency for diabetic renal complications, which could be mediated by changes in hepatic glucose metabolism and the renal polyol pathway. High-dose UA was more effective anti-dyslipidemia therapy in non-obese type 2 diabetic mice.

Comparative plasma salicylate and urine salicylurate levels following administration of aspirin, magnesium salicylate, and choline magnesium trisalicylate.

PubMed

Mason, W D

1980-11-01

Eighteen healthy volunteers were administered single doses of commercially available solid dosage forms of aspirin, magnesium salicylate (I), and choline magnesium trisalicylate (II), equivalent to approximately 500 mg of salicylic acid, in a randomized, complete crossover design. Plasma salicylate and urine salicylurate levels were measured by high-pressure liquid chromatography at frequent intervals following dosing; the resultant profiles, areas under the curve (AUC), and percentages of dose excreted as salicylurate were statistically analyzed by an analysis of variance. The plasma salicylate levels following the two dosage forms containing I and II were virtually identical when corrected for small differences in the dose. The plasma salicylic acid level following aspirin was approximately 10% lower during the 1.5--3.0-hr interval due to a portion of unhydrolyzed aspirin, but the dose-corrected AUC for the products tested did not differ significantly (p < 0.05). During the 24 hr following dosing, 66.5 +/- 12.1 68.4 +/- 7.1, and 60.9 +/- 14.1% of the salicylic acid were excreted as urine salicylurate for aspirin, I, and II, respectively, with no significant difference (p < 0.05). Based on this study, there are no significant differences in the rate and extent of absorption of salicylate following the three dosage forms tested, and the elimination kinetics of salicylic acid are not altered by these dosage forms.

Pharmacokinetics, pharmacodynamics, safety and tolerability of an intravaginal ring releasing anastrozole and levonorgestrel in healthy premenopausal women: a Phase 1 randomized controlled trial.

PubMed

Schultze-Mosgau, M-H; Waellnitz, K; Nave, R; Klein, S; Kraetzschmar, J; Rautenberg, T; Schmitz, H; Rohde, B

2016-08-01

What are suitable doses of the aromatase inhibitor anastrozole (ATZ) and the progestin levonorgestrel (LNG), when delivered to the systemic circulation by an intravaginal ring (IVR), for further clinical development as a potential new therapy for the treatment of endometriosis? Anticipated targets for pharmacokinetics, pharmacodynamics and safety/tolerability were achieved for both drug components of the IVR at the doses investigated, supporting selection of the doses to be investigated in Phase 2 studies. Aromatase is a key enzyme in the biosynthesis of estrogens and is known to increase local levels of estradiol (E2) at extragonadal sites. Up-regulation of aromatase expression has been demonstrated in endometriotic lesions and the use of oral aromatase inhibitors has been shown to reduce endometriosis-associated pelvic pain in small-scale clinical trials. This Phase 1, randomized, multicentre, parallel-group, three-arm, open-label study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of various IVRs intended for systemic drug delivery. After screening, healthy, ovulating women aged 18-35 years were randomized to use IVRs releasing one of the three ATZ/LNG dose combinations (in vitro nominal daily drug release rates on Day 29: ATZ/LNG 500 µg/20 µg [low dose], ATZ/LNG 1000 µg/30 µg [mid dose] or ATZ/LNG 1500 µg/40 µg [high dose]) for two consecutive 28-day wearing periods without a treatment break. Sixty women were included in the per protocol set. The primary variables were plasma concentrations of ATZ and LNG at the end of each treatment period and the mean size of largest follicle-like structures (FLSs) over 56 days. Serum concentrations of several hormones were also evaluated, with emphasis on E2 levels. At the end of the first treatment period, geometric mean plasma concentrations of LNG and ATZ, respectively, were 0.228 and 12.5 µg/l for the low dose, 0.269 and 19.8 µg/l for the mid dose and 0.384 and 37.3 µg/l for the high dose; results were similar at the end of the second treatment period. Over the entire treatment period, mean FLS sizes were higher in all three treatment groups than during the pretreatment cycle; more women in the mid- and high-dose groups had FLSs of at least 30 mm (32-45%) than those in the low-dose group (14-24%). Changes in the mean size of FLSs were similar to those reported for low-dose progestin-only oral contraceptives and generally resolved during the 2-month treatment period. Serum E2 levels were decreased, but only one woman in each of the mid- and high-dose groups, and no woman in the low-dose group, had a serum E2 level below 20 pg/ml in both cycles. All ATZ and LNG combinations showed good tolerability. This was an exploratory study; no formal power calculation was performed. The results of this first-in-human study of the ATZ/LNG IVR facilitated the selection of ATZ and LNG doses to be investigated in the Phase 2 studies of patients with endometriosis. The study was funded by Bayer Pharma AG. T.R. is an employee of DINOX GmbH, which received funding from Bayer Pharma AG to perform this study. M.-H.S.-M., K.W., R.N., S.K., J.K., H.S. and B.R. are or have been employees of Bayer Pharma AG. H.S. is a named inventor on EP 2 552 404 B1, a patent application relating to this work. EudraCT number: 2011-005620-18. 16 November 2011. 14 March 2012. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Opioid doses required for pain management in lung cancer patients with different cholesterol levels: negative correlation between opioid doses and cholesterol levels.

PubMed

Huang, Zhenhua; Liang, Lining; Li, Lingyu; Xu, Miao; Li, Xiang; Sun, Hao; He, Songwei; Lin, Lilong; Zhang, Yixin; Song, Yancheng; Yang, Man; Luo, Yuling; Loh, Horace H; Law, Ping-Yee; Zheng, Dayong; Zheng, Hui

2016-03-08

Pain management has been considered as significant contributor to broad quality-of-life improvement for cancer patients. Modulating serum cholesterol levels affects analgesia abilities of opioids, important pain killer for cancer patients, in mice system. Thus the correlation between opioids usages and cholesterol levels were investigated in human patients with lung cancer. Medical records of 282 patients were selected with following criteria, 1) signed inform consent, 2) full medical records on total serum cholesterol levels and opioid administration, 3) opioid-naïve, 4) not received/receiving cancer-related or cholesterol lowering treatment, 5) pain level at level 5-8. The patients were divided into different groups basing on their gender and cholesterol levels. Since different opioids, morphine, oxycodone, and fentanyl, were all administrated at fixed low dose initially and increased gradually only if pain was not controlled, the percentages of patients in each group who did not respond to the initial doses of opioids and required higher doses for pain management were determined and compared. Patients with relative low cholesterol levels have larger percentage (11 out of 28 in female and 31 out of 71 in male) to not respond to the initial dose of opioids than those with high cholesterol levels (0 out of 258 in female and 8 out of 74 in male). Similar differences were obtained when patients with different opioids were analyzed separately. After converting the doses of different opioids to equivalent doses of oxycodone, significant correlation between opioid usages and cholesterol levels was also observed. Therefore, more attention should be taken to those cancer patients with low cholesterol levels because they may require higher doses of opioids as pain killer.

Evaluation of Radiation Exposure to Staff and Environment Dose from [18F]-FDG in PET/CT and Cyclotron Center using Thermoluminescent Dosimetry

PubMed Central

Zargan, S.; Ghafarian, P.; Shabestani Monfared, A.; Sharafi, A.A.; Bakhshayeshkaram, M.; Ay, M.R.

2017-01-01

Background: PET/CT imaging using [18F]-FDG is utilized in clinical oncology for tumor detecting, staging and responding to therapy procedures. Essential consideration must be taken for radiation staff due to high gamma radiation in PET/CT and cyclotron center. The aim of this study was to assess the staff exposure regarding whole body and organ dose and to evaluate environment dose in PET/CT and cyclotron center. Materials and Methods: 80 patients participated in this study. Thermoluminescence, electronic personal dosimeter and Geiger-Muller dosimeter were also utilized for measurement purpose. Results: The mean annual equivalent organ dose for scanning operator with regard to lens of eyes, thyroid, breast and finger according to mean±SD value, were 0.262±0.044, 0.256±0.046, 0.257±0.040 and 0.316±0.118, respectively. The maximum and minimum estimated annual whole body doses were observed for injector and the chemist group with values of (3.98±0.021) mSv/yr and (1.64±0.014) mSv/yr, respectively. The observed dose rates were 5.67 µSv/h in uptake room at the distance of 0.5 meter from the patient whereas the value 4.94 and 3.08 µSv/h were recorded close to patient’s head in PET/CT room and 3.5 meter from the reception desk. Conclusion: In this study, the injector staff and scanning operator received the first high level and second high level of radiation. This study confirmed that low levels of radiation dose were received by all radiation staff during PET/CT procedure using 18F-FDG due to efficient shielding and using trained radiation staff in PET/CT and cyclotron center of Masih Daneshvari hospital. PMID:28451574

Dose-response toxicity studies on tributoxyethyl phosphate orally administered to Sprague-Dawley rats

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

Laham, S.; Szabo, J.; Long, G.

The response of the peripheral nervous system to various dose levels of tributoxyethyl phosphate (TBOP) was investigated in Sprague-Dawley rats. Groups of randomized female and male rats (10 rats/gender/dose level) were administered a single oral dose of TBOP (1.0 to 3.2 g/kg for females;1.0 to 9.0 g/kg for males). Physiological parameters were measured in surviving rats three weeks following TBOP administration. A significant reduction (p<0.05) in caudal nerve conduction velocity (NCV) was observed in both female and male rats. Light and electron microscopic examination of sciatic nerve sections showed degenerative changes in both myelinated and unmyelinated fibers of female (2.0more » g/kg) and male (6.8 g/kg) groups. Advanced degeneration was observed only in the highest dose level of both genders (3.2 g/kg for females; 8.0 and 9.0 g/kg for males). Although similar morphological changes were observed in both genders, females were more susceptible than males to the toxic effects of this compound.« less

MGMT hypomethylation is associated with DNA damage in workers exposed to low-dose benzene.

PubMed

Li, Jie; Zhang, Xinjie; He, Zhini; Sun, Qing; Qin, Fei; Huang, Zhenlie; Zhang, Xiao; Sun, Xin; Liu, Linhua; Chen, Liping; Gao, Chen; Wang, Shan; Wang, Fangping; Li, Daochuan; Zeng, Xiaowen; Deng, Qifei; Wang, Qing; Zhang, Bo; Tang, Huanwen; Chen, Wen; Xiao, Yongmei

2017-07-01

This study aims to assess the effects of low-dose benzene on DNA damage and O 6 -methylguanine-DNA methyltransferase (MGMT) methylation in occupational workers. We recruited 96 nonsmoking male petrochemical industry workers exposed to low-dose benzene and 100 matched control workers. Urinary S-phenylmercapturic acid (SPMA) and S-benzylmercapturic acid (SBMA) were measured for indicating internal exposure of benzene and toluene. The degree of DNA damage was determined by the Comet assay. The levels of MGMT methylation were detected quantitatively by bisulphite-PCR pyrosequencing assay. The benzene-exposed workers had significantly higher levels of urinary SPMA, degree of DNA damage but decreased MGMT methylation than the controls (all p < 0.05). In contrast, the level of urinary SBMA does not differ between benzene-exposed workers and the controls. In all participants, MGMT methylation was negatively associated with the urinary SPMA and the degree of DNA damage, indicating that epigenetic regulation might be involved in response to low-dose benzene exposure-induced genetic damage. MGMT methylation could be a potent biomarker associated with low-dose benzene exposure and benzene-induced DNA damage.

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

Influence of ketamine on regional brain glucose use

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

Davis, D.W.; Mans, A.M.; Biebuyck, J.F.

1988-08-01

The purpose of this study was to determine the effect of different doses of ketamine on cerebral function at the level of individual brain structures as reflected by glucose use. Rats received either 5 or 30 mg/kg ketamine intravenously as a loading dose, followed by an infusion to maintain a steady-state level of the drug. An additional group received 30 mg/kg as a single injection only, and was studied 20 min later, by which time they were recovering consciousness (withdrawal group). Regional brain energy metabolism was evaluated with (6-/sup 14/C)glucose and quantitative autoradiography during a 5-min experimental period. A subhypnotic,more » steady-state dose (5 mg/kg) of ketamine caused a stimulation of glucose use in most brain areas, with an average increase of 20%. At the larger steady-state dose (30 mg/kg, which is sufficient to cause anesthesia), there was no significant effect on most brain regions; some sensory nuclei were depressed (inferior colliculus, -29%; cerebellar dentate nucleus, -18%; vestibular nucleus, -16%), but glucose use in the ventral posterior hippocampus was increased by 33%. In contrast, during withdrawal from a 30-mg/kg bolus, there was a stimulation of glucose use throughout the brain (21-78%), at a time when plasma ketamine levels were similar to the levels in the 5 mg/kg group. At each steady-state dose, as well as during withdrawal, ketamine caused a notable stimulation of glucose use by the hippocampus.« less

TU-H-CAMPUS-JeP1-05: Dose Deformation Error Associated with Deformable Image Registration Pathways

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

Surucu, M; Woerner, A; Roeske, J

Purpose: To evaluate errors associated with using different deformable image registration (DIR) pathways to deform dose from planning CT (pCT) to cone-beam CT (CBCT). Methods: Deforming dose is controversial because of the lack of quality assurance tools. We previously proposed a novel metric to evaluate dose deformation error (DDE) by warping dose information using two methods, via dose and contour deformation. First, isodose lines of the pCT were converted into structures and then deformed to the CBCT using an image based deformation map (dose/structure/deform). Alternatively, the dose matrix from the pCT was deformed to CBCT using the same deformation map,more » and then the same isodose lines of the deformed dose were converted into structures (dose/deform/structure). The doses corresponding to each structure were queried from the deformed dose and full-width-half-maximums were used to evaluate the dose dispersion. The difference between the FWHM of each isodose level structure is defined as the DDE. Three head-and-neck cancer patients were identified. For each patient, two DIRs were performed between the pCT and CBCT, either deforming pCT-to-CBCT or CBCT-to-pCT. We evaluated the errors associated by using either of these pathways to deform dose. A commercially available, Demons based DIR was used for this study, and 10 isodose levels (20% to 105%) were used to evaluate the errors in various dose levels. Results: The prescription dose for all patients was 70 Gy. The mean DDE for CT-to-CBCT deformation was 1.0 Gy (range: 0.3–2.0 Gy) and this was increased to 4.3 Gy (range: 1.5–6.4 Gy) for CBCT-to-CT deformation. The mean increase in DDE between the two deformations was 3.3 Gy (range: 1.0–5.4 Gy). Conclusion: The proposed DDF was used to quantitatively estimate dose deformation errors caused by different pathways to perform DIR. Deforming dose using CBCT-to-CT deformation produced greater error than CT-to-CBCT deformation.« less

PAEDIATRIC CT EXPOSURE PRACTICE IN THE COUNTY OF RIO DE JANEIRO: THE NEED TO ESTABLISH DIAGNOSTIC REFERENCE LEVELS.

PubMed

de Jesus, Fillipe M; Magalhães, Luis A G; Kodlulovich, Simone

2016-11-01

A pilot study of dose indicators in paediatric computed tomography (CT) was conducted to prove the need to establish diagnostic reference levels (DRLs) for the county of Rio de Janeiro. The dose descriptors were estimated from the beam dosimetry by applying the protocols used in each examination. The total patient sample included 279 children. Regarding the comparison of the dose-length product values among the hospitals, the high-resolution chest CT scans were distinguished among the three types of examinations, due to the discrepancies of 1148 % (1-5 y age group) and 2248 % (5-10 y age group) presented in Hospital A's dose-length product values relative to Hospital D's dose-length product values. The results showed that without DRL, the dose variation can be significant between hospitals in the same county for the same age group in the same examination. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice

PubMed Central

De Cock, R. F. W.; Allegaert, K.; Vanhaesebrouck, S.; Danhof, M.; Knibbe, C. A. J.

2015-01-01

Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization. PMID:26248375

The effects of cannabinoids on serum cortisol and prolactin in humans

PubMed Central

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

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

Li, Ke; Chen, Guang-Hong, E-mail: gchen7@wisc.edu; Garrett, John

Purpose: Statistical model based iterative reconstruction (MBIR) methods have been introduced to clinical CT systems and are being used in some clinical diagnostic applications. The purpose of this paper is to experimentally assess the unique spatial resolution characteristics of this nonlinear reconstruction method and identify its potential impact on the detectabilities and the associated radiation dose levels for specific imaging tasks. Methods: The thoracic section of a pediatric phantom was repeatedly scanned 50 or 100 times using a 64-slice clinical CT scanner at four different dose levels [CTDI{sub vol} =4, 8, 12, 16 (mGy)]. Both filtered backprojection (FBP) and MBIRmore » (Veo{sup ®}, GE Healthcare, Waukesha, WI) were used for image reconstruction and results were compared with one another. Eight test objects in the phantom with contrast levels ranging from 13 to 1710 HU were used to assess spatial resolution. The axial spatial resolution was quantified with the point spread function (PSF), while the z resolution was quantified with the slice sensitivity profile. Both were measured locally on the test objects and in the image domain. The dependence of spatial resolution on contrast and dose levels was studied. The study also features a systematic investigation of the potential trade-off between spatial resolution and locally defined noise and their joint impact on the overall image quality, which was quantified by the image domain-based channelized Hotelling observer (CHO) detectability index d′. Results: (1) The axial spatial resolution of MBIR depends on both radiation dose level and image contrast level, whereas it is supposedly independent of these two factors in FBP. The axial spatial resolution of MBIR always improved with an increasing radiation dose level and/or contrast level. (2) The axial spatial resolution of MBIR became equivalent to that of FBP at some transitional contrast level, above which MBIR demonstrated superior spatial resolution than FBP (and vice versa); the value of this transitional contrast highly depended on the dose level. (3) The PSFs of MBIR could be approximated as Gaussian functions with reasonably good accuracy. (4) Thez resolution of MBIR showed similar contrast and dose dependence. (5) Noise standard deviation assessed on the edges of objects demonstrated a trade-off with spatial resolution in MBIR. (5) When both spatial resolution and image noise were considered using the CHO analysis, MBIR led to significant improvement in the overall CT image quality for both high and low contrast detection tasks at both standard and low dose levels. Conclusions: Due to the intrinsic nonlinearity of the MBIR method, many well-known CT spatial resolution and noise properties have been modified. In particular, dose dependence and contrast dependence have been introduced to the spatial resolution of CT images by MBIR. The method has also introduced some novel noise-resolution trade-off not seen in traditional CT images. While the benefits of MBIR regarding the overall image quality, as demonstrated in this work, are significant, the optimal use of this method in clinical practice demands a thorough understanding of its unique physical characteristics.« less

Statistical model based iterative reconstruction (MBIR) in clinical CT systems. Part II. Experimental assessment of spatial resolution performance.

PubMed

Li, Ke; Garrett, John; Ge, Yongshuai; Chen, Guang-Hong

2014-07-01

Statistical model based iterative reconstruction (MBIR) methods have been introduced to clinical CT systems and are being used in some clinical diagnostic applications. The purpose of this paper is to experimentally assess the unique spatial resolution characteristics of this nonlinear reconstruction method and identify its potential impact on the detectabilities and the associated radiation dose levels for specific imaging tasks. The thoracic section of a pediatric phantom was repeatedly scanned 50 or 100 times using a 64-slice clinical CT scanner at four different dose levels [CTDIvol =4, 8, 12, 16 (mGy)]. Both filtered backprojection (FBP) and MBIR (Veo(®), GE Healthcare, Waukesha, WI) were used for image reconstruction and results were compared with one another. Eight test objects in the phantom with contrast levels ranging from 13 to 1710 HU were used to assess spatial resolution. The axial spatial resolution was quantified with the point spread function (PSF), while the z resolution was quantified with the slice sensitivity profile. Both were measured locally on the test objects and in the image domain. The dependence of spatial resolution on contrast and dose levels was studied. The study also features a systematic investigation of the potential trade-off between spatial resolution and locally defined noise and their joint impact on the overall image quality, which was quantified by the image domain-based channelized Hotelling observer (CHO) detectability index d'. (1) The axial spatial resolution of MBIR depends on both radiation dose level and image contrast level, whereas it is supposedly independent of these two factors in FBP. The axial spatial resolution of MBIR always improved with an increasing radiation dose level and/or contrast level. (2) The axial spatial resolution of MBIR became equivalent to that of FBP at some transitional contrast level, above which MBIR demonstrated superior spatial resolution than FBP (and vice versa); the value of this transitional contrast highly depended on the dose level. (3) The PSFs of MBIR could be approximated as Gaussian functions with reasonably good accuracy. (4) Thez resolution of MBIR showed similar contrast and dose dependence. (5) Noise standard deviation assessed on the edges of objects demonstrated a trade-off with spatial resolution in MBIR. (5) When both spatial resolution and image noise were considered using the CHO analysis, MBIR led to significant improvement in the overall CT image quality for both high and low contrast detection tasks at both standard and low dose levels. Due to the intrinsic nonlinearity of the MBIR method, many well-known CT spatial resolution and noise properties have been modified. In particular, dose dependence and contrast dependence have been introduced to the spatial resolution of CT images by MBIR. The method has also introduced some novel noise-resolution trade-off not seen in traditional CT images. While the benefits of MBIR regarding the overall image quality, as demonstrated in this work, are significant, the optimal use of this method in clinical practice demands a thorough understanding of its unique physical characteristics.

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

PubMed

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

2016-11-01

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

Radionuclides in bats using a contaminated pond on the Nevada National Security Site, USA

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

Warren, Ronald W.; Hall, Derek B.; Greger, Paul D.

In this study, perched groundwater percolating through radionuclide contamination in the E Tunnel Complex on the Nevada National Security Site, formerly the Nevada Test Site, emerges and is stored in a series of ponds making it available to wildlife, including bats. Since many bat species using the ponds are considered sensitive or protected/regulated and little information is available on dose to bats from radioactive water sources, bats were sampled to determine if the dose they were receiving exceeded the United States Department of Energy dose limit of 1.0E-3 Gy/day. Radionuclide concentrations in water, sediment, and flying insects were also measuredmore » as input parameters to the dose rate model and to examine trophic level relationships. The RESRAD-Biota model was used to calculate dose rates to bats using different screening levels. Efficacy of RESRAD-Biota and suggested improvements are discussed. Finally, dose to bats foraging and drinking at these ponds is well below the dose limit set to protect terrestrial biota populations.« less

Radionuclides in bats using a contaminated pond on the Nevada National Security Site, USA

DOE PAGES

Warren, Ronald W.; Hall, Derek B.; Greger, Paul D.

2014-01-03

In this study, perched groundwater percolating through radionuclide contamination in the E Tunnel Complex on the Nevada National Security Site, formerly the Nevada Test Site, emerges and is stored in a series of ponds making it available to wildlife, including bats. Since many bat species using the ponds are considered sensitive or protected/regulated and little information is available on dose to bats from radioactive water sources, bats were sampled to determine if the dose they were receiving exceeded the United States Department of Energy dose limit of 1.0E-3 Gy/day. Radionuclide concentrations in water, sediment, and flying insects were also measuredmore » as input parameters to the dose rate model and to examine trophic level relationships. The RESRAD-Biota model was used to calculate dose rates to bats using different screening levels. Efficacy of RESRAD-Biota and suggested improvements are discussed. Finally, dose to bats foraging and drinking at these ponds is well below the dose limit set to protect terrestrial biota populations.« less

A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

PubMed

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.

Association between physical activity and risk of nonalcoholic fatty liver disease: a meta-analysis.

PubMed

Qiu, Shanhu; Cai, Xue; Sun, Zilin; Li, Ling; Zügel, Martina; Steinacker, Jürgen Michael; Schumann, Uwe

2017-09-01

Increased physical activity (PA) is a key element in the management of patients with nonalcoholic fatty liver disease (NAFLD); however, its association with NAFLD risk has not been systematically assessed. This meta-analysis of observational studies was to quantify this association with dose-response analysis. Electronic databases were searched to January 2017 for studies of adults reporting the risk of NAFLD in relation to PA with cohort or case-control designs. Studies that reported sex-specific data were included as separate studies. The overall risk estimates were pooled using a random-effects model, and the dose-response analysis was conducted to shape the quantitative relationship. A total of 6 cohort studies from 5 articles with 32,657 incident NAFLD cases from 142,781 participants, and 4 case-control studies from 3 articles with 382 NAFLD cases and 302 controls were included. Compared with the lowest PA level, the highest PA level was associated with a risk reduction of NAFLD in cohort [RR (risk ratio) 0.79, 95% CI (confidence interval) 0.71-0.89] and case-control studies [OR (odds ratio) 0.43, 95% CI 0.27-0.68]. For cohort studies, both highest and moderate PA levels were superior to the light one in lowering NAFLD risk ( p for interaction = 0.006 and 0.02, respectively), and there was a log-linear dose-response association ( p for nonlinearity = 0.10) between PA and NAFLD risk [RR 0.82 (95% CI 0.73-0.91) for every 500 metabolic equivalent (MET)-minutes/week increment in PA]. Increased PA may lead to a reduced risk of NAFLD in a dose-dependent manner, and the current guideline-recommended minimum PA level that approximates to 500 MET-minutes/week is able to moderately reduce the NAFLD risk.

Dose-dependent bioavailability indicators for curcumin and two of its novel derivatives.

PubMed

Abd el Aziz, Mohamed; El-Asmer, Mohamed; Rezq, Ameen; Al-Malki, Abdulrahman; Kumosani, Taha; Fouad, Hanan; Ahmed, Hanan; Taha, Fatma; Hassouna, Amira; Hafez, Hafez

2014-01-01

Novel water-soluble curcumin derivatives have been developed to overcome low in vivo bioavailability of curcumin. The aim of this work is to assess the potential utility of certain downstream targets as bioavailability indicators of systemic activity of pure curcumin and two novel water-soluble curcumin derivatives (NCD) by constructing dose-dependent response curves and to prove whether this novel curcumin derivatives retained, improved, or abolished biological activity of pure curcumin when applied in vivo. Pure curcumin (CUR), curcumin-carboxy derivative (NCD-1), and curcumin protein conjugate (NCD-2) were administered orally to rats at escalating doses: 37, 74, 148, and 296 μM/kg body weight, respectively. Plasma levels of GST activity, cavernous tissue levels of cGMP, and enzymatic activity of both HO-1 and GST were assessed one and half and 24 hours after oral administration of curcumin formulae. This study showed that there was a progressive elevation of cavernous tissue levels of cGMP and enzymatic activity of both HO-1 and GST in a dose-dependent manner that was maintained for 24 h with CUR, NCD-1, and NCD-2. Plasma GST activity was decreased by the lowest doses on the curve. The three dose-dependent bioavailability indicators as surrogates of curcumin and two of its novel derivatives are valid in the studied range of concentration and extended time. The novel curcumin derivatives still conserve with improvement the biological activity of natural curcumin when applied in vivo. © 2013 International Union of Biochemistry and Molecular Biology.

Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects.

PubMed

Strassman, R J; Qualls, C R

1994-02-01

To begin applying basic neuropharmacological hypotheses of hallucinogenic drug actions to humans, we generated dose-response data for intravenously administered dimethyltryptamine fumarate's (DMT) neuroendocrine, cardiovascular, autonomic, and subjective effects in a group of experienced hallucinogen users. Dimethyltryptamine, an endogenous mammalian hallucinogen and drug of abuse, was administered intravenously at 0.05, 0.1, 0.2, and 0.4 mg/kg to 11 experienced hallucinogen users, in a double-blind, saline placebo-controlled, randomized design. Treatments were separated by at least 1 week. Peak DMT blood levels and subjective effects were seen within 2 minutes after drug administration, and were negligible at 30 minutes. Dimethyltryptamine dose dependently elevated blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of beta-endorphin, corticotropin, cortisol, and prolactin. Growth hormone blood levels rose equally in response to all doses of DMT, and melatonin levels were unaffected. Threshold doses for significant effects relative to placebo were also hallucinogenic (0.2 mg/kg and higher). Subjects with five or more exposures to 3,4-methylenedioxymethamphetamine demonstrated less robust pupil diameter effects than those with two or fewer exposures. Dimethyltryptamine can be administered safely to experienced hallucinogen users and dose-response data generated for several measures hypothesized under serotonergic modulatory control. Additional studies characterizing the specific mechanisms mediating DMT's biological effects may prove useful in psychopharmacological investigations of drug-induced and endogenous alterations in brain function.

Safety of docosahexaenoic acid (DHA) administered as DHA ethyl ester in a 9-month toxicity study in dogs.

PubMed

Dahms, Irina; Beilstein, Paul; Bonnette, Kimberly; Salem, Norman

2016-06-01

DHA Ethyl Ester (DHA-EE) is a 90% concentrated ethyl ester of docosahexaenoic acid manufactured from the microalgal oil. The objective of the 9-month study was to evaluate safety of DHA-EE administered to beagle dogs at dose levels 150, 1000 and 2000 mg/kg bw/day by oral gavage and to determine reversibility of any findings after a 2-month recovery period. DHA-EE was well tolerated at all doses. There were observations of dry flaky skin with occasional reddened areas at doses ≥1000 mg/kg bw/day. These findings lacked any microscopic correlate and were no longer present after the recovery period. There were no toxicologically relevant findings in body weights, body weight gains, food consumption, ophthalmological examinations, and ECG measurements. Test article-related changes in hematology parameters were limited to decreases in reticulocyte count in the high-dose males and considered non-adverse. In clinical chemistry parameters, dose-related decreases in cholesterol and triglycerides levels were observed at all doses in males and females and attributed to the known lipid-lowering effects of DHA. There were no effects on other clinical chemistry, urinalysis or coagulation parameters. There were no abnormal histopathology findings attributed to test article. The No-Observable-Adverse-Effect Level of DHA-EE was established at 2000 mg/kg bw/day for both genders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Safety evaluation of mercury based Ayurvedic formulation (Sidh Makardhwaj) on brain cerebrum, liver & kidney in rats

PubMed Central

Kumar, Gajendra; Srivastava, Amita; Sharma, Surinder Kumar; Gupta, Yogendra Kumar

2014-01-01

Background & objectives: Sidh Makardhwaj (SM) is a mercury based Ayurvedic formulation used in rheumatoid arthritis and neurological disorders. However, toxicity concerns due to mercury content are often raised. Therefore, the present study was carried out to evaluate the effect of SM on brain cerebrum, liver and kidney in rats. Methods: Graded doses of SM (10, 50, 100 mg/kg), mercuric chloride (1 mg/kg) and normal saline were administered orally to male Wistar rats for 28 days. Behavioural parameters were assessed on days 1, 7, 14 and 28 using Morris water maze, passive avoidance, elevated plus maze and rota rod. Liver and kidney function tests were done on day 28. Animals were sacrificed and brain cerebrum acetylcholinesterase activity, levels of malondialdehyde (MDA), reduced glutathione (GSH) in brain cerebrum, liver, kidney were estimated. The levels of mercury in brain cerebrum, liver and kidney were estimated and histopathology of these tissues was also performed. Results: SM in the doses used did not cause significant change in neurobehavioural parameters, brain cerebrum AChE activity, liver (ALT, AST, ALP bilirubin) and kidney (serum urea and creatinine) function tests as compared to control. The levels of mercury in brain cerebrum, liver, and kidney were found to be raised in dose dependent manner. However, the levels of MDA and GSH in these tissues did not show significant changes at doses of 10 and 50 mg/kg. Also, there was no histopathological change in cytoarchitecture of brain cerebrum, liver, and kidney tissues at doses of 10 and 50 mg/kg. Interpretation & conclusions: The findings of the present study suggest that Sidh Makardhwaj upto five times the equivalent human dose administered for 28 days did not show any toxicological effects on rat brain cerebrum, liver and kidney. PMID:24927349

Safety evaluation of mercury based Ayurvedic formulation (Sidh Makardhwaj) on brain cerebrum, liver & kidney in rats.

PubMed

Kumar, Gajendra; Srivastava, Amita; Sharma, Surinder Kumar; Gupta, Yogendra Kumar

2014-04-01

Sidh Makardhwaj (SM) is a mercury based Ayurvedic formulation used in rheumatoid arthritis and neurological disorders. However, toxicity concerns due to mercury content are often raised. Therefore, the present study was carried out to evaluate the effect of SM on brain cerebrum, liver and kidney in rats. Graded doses of SM (10, 50, 100 mg/kg), mercuric chloride (1 mg/kg) and normal saline were administered orally to male Wistar rats for 28 days. Behavioural parameters were assessed on days 1, 7, 14 and 28 using Morris water maze, passive avoidance, elevated plus maze and rota rod. Liver and kidney function tests were done on day 28. Animals were sacrificed and brain cerebrum acetylcholinesterase activity, levels of malondialdehyde (MDA), reduced glutathione (GSH) in brain cerebrum, liver, kidney were estimated. The levels of mercury in brain cerebrum, liver and kidney were estimated and histopathology of these tissues was also performed. SM in the doses used did not cause significant change in neurobehavioural parameters, brain cerebrum AChE activity, liver (ALT, AST, ALP bilirubin) and kidney (serum urea and creatinine) function tests as compared to control. The levels of mercury in brain cerebrum, liver, and kidney were found to be raised in dose dependent manner. However, the levels of MDA and GSH in these tissues did not show significant changes at doses of 10 and 50 mg/kg. Also, there was no histopathological change in cytoarchitecture of brain cerebrum, liver, and kidney tissues at doses of 10 and 50 mg/kg. The findings of the present study suggest that Sidh Makardhwaj upto five times the equivalent human dose administered for 28 days did not show any toxicological effects on rat brain cerebrum, liver and kidney.

Rotavirus specific maternal antibodies and immune response to RV3-BB neonatal rotavirus vaccine in New Zealand

PubMed Central

Chen, Mee-Yew; Kirkwood, Carl D.; Bines, Julie; Cowley, Daniel; Pavlic, Daniel; Lee, Katherine J.; Orsini, Francesca; Watts, Emma; Barnes, Graeme; Danchin, Margaret

2017-01-01

ABSTRACT Background: Maternal antibodies, acquired passively via placenta and/or breast milk, may contribute to the reduced efficacy of oral rotavirus vaccines observed in children in developing countries. This study aimed to investigate the effect of rotavirus specific maternal antibodies on the serum IgA response or stool excretion of vaccine virus after any dose of an oral rotavirus vaccine, RV3-BB, in parallel to a Phase IIa clinical trial conducted at Dunedin Hospital, New Zealand. At the time of the study rotavirus vaccines had not been introduced in New Zealand and the burden of rotavirus disease was evident. Methods: Rotavirus specific IgG and serum neutralizing antibody (SNA) levels in cord blood and IgA levels in colostrum and breast milk samples collected ∼4 weeks, ∼20 weeks and ∼28 weeks after birth were measured. Infants were randomized to receive the first dose of vaccine at 0–5 d (neonatal schedule) or 8 weeks (infant schedule). Breast feeding was with-held for 30 minutes before and after vaccine administration. The relationship between rotavirus specific IgG and SNA levels in cord blood and IgA in colostrum and breast milk at the time of first active dose of RV3-BB vaccine and level of IgA response and stool excretion after 3 doses of vaccine was assessed using linear and logistic regression. Results: Forty infants received 3 doses of RV3-BB rotavirus vaccine and were included in the analysis of the neonatal and infant groups. Rotavirus specific IgA in colostrum (neonatal schedule group) and breast milk at 4 weeks (infant schedule group) was identified in 14/21 (67%) and 14/17 (82%) of infants respectively. There was little evidence of an association between IgA in colostrum or breast milk IgA at 4 weeks, or between cord IgG or SNA level, and IgA response or stool excretion after 3 doses of RV3-BB, or after one dose (neonatal schedule) (all p>0.05). Conclusions: The level of IgA in colostrum or breast milk and level of placental IgG and SNA did not impact on the serum IgA response or stool excretion following 3 doses of RV3-BB Rotavirus Vaccine administered using either a neonatal or infant schedule in New Zealand infants. PMID:28059609

Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.

PubMed

Viluksela, Matti; Heikkinen, Päivi; van der Ven, Leo T M; Rendel, Filip; Roos, Robert; Esteban, Javier; Korkalainen, Merja; Lensu, Sanna; Miettinen, Hanna M; Savolainen, Kari; Sankari, Satu; Lilienthal, Hellmuth; Adamsson, Annika; Toppari, Jorma; Herlin, Maria; Finnilä, Mikko; Tuukkanen, Juha; Leslie, Heather A; Hamers, Timo; Hamscher, Gerd; Al-Anati, Lauy; Stenius, Ulla; Dervola, Kine-Susann; Bogen, Inger-Lise; Fonnum, Frode; Andersson, Patrik L; Schrenk, Dieter; Halldin, Krister; Håkansson, Helen

2014-01-01

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.

Toxicological Profile of Ultrapure 2,2′,3,4,4′,5,5′-Heptachlorbiphenyl (PCB 180) in Adult Rats

PubMed Central

Viluksela, Matti; Heikkinen, Päivi; van der Ven, Leo T. M.; Rendel, Filip; Roos, Robert; Esteban, Javier; Korkalainen, Merja; Lensu, Sanna; Miettinen, Hanna M.; Savolainen, Kari; Sankari, Satu; Lilienthal, Hellmuth; Adamsson, Annika; Toppari, Jorma; Herlin, Maria; Finnilä, Mikko; Tuukkanen, Juha; Leslie, Heather A.; Hamers, Timo; Hamscher, Gerd; Al-Anati, Lauy; Stenius, Ulla; Dervola, Kine-Susann; Bogen, Inger-Lise; Fonnum, Frode; Andersson, Patrik L.; Schrenk, Dieter; Halldin, Krister; Håkansson, Helen

2014-01-01

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions. PMID:25137063

Influence of radiation dose and reconstruction algorithm in MDCT assessment of airway wall thickness: A phantom study

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

Gomez-Cardona, Daniel; Nagle, Scott K.; Department of Radiology, University of Wisconsin-Madison School of Medicine and Public Health, 600 Highland Avenue, Madison, Wisconsin 53792

Purpose: Wall thickness (WT) is an airway feature of great interest for the assessment of morphological changes in the lung parenchyma. Multidetector computed tomography (MDCT) has recently been used to evaluate airway WT, but the potential risk of radiation-induced carcinogenesis—particularly in younger patients—might limit a wider use of this imaging method in clinical practice. The recent commercial implementation of the statistical model-based iterative reconstruction (MBIR) algorithm, instead of the conventional filtered back projection (FBP) algorithm, has enabled considerable radiation dose reduction in many other clinical applications of MDCT. The purpose of this work was to study the impact of radiationmore » dose and MBIR in the MDCT assessment of airway WT. Methods: An airway phantom was scanned using a clinical MDCT system (Discovery CT750 HD, GE Healthcare) at 4 kV levels and 5 mAs levels. Both FBP and a commercial implementation of MBIR (Veo{sup TM}, GE Healthcare) were used to reconstruct CT images of the airways. For each kV–mAs combination and each reconstruction algorithm, the contrast-to-noise ratio (CNR) of the airways was measured, and the WT of each airway was measured and compared with the nominal value; the relative bias and the angular standard deviation in the measured WT were calculated. For each airway and reconstruction algorithm, the overall performance of WT quantification across all of the 20 kV–mAs combinations was quantified by the sum of squares (SSQs) of the difference between the measured and nominal WT values. Finally, the particular kV–mAs combination and reconstruction algorithm that minimized radiation dose while still achieving a reference WT quantification accuracy level was chosen as the optimal acquisition and reconstruction settings. Results: The wall thicknesses of seven airways of different sizes were analyzed in the study. Compared with FBP, MBIR improved the CNR of the airways, particularly at low radiation dose levels. For FBP, the relative bias and the angular standard deviation of the measured WT increased steeply with decreasing radiation dose. Except for the smallest airway, MBIR enabled significant reduction in both the relative bias and angular standard deviation of the WT, particularly at low radiation dose levels; the SSQ was reduced by 50%–96% by using MBIR. The optimal reconstruction algorithm was found to be MBIR for the seven airways being assessed, and the combined use of MBIR and optimal kV–mAs selection resulted in a radiation dose reduction of 37%–83% compared with a reference scan protocol with a dose level of 1 mGy. Conclusions: The quantification accuracy of airway WT is strongly influenced by radiation dose and reconstruction algorithm. The MBIR algorithm potentially allows the desired WT quantification accuracy to be achieved with reduced radiation dose, which may enable a wider clinical use of MDCT for the assessment of airway WT, particularly for younger patients who may be more sensitive to exposures with ionizing radiation.« less

Kt/Vurea and Nonurea Small Solute Levels in the Hemodialysis Study

PubMed Central

Sirich, Tammy L.; Fong, Kara D.; Plummer, Natalie S.; Shafi, Tariq; Hwang, Seungyoung; Banerjee, Tanushree; Zhu, Yunnuo; Powe, Neil R.; Hai, Xin; Hostetter, Thomas H.

2016-01-01

The Hemodialysis (HEMO) Study showed that high-dose hemodialysis providing a single-pool Kt/Vurea of 1.71 provided no benefit over a standard treatment providing a single-pool Kt/Vurea of 1.32. Here, we assessed whether the high-dose treatment used lowered plasma levels of small uremic solutes other than urea. Measurements made ≥3 months after randomization in 1281 patients in the HEMO Study showed a range in the effect of high-dose treatment compared with that of standard treatment: from no reduction in the level of p-cresol sulfate or asymmetric dimethylarginine to significant reductions in the levels of trimethylamine oxide (−9%; 95% confidence interval [95% CI], −2% to −15%), indoxyl sulfate (−11%; 95% CI, −6% to −15%), and methylguanidine (−22%; 95% CI, −18% to −27%). Levels of three other small solutes also decreased slightly; the level of urea decreased 9%. All-cause mortality did not significantly relate to the level of any of the solutes measured. Modeling indicated that the intermittency of treatment along with the presence of nondialytic clearance and/or increased solute production accounted for the limited reduction in solute levels with the higher Kt/Vurea. In conclusion, failure to achieve greater reductions in solute levels may explain the failure of high Kt/Vurea treatment to improve outcomes in the HEMO Study. Furthermore, levels of the nonurea solutes varied widely among patients in the HEMO Study, and achieved Kt/Vurea accounted for very little of this variation. These results further suggest that an index only on the basis of urea does not provide a sufficient measure of dialysis adequacy. PMID:27026365

Phase I study of nanoparticle albumin-bound paclitaxel, carboplatin and trastuzumab in women with human epidermal growth factor receptor 2-overexpressing breast cancer

PubMed Central

Tezuka, Kenji; Takashima, Tsutomu; Kashiwagi, Shinichiro; Kawajiri, Hidemi; Tokunaga, Shinya; Tei, Seika; Nishimura, Shigehiko; Yamagata, Shigehito; Noda, Satoru; Nishimori, Takeo; Mizuyama, Yoko; Sunami, Takeshi; Ikeda, Katsumi; Ogawa, Yoshinari; Onoda, Naoyoshi; Ishikawa, Tetsuro; Kudoh, Shinzoh; Takada, Minoru; Hirakawa, Kosei

2017-01-01

Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study. Based on these results, a phase I study of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its efficacy and safety for HER2-overexpressing locally advanced breast cancer. The present study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced breast cancer. The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2). Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly. A total of 6 patients were enrolled. Although no DLT was observed during the first cycle, 4 patients developed grade 4 thrombocytopenia, 2 had grade 4 neutropenia and 3 exhibited a grade 4 decrease in hemoglobin levels. In the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well tolerated. However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose setting should be conducted. PMID:28413662

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

PubMed

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

2017-12-23

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

LEUKEMIA, LYMPHOMA AND MULTIPLE MYELOMA MORTALITY (1950–1999) AND INCIDENCE (1969–1999) IN THE ELDORADO URANIUM WORKERS COHORT

PubMed Central

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

Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment.

PubMed

Ranganath, Lakshminarayan R; Milan, Anna M; Hughes, Andrew T; Dutton, John J; Fitzgerald, Richard; Briggs, Michael C; Bygott, Helen; Psarelli, Eftychia E; Cox, Trevor F; Gallagher, James A; Jarvis, Jonathan C; van Kan, Christa; Hall, Anthony K; Laan, Dinny; Olsson, Birgitta; Szamosi, Johan; Rudebeck, Mattias; Kullenberg, Torbjörn; Cronlund, Arvid; Svensson, Lennart; Junestrand, Carin; Ayoob, Hana; Timmis, Oliver G; Sireau, Nicolas; Le Quan Sang, Kim-Hanh; Genovese, Federica; Braconi, Daniela; Santucci, Annalisa; Nemethova, Martina; Zatkova, Andrea; McCaffrey, Judith; Christensen, Peter; Ross, Gordon; Imrich, Richard; Rovensky, Jozef

2016-02-01

Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Open-Label Single-Sequence Crossover Study Evaluating Pharmacokinetics, Efficacy, and Safety of Once-Daily Dosing of Nitisinone in Patients with Hereditary Tyrosinemia Type 1.

PubMed

Guffon, Nathalie; Bröijersén, Anders; Palmgren, Ingrid; Rudebeck, Mattias; Olsson, Birgitta

2018-01-01

Although nitisinone is successfully used to treat hereditary tyrosinemia type 1 (HT-1) with the recommended twice-daily dosing, data describing a long half-life motivate less frequent dosing. Therefore, in agreement with the Pharmacovigilance Risk Assessment Committee at the European Medicines Agency, this study was performed to investigate the switch to once-daily dosing. This open-label, non-randomized, single-sequence crossover study evaluated the pharmacokinetics, efficacy, and safety of once-daily compared to twice-daily dosing of nitisinone in patients with HT-1 (NCT02323529). Well-controlled patients of <2, 2 to <12, 12 to <18, and ≥18 years of age who were on twice-daily dosing were eligible for participation. Nitisinone and succinylacetone levels were determined from dry blood spots by tandem mass spectrometry. The primary endpoint was C min of nitisinone after ≥4 weeks of treatment on each dosing regimen. Secondary objectives were evaluation of efficacy and safety during each dosing regimen. In total, 19 patients were enrolled and 17 included in the per-protocol analysis set. The mean (SD) nitisinone C min decreased by 23%, from 26.4 (10.2) to 21.2 (9.9) μmol/L in dry blood spot samples (not equivalent to plasma concentrations), when patients switched from twice- to once-daily dosing. There was no apparent age- or bodyweight-related trend in the degree of C min decrease. No patient had quantifiable succinylacetone levels during the once-daily treatment period, indicating efficacious treatment. All adverse events were mild or moderate and judged unrelated to nitisinone. The switch to once-daily treatment with nitisinone appeared efficacious and safe in the treatment of patients with HT-1.

Low dose evaluation of the antiandrogen flutamide following a Mode of Action approach.

PubMed

Sarrabay, A; Hilmi, C; Tinwell, H; Schorsch, F; Pallardy, M; Bars, R; Rouquié, D

2015-12-15

The dose-response characterization of endocrine mediated toxicity is an on-going debate which is controversial when exploring the nature of the dose-response curve and the effect at the low-end of the curve. To contribute to this debate we have assessed the effects of a wide range of dose levels of the antiandrogen flutamide (FLU) on 7-week male Wistar rats. FLU was administered by oral gavage at doses of 0, 0.001, 0.01, 0.1, 1 and 10mg/kg/day for 28 days. To evaluate the reproducibility, the study was performed 3 times. The molecular initiating event (MIE; AR antagonism), the key events (LH increase, Leydig cell proliferation and hyperplasia increases) and associated events involved in the mode of action (MOA) of FLU induced testicular toxicity were characterized to address the dose response concordance. Results showed no effects at low doses (<0.1mg/kg/day) for the different key events studied. The histopathological changes (Leydig cell hyperplasia) observed at 1 and 10mg/kg/day were associated with an increase in steroidogenesis gene expression in the testis from 1mg/kg/day, as well as an increase in testosterone blood level at 10mg/kg/day. Each key event dose-response was in good concordance with the MOA of FLU on the testis. From the available results, only monotonic dose-response curves were observed for the MIE, the key events, associated events and in effects observed in other sex related tissues. All the results, so far, show that the reference endocrine disruptor FLU induces threshold effects in a standard 28-day toxicity study on adult male rats. Copyright © 2015 Elsevier Inc. All rights reserved.

A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors

PubMed Central

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

A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors.

PubMed

Fakih, Marwan G; Fetterly, Gerald; Egorin, Merrill J; Muindi, Josephia R; Espinoza-Delgado, Igor; Zwiebel, James A; Litwin, Alan; Holleran, Julianne L; Wang, Kangsheng; Diasio, Robert B

2010-07-15

We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2). Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. Copyrighth 2010 AACR.

A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Two Schedules of Vorinostat in Combination with 5-Fluorouracil and Leucovorin in Patients with Refractory Solid Tumors

PubMed Central

Fakih, Marwan G.; Fetterly, Gerald; Egorin, Merrill J.; Muindi, Josephia R.; Espinoza-Delgado, Igor; Zwiebel, James A.; Litwin, Alan; Holleran, Julianne L.; Wang, Kangsheng; Diasio, Robert B.

2010-01-01

Purpose We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat × 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Experimental Design Vorinostat doses were escalated in a standard 3 × 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hours followed by FU 400 mg/m2 i.v. bolus and 2,400 mg/m2 over 46 hours (sLV5FU2). Results Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. Conclusions The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily × 3 or 600 mg orally twice daily × 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. PMID:20463088

Dose- dependent ameliorative effects of quercetin and l-Carnitine against atrazine- induced reproductive toxicity in adult male Albino rats.

PubMed

Abdel Aziz, Rabie L; Abdel-Wahab, Ahmed; Abo El-Ela, Fatma I; Hassan, Nour El-Houda Y; El-Nahass, El-Shaymaa; Ibrahim, Marwa A; Khalil, Abdel-Tawab A Y

2018-06-01

This study aimed to determine the protective effects of co-administration of Quercetin (QT) or l-Carnitine (LC) against the oxidative stress induced by Atrazine (ATZ) in the reproductive system of intact male Albino rats. 36 rats were divided equally into 6 groups. Rats in the control negative "CNT" group received 1.5 ml distilled water for 21 days. All rats in the other groups received ATZ (120 mg/kg bw) through gavage. Groups 3 and 4 were co-administered with either low or high dose of QT (10 "ATZLQT" and 50 "ATZHQT" mg/kg bw, respectively). Groups 5 and 6 were co-administered with either low or high dose of LC (200 "ATZLLC" and 400 "ATZHLC" mg/kg bw, respectively). At the end of the experiment, animals were sacrificed and all samples were collected. ATZ significantly increased serum level of malondialdehyde (MDA) and decreased total antioxidant capacity (TAC). Also, ATZ increased significantly the sperm cell abnormalities and reduced both testicular IgA and serum testosterone levels. Testicular DNA laddering % and CYP17A1 mRNA expression were significantly reduced in ATZ group. Interestingly, co-administration with low dose QT or different doses of LC succeeded to counteract the negative toxic effects of ATZ on serum oxidative stress indicators, serum testosterone levels, testicular IgA level and improved testicular CYP17A1 mRNA expression. In conclusion, QT in low dose and LC in both low and high doses exerted a significant protective action against the reproductive toxicity of ATZ, while higher dose of QT failed induce immune-stimulant effect against ATZ in adult male Albino rats. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

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

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

Ma, L; Braunstein, S; Chiu, J

2016-06-15

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

Effect of various methods for rectum delineation on relative and absolute dose-volume histograms for prostate IMRT treatment planning

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

Kusumoto, Chiaki; Ohira, Shingo; Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Suita

2016-07-01

Several reports have dealt with correlations of late rectal toxicity with rectal dose-volume histograms (DVHs) for high dose levels. There are 2 techniques to assess rectal volume for reception of a specific dose: relative-DVH (R-DVH, %) that indicates relative volume for a vertical axis, and absolute-DVH (A-DVH, cc) with its vertical axis showing absolute volume of the rectum. The parameters of DVH vary depending on the rectum delineation method, but the literature does not present any standardization of such methods. The aim of the present study was to evaluate the effects of different delineation methods on rectal DVHs. The enrollmentmore » for this study comprised 28 patients with high-risk localized prostate cancer, who had undergone intensity-modulated radiation therapy (IMRT) with the prescription dose of 78 Gy. The rectum was contoured with 4 different methods using 2 lengths, short (Sh) and long (Lg), and 2 cross sections, rectum (Rec) and rectal wall (Rw). Sh means the length from 1 cm above the seminal vesicles to 1 cm below the prostate and Lg the length from the rectosigmoid junction to the anus. Rec represents the entire rectal volume including the rectal contents and Rw the rectal volume of the area with a wall thickness of 4 mm. We compared dose-volume parameters by using 4 rectal contour methods for the same plan with the R-DVHs as well as the A-DVHs. For the high dose levels, the R-DVH parameters varied widely. The mean of V{sub 70} for Sh-Rw was the highest (19.4%) and nearly twice as high as that for Lg-Rec (10.4%). On the contrary, only small variations were observed in the A-DVH parameters (4.3, 4.3, 5.5, and 5.5 cc for Sh-Rw, Lg-Rw, Sh-Rec, and Lg-Rec, respectively). As for R-DVHs, the parameters of V{sub 70} varied depending on the rectal lengths (Sh-Rec vs Lg-Rec: R = 0.76; Sh-Rw vs Lg-Rw: R = 0.85) and cross sections (Sh-Rec vs Sh-Rw: R = 0.49; Lg-Rec vs Lg-Rw: R = 0.65). For A-DVHs, however, the parameters of Sh rectal A-DVHs hardly changed regardless of differences in rectal length at all dose levels. Moreover, at high dose levels (V{sub 70}), the parameters of A-DVHs showed less dependence on rectal cross sections (Sh-Rec vs Sh-Rw: R = 0.66; Lg-Rec vs Lg-Rw: R = 0.59). This study showed that A-DVHs were less dependent on the delineation methods than R-DVHs, especially for evaluating the rectal dose at higher dose levels. It can therefore be assumed that, in addition to R-DVHs, A-DVHs can be used for evaluating rectal toxicity.« less

The Value of Botox-A in Acute Radiation Proctitis: Results From a Phase I/II Study Using a Three-Dimensional Scoring System

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

Vuong, Te, E-mail: tvuong@jgh.mcgill.ca; Waschke, Kevin; Niazi, Tamim

Purpose: Acute radiation proctitis (ARP) is a common side effect of pelvic radiotherapy, and its management is challenging in daily practice. The present phase I/II study evaluates the safety and efficacy of the botulinum toxin A (BTX-A) in ARP treatment for rectal cancer patients undergoing neoadjuvant high-dose-rate endorectal brachytherapy (HDREBT). Methods and Materials: Fifteen patients, treated with neoadjuvant HDREBT, 26-Gy in 4 fractions, received the study treatment that consisted of a single injection of BTX-A into the rectal wall. The injection was performed post-HDREBT and prior to the development of ARP. The control group, 20 such patients, did not receivemore » the BTX-A injection. Both groups had access to standard treatment with hydrocortisone rectal aerosol foam (Cortifoam) and anti-inflammatory and narcotic medication. The ARP was clinically evaluated by self-administered daily questionnaires using visual analog scores to document frequency and urgency of bowel movements, rectal burning/tenesmus, and pain symptoms before and after HDREBT. Results: At the time of this analysis, there was no observed systemic toxicity. Patient compliance with the self-administered questionnaire was 100% from week 1 to 4, 70% during week 5, and 40% during week 6. The maximum tolerated dose was established at the 100-U dose level, and noticeable mean differences were observed in bowel frequency (p = 0.016), urgency (p = 0.007), and pain (p = 0.078). Conclusions: This study confirms the feasibility and efficacy of BTX-A intervention at 100-U dose level for study patients compared to control patients. A phase III study with this dose level is planned to validate these results.« less

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

PubMed

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

2015-03-01

In the present investigation, microarray analysis was used to monitor transcriptional activity in thyroids in mice 24 h after (131)I exposure. The aims of this study were to 1) assess the transcriptional patterns associated with (131)I exposure in normal mouse thyroid tissue and 2) propose biomarkers for (131)I exposure of the thyroid. Adult BALB/c nude mice were i.v. injected with 13, 130 or 260 kBq of (131)I and killed 24h after injection (absorbed dose to thyroid: 0.85, 8.5, or 17 Gy). Mock-treated mice were used as controls. Total RNA was extracted from thyroids and processed using the Illumina platform. In total, 497, 546, and 90 transcripts were regulated (fold change ≥1.5) in the thyroid after 0.85, 8.5, and 17 Gy, respectively. These were involved in several biological functions, e.g. oxygen access, inflammation and immune response, and apoptosis/anti-apoptosis. Approximately 50% of the involved transcripts at each absorbed dose level were dose-specific, and 18 transcripts were commonly detected at all absorbed dose levels. The Agpat9, Plau, Prf1, and S100a8 gene expression displayed a monotone decrease in regulation with absorbed dose, and further studies need to be performed to evaluate if they may be useful as dose-related biomarkers for 131I exposure. Distinct and substantial differences in gene expression and affected biological functions were detected at the different absorbed dose levels. The transcriptional profiles were specific for the different absorbed dose levels. We propose that the Agpat9, Plau, Prf1, and S100a8 genes might be novel potential absorbed dose-related biomarkers to (131)I exposure of thyroid. During the recent years, genomic techniques have been developed; however, they have not been fully utilized in nuclear medicine and radiation biology. We have used RNA microarrays to investigate genome-wide transcriptional regulations in thyroid tissue in mice after low, intermediate, and high absorbed doses from (131)I exposure in vivo. Using this approach, we have identified novel biological responses and potential absorbed dose-related biomarkers to (131)I exposure. Our research shows the importance of embracing technological advances and multi-disciplinary collaboration in order to apply them in radiation therapy, nuclear medicine, and radiation biology. This work may contribute with new knowledge of potential normal tissue effects or complications that may occur after exposure to ionizing radiation in diagnostic and therapeutic nuclear medicine, and due to radioactive fallout or accident with radionuclide spread. Copyright © 2014 Elsevier Inc. All rights reserved.

Different Doses of Tripterygium Glycosides in the Treatment of Diabetic Nephropathy: Effects on Blood Lipids.

PubMed

Wang, Wei

2018-06-07

The aim of this study was to investigate the therapeutic effect of different doses of tripterygium glycosides (TG) in the treatment of diabetic nephropathy (DN). The effect of TG on blood lipids and safety were also evaluated. Sixty patients with type 2 DN were randomly divided into three groups (n=20 per group): low-dose (30 mg/day TG), double-dose (60 mg/day TG) and control (placebo) groups, all three times daily for 6 months. The levels of triglycerides, total cholesterol, urinary protein, plasma albumin and serum tumour necrosis factor (TNF)-α were compared between the three groups. After treatment, urinary protein and TNF-α level significantly decreased in patients in the treatment groups, compared with the control group. This decrease was significantly larger in the double-dose group than in the low-dose group. However, there was no significant decrease in triglycerides and total cholesterol in the two treatment groups. Furthermore, plasma albumin was lower in the treatment groups than in the control group. The double dose of TG has improved clinical efficacy, compared with the low dose, and the same safety profile. © 2018 The Author(s). Published by S. Karger AG, Basel.

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

PubMed

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

1983-01-01

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

Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin.

PubMed

Yokoyama, Shota; Tsuji, Hideyuki; Hiraoka, Sachiko; Nishihara, Masayuki

2016-01-01

Metformin is a biguanaide antidiabetic drug used worldwide, and its effectiveness and benefits have already been established. However, the safety of high doses of metformin in Japanese patients, especially in elderly patients with a decreased renal function, remains unclear. Among the side effects of metformin, lactate acidosis is the most problematic due to a high mortality rate. Therefore, we assessed plasma lactate levels in metformin-treated patients to identify independent risk factors for hyperlactemia. 290 outpatients receiving various doses of metformin at our hospital were enrolled between March and July 2014. Serum electrolytes, Cre (creatinine), BUN (blood urea nitrogen), UA (uric acid), HbA1c (hemoglobin A1c), and lactate levels were investigated. Lactate levels did not significantly differ between the elderly (≥75 years) and non-elderly (<75 years) groups. Patients in the elderly group had a significantly lower daily metformin dose and estimated glomerular filtration rate (eGFR), compared with the non-elderly group (both p<0.005). Between with and without hyperlactemia groups, no significant differences were observed in either Cre or age. On the other hand, patients with hyperlactemia had a significantly higher dose of metformin than those without hyperlactemia (p<0.05). In this study, we found that old age and mildly impaired kidney function were not associated with increased lactate levels, and that a higher dose of metformin may be an independent risk factor for elevated lactate levels in Japanese patients.

The effects of chronic oral methyl mercury exposure on the lysosome system of rat kidney. Morphometric and biochemical studies.

PubMed

Fowler, B A; Brown, H W; Lucier, G W; Krigman, M R

1975-03-01

This report describes morphometric and biochemical changes in the renal lysosome system of rats exposed to 3, 5, or 10 p.p.m. concentrations of methyl mercury hydroxide in their drinking water for 4 weeks. Increased numbers of dense, granular lysosomes, previously found to contain mercury, were observed in tubule cells of rats receiving the 3 and 5 p.p.m. dose levels but not those of the 10 p.p.m. group. Tubule cells from animals given the 10 p.p;m. dose level displayed proteinaceous vacuoles with dense crystalloid structures, apical cytoplasmic extrusion, and cellular degeneration; Mitochondrial swelling within tubule cells of treated animals showed a marked dose-response relationship. Renal microsomal activity levels of ss-glucuronidase were strongly inhibited by methyl mercury hydroxide exposure at all dose levels, whereas the activity levels of acid phosphatase were unchanged. Lysosomal beta-glucuronidase was also inhibited by methyl mercury hydroxide exposure, whereas lysosomal acid phosphatase showed approximately a 2-fold increase in activity. The results are discussed in relation to the role of lysosomes in mediating the nephrotoxic effects of methyl mercury and other toxic trace metals.

TH-CD-207A-12: Impacts of Inter- and Intra-Fractional Organ Motion for High-Risk Prostate Cancer Stereotactic Body Radiation Therapy

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

Hassan Rezaeian, N; Chi, Y; Zhou, Y

2016-06-15

Purpose: We are conducting a clinical trial on stereotactic body radiation therapy (SBRT) for high-risk prostate cancer. Doses to three targets, prostate, intra-prostatic lesion, and pelvic lymph node (PLN) region, are escalated to three different levels via simultaneous integrated boost technique. Inter-/intra-fractional organ motions deteriorate planned dose distribution. This study aims at developing a dose reconstruction system to comprehensively understand the impacts of organ motion in our clinical trial. Methods: A 4D dose reconstruction system has been developed for this study. Using a GPU-based Monte-Carlo dose engine and delivery log file, the system is able to reconstruct dose on staticmore » or dynamic anatomy. For prostate and intra-prostatic targets, intra-fractional motion is the main concern. Motion trajectory acquired from Calypso in previously treated SBRT patients were used to perform 4D dose reconstructions. For pelvic target, inter-fractional motion is one concern. Eight patients, each with four cone beam CTs, were used to derive fractional motion. The delivered dose was reconstructed on the deformed anatomy. Dosimetric parameters for delivered dose distributions of the three targets were extracted and compared with planned levels. Results: For prostate intra-fractional motion, the mean 3D motion amplitude during beam delivery ranged from 1.5mm to 5.0mm and the average among all patients was 2.61mm. Inter-fractional motion for the PLN target was more significant. The average amplitude among patients was 4mm with the largest amplitude up to 9.6mm. The D95% deviation from planned level for prostate PTVs and GTVs are on average less than<0.1% and this deviation for intra-prostatic lesion PTVs and GTVs were more prominent. The dose at PLN was significantly affected with D{sub 95}% reduced by up to 44%. Conclusion: Intra-/inter-fractional organ motion is a concern for high-risk prostate SBRT, particularly for the PLN target. Our dose reconstruction approach can also serve as the basis to guide treatment adaptation.« less

Dosimetric analysis of testicular doses in prostate intensity-modulated and volumetric-modulated arc radiation therapy at different energy levels

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

Onal, Cem, E-mail: hcemonal@hotmail.com; Arslan, Gungor; Dolek, Yemliha

2016-01-01

The aim of this study is to evaluate the incidental testicular doses during prostate radiation therapy with intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc radiotherapy (VMAT) at different energies. Dosimetric data of 15 patients with intermediate-risk prostate cancer who were treated with radiotherapy were analyzed. The prescribed dose was 78 Gy in 39 fractions. Dosimetric analysis compared testicular doses generated by 7-field intensity-modulated radiotherapy and volumetric-modulated arc radiotherapy with a single arc at 6, 10, and 15 MV energy levels. Testicular doses calculated from the treatment planning system and doses measured from the detectors were analyzed. Mean testicular doses from themore » intensity-modulated radiotherapy and volumetric-modulated arc radiotherapy per fraction calculated in the treatment planning system were 16.3 ± 10.3 cGy vs 21.5 ± 11.2 cGy (p = 0.03) at 6 MV, 13.4 ± 10.4 cGy vs 17.8 ± 10.7 cGy (p = 0.04) at 10 MV, and 10.6 ± 8.5 cGy vs 14.5 ± 8.6 cGy (p = 0.03) at 15 MV, respectively. Mean scattered testicular doses in the phantom measurements were 99.5 ± 17.2 cGy, 118.7 ± 16.4 cGy, and 193.9 ± 14.5 cGy at 6, 10, and 15 MV, respectively, in the intensity-modulated radiotherapy plans. In the volumetric-modulated arc radiotherapy plans, corresponding testicular doses per course were 90.4 ± 16.3 cGy, 103.6 ± 16.4 cGy, and 139.3 ± 14.6 cGy at 6, 10, and 15 MV, respectively. In conclusions, this study was the first to measure the incidental testicular doses by intensity-modulated radiotherapy and volumetric-modulated arc radiotherapy plans at different energy levels during prostate-only irradiation. Higher photon energy and volumetric-modulated arc radiotherapy plans resulted in higher incidental testicular doses compared with lower photon energy and intensity-modulated radiotherapy plans.« less

Comparative assessment of onion and garlic extracts on endogenous hepatic and renal antioxidant status in rat.

PubMed

Suru, Stephen M; Ugwu, Chidiebere E

2015-07-01

Despite growing claims of functional health benefits in folkloric medicine, the safety of chronic/elevated intakes of onion and garlic cannot be assumed. Therefore, this study assesses oral administration of varied doses of onion and garlic on some biomarkers of hepatic and renal functions in rats. Animals were divided into five groups: control group received vehicle and extract-treated groups received varied doses of onion or garlic extract (0.5 mL and 1.0 mL/100 g bwt/day) for 6 weeks. Both doses of onion caused marked (p<0.05) increase in hepatic and renal levels of glutathione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and marked (p<0.05) decrease in malondialdehyde (MDA). Treatment with low dose of garlic elicited similar trend except in hepatic CAT, renal SOD and GST levels. A high dose of garlic only caused marked (p<0.05) increase in hepatic GST, renal GST, and SOD. Both doses of onion and low dose of garlic significantly (p<0.05) enhanced renal Na+/K+-ATPase activity. Only a high dose of onion caused significant (p<0.05) increase in hepatic aspartate transaminase (AST), alkaline phosphatase (ALP), and decrease in plasma AST activities. These findings suggest antioxidant enhancing capability for both doses of onion and low dose of garlic, while high dose of garlic elicited pro-oxidant conditions.

Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum

NASA Technical Reports Server (NTRS)

Kaakkola, S.; Tuomainen, P.; Wurtman, R. J.; Maennistoe, P. T.

1991-01-01

Significant concentrations of carbidopa (CD) were found in rat hypothalamus, striatum, and in striatal microdialysis efflux after intraperitoneal administration of the drug. Efflux levels peaked one hour after administration of 100 mg/kg at 0.37 microg/kg or about 2 percent of serum levels. Concurrent CD levels in hypothalamus and striatum were about 2.5 percent and 1.5 percent, respectively, of corresponding serum levels. Levels of dopamine and its principal metabolites in striatal efflux were unaffected. The removal of the brain blood by saline perfusion decreased the striatal and hypothalamic CD concentrations only by 33 percent and 16 percent, respectively. In other rats receiving both CD and levodopa (LD), brain L-dopa, dopamine, and 3,4-dihydroxyphenvlacetic acid (DOPAC) levels after one hour tended to be proportionate to LD dose. When the LD dose remained constant, increasing the CD dose dose-dependently enhanced L-dopa levels in the hypothalamus and striatum. However, dopamine levels did not increase but, in contrast, decreased dose-dependently (although significantly only in the hypothalamus). CD also caused dose-dependent decrease in striatal 3-O-methyldopa (3-OMD) and in striatal and hypothalamic homovanillic acid (HVA), when the LD dose was 50 mg/kg. We conclude that, at doses exceedimg 50 mg/kg, sufficient quantities of CD enter the brain to inhibit dopamine formation, especially in the hypothalamus. Moreover, high doses of LD/CD, both of which are themselves catechols, can inhibit the O-methylation of brain catecholamines formed from the LD.

Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum

NASA Technical Reports Server (NTRS)

Kaakkola, S.; Tuomainen, P.; Wurtman, R. J.; Mannisto, P. T.

1992-01-01

Significant concentrations of carbidopa (CD) were found in rat hypothalamus, striatum, and in striatal microdialysis efflux after intraperitoneal administration of the drug. Efflux levels peaked one hour after administration of 100 mg/kg at 0.37 micrograms/ml, or about 2% of serum levels. Concurrent CD levels in hypothalamus and striatum were about 2.5% and 1.5%, respectively, of corresponding serum levels. Levels of dopamine and its principal metabolites in striatal efflux were unaffected. The removal of the brain blood by saline perfusion decreased the striatal and hypothalamic CD concentrations only by 33% and 16%, respectively. In other rats receiving both CD and levodopa (LD), brain L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels after one hour tended to be proportionate to LD dose. When the LD dose remained constant, increasing the CD dose dose-dependently enhanced L-dopa levels in the hypothalamus and striatum. However dopamine levels did not increase but, in contrast, decreased dose-dependently (although significantly only in the hypothalamus). CD also caused dose-dependent decrease in striatal 3-O-methyldopa (3-OMD) and in striatal and hypothalamic homovanillic acid (HVA), when the LD dose was 50 mg/kg. We conclude that, at doses exceeding 50 mg/kg, sufficient quantities of CD enter the brain to inhibit dopamine formation, especially in the hypothalamus. Moreover, high doses of LD/CD, both of which are themselves catechols, can inhibit the O-methylation of brain catecholamines formed from the LD.

Effect of Two Different Doses of Dexmedetomidine on Stress Response in Laparoscopic Pyeloplasty: A Randomized Prospective Controlled Study.

PubMed

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.

Technogenesis and the main levels of soil ecosystems' transformation in oil production areas

NASA Astrophysics Data System (ADS)

Buzmakov, Sergey

2017-04-01

The obtained experimental data, the results of field studies and the analysis of references make it possible to describe peculiarities of technogenic transformation of ecosystems. Experimental data allow to determine the main levels of oil pollution on the basis of changes in biotope properties and reaction of a biota. Background level. Pollution is absent. Biotope corresponds to natural zonal sequence. The content of oil products is up to 0,11 g/kg. First level: the dose of pollution is 0,8-1g of oil on 1 kg of soil. Conditions for plants' growth are optimum. Initially plants gain gross weight, and then lose it to the background level. The number of saprotrophes and oil oxidizing microorganisms rises. Second level: the pollution dose is up to 15 g per 1 kg of soil. The capillary moisture capacity increases reaching the maximum. The number of saprophytes and oil oxidizing microorganisms rises. Third level: the pollution dose is 15-21g per 1 kg of soil. Capillary capacity of soils decreases to background level. Time of filtration and absorption of moisture is increased. Fourth level: the pollution dose is 21-32g per 1 kg of soil. Anaerobic and hydrophobic conditions develop. The number of saprophytes and oil oxidizing microorganisms rises. Fifth level: the dose of pollution is 32 - 50g per 1 kg of soil. Formation of 3,4 benzpyrene increases sharply. The number of saprophytes and oil oxidizing microorganisms is at maximum level. Sixth level: the dose of pollution is 50 - 91g per 1 kg of soil. Formation of 3,4 benzpyrene is dangerous for biota. Time of absorption and filtration of water through the soil reaches its maximum. The number of saprophytes and oil oxidizing microorganisms decreases, but remains higher than at background level. Seventh level: the pollution dose is 91-150g per 1 kg of soil. The number of saprophytes and oil oxidizing microorganisms decreases to background level. Eighth level: the pollution dose is of 150-300 g per 1 kg of soil. The substratum becomes toxic. The number of saprophytes and oil oxidizing microorganisms is lower than at background level. Ninth level: the dose of pollution is 300 g per 1 kg of soil and above. Substratum is abiogenic. Field researches show that the influence of oil fields is manifested in the form of intake of emergency oil and emergency salty waters as well as ground water runoff and surface water containing salts and oil products from platforms of oil sites into surrounding land ecosystems, along with their atmospheric pollution. Degradation and recovery process is manifested in formation of a natural- technogenic ecosystem with azonal biotopes. Around powerful sources of pollution there should be created the manageable natural and technogenic ecosystems facilitating self-restoration of the environment. It is necessary to create a system of accumulating and transit ecosystems which would make it possible to carry out the degradation and dispersion of accumulated pollutants. Implementation of our proposals will result in stabilization of ecological situation.

75 FR 19272 - Thifensulfuron methyl; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-14

... background exposure level). A short and intermediate-term adverse effect was identified; however... of small renal papillae (only at the highest dose level). Thifensulfuron methyl is classified as... only at the mid-level dose of 177 mg/kg. The lack of response at the high-level dose, the occurrence in...

Hemodynamic effects of IV sodium nitrite in hospitalized comatose survivors of out of hospital cardiac arrest.

PubMed

Dezfulian, Cameron; Olsufka, Michele; Fly, Deborah; Scruggs, Sue; Do, Rose; Maynard, Charles; Nichol, Graham; Kim, Francis

2018-01-01

Patients resuscitated from cardiac arrest have brain and cardiac injury. Recent animal studies suggest that the administration of sodium nitrite after resuscitation from 12min of asystole limits acute cardiac dysfunction and improves survival and neurologic outcomes. It has been hypothesized that low doses of IV sodium nitrite given during resuscitation of out of hospital cardiac arrest (OHCA) will improve survival. Low doses of sodium nitrite (e.g., 9.6mg of sodium nitrite) are safe in healthy individuals, however the effect of nitrite on blood pressure in resuscitated cardiac arrest patients is unknown. We performed a single-center, pilot trial of low dose sodium nitrite (1 or 9.6mg dose) vs. placebo in hospitalized out-of-hospital cardiac arrest patient to determine whether nitrite administration reduced blood pressure and whether whole blood nitrite levels increased in response to nitrite administration. This is the first reported study of sodium nitrite in cardiac arrest patients. Infusion of low doses of sodium nitrite in comatose survivors of OHCA (n=7) compared to placebo (n=4) had no significant effects on heart rate within 30min after infusion (70±20 vs. 78±3 beats per minute, p=0.18), systolic blood pressure (103±20 vs 108±15mmHg, p=0.3), or methemoglobin levels (0.92±0.33 vs. 0.70±0.26, p=0.45). Serum nitrite levels of 2-4μM were achieved within 15min of a 9.6mg nitrite infusion. Low dose sodium nitrite does not cause significant hemodynamic effect in patients with OHCA, which suggests that nitrite can be delivered safely in this critically ill patient population. Higher doses of sodium nitrite are necessary in order to achieve target serum level of 10μM. Copyright © 2017 Elsevier B.V. All rights reserved.

Radiation induced changes in the cuticular hydrocarbons of the granary weevil and their relationship to dessication and adult mortality. Quarterly report, February 15-May 14, 1986. [Sitophilus granarius

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

Sriharan, S.

1986-01-01

The weevils (Sitophilus granarius) were irradiated with gamma radiation at dose levels of 15, 30 and 80 krad in /sup 131/Cs irradiator at Tuskegee University. Survival studies showed that the weevils could live up to three weeks after irradiation. The higher dose level did not show any detrimental effect on the survival. The present studies were conducted with weevils of mixed age groups. This may be one factor in reduced mortality.

The effect of two different doses comprising the simultaneous administration of intravenous B-complex vitamins and oral folic acid on serum homocysteine levels in hemodialysis patients.

PubMed

Sombolos, Kostas; Papaioannou, Anna; Christidou, Fotini; Natse, Taisir; Bamichas, Gerasimos; Gionanlis, Lazaros; Katsaris, George; Progia, Evagelia

2006-01-01

Several regimens using different doses of folic acid (FA) alone or supplemented with B-complex vitamins (BCVs) have been tested for their ability to reduce total homocysteine (tHcy) serum levels in hemodialysis (HD) patients. In the present study, we assessed the effect of two different doses comprising the simultaneous administration of intravenous (IV) BCVs and an oral FA supplementation on serum tHCy levels in HD patients. In a cohort of 49 patients (31 male, 18 female) undergoing chronic HD treatment for a mean of 40.0+/-40.7 months, serum concentrations of tHcy, folate and vitamin-B12 (vB12) were determined at the end of three sequential periods as follows: 20 weeks without any BCV and/or FA supplementation (period A), 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA once a week (period B), and 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA thrice a week (period C). An IV dose of BCVs consisting of a 5 mL solution containing vitamin B1 (250 mg), vitamin B6 (250 mg) and vitamin B12 (1.5 mg) was administered at the end of hemodialysis. Mean serum tHcy levels were significantly higher at the end of period A relative to levels at the end of periods B and C (35.8+/-23 micromol/L vs. 22.0+/-17.6 and 15.0+/-4.5 micromol/L, respectively; p<0.000001). Mean serum folate levels and mean serum vB12 levels were significantly lower at the end of period A relative to levels at the end of periods B and C (p<0.000001). Mean serum tHcy levels were lowest at the end of period C (p<0.000001 in comparison to periods A and B), and 26 of the 49 HD patients (67.3%) possessed tHcy levels below 16 micromol/L. In HD patients, high doses consisting of the simultaneous administration of IV BCVs and an oral FA supplementation resulted in the efficient reduction of serum tHcy levels.

Reduction in radiation dose with reconstruction technique in the brain perfusion CT

NASA Astrophysics Data System (ADS)

Kim, H. J.; Lee, H. K.; Song, H.; Ju, M. S.; Dong, K. R.; Chung, W. K.; Cho, M. S.; Cho, J. H.

2011-12-01

The principal objective of this study was to verify the utility of the reconstruction imaging technique in the brain perfusion computed tomography (PCT) scan by assessing reductions in the radiation dose and analyzing the generated images. The setting used for image acquisition had a detector coverage of 40 mm, a helical thickness of 0.625 mm, a helical shuttle mode scan type and a rotation time of 0.5 s as the image parameters used for the brain PCT scan. Additionally, a phantom experiment and an animal experiment were carried out. In the phantom and animal experiments, noise was measured in the scanning with the tube voltage fixed at 80 kVp (kilovolt peak) and the level of the adaptive statistical iterative reconstruction (ASIR) was changed from 0% to 100% at 10% intervals. The standard deviation of the CT coefficient was measured three times to calculate the mean value. In the phantom and animal experiments, the absorbed dose was measured 10 times under the same conditions as the ones for noise measurement before the mean value was calculated. In the animal experiment, pencil-type and CT-dedicated ionization chambers were inserted into the central portion of pig heads for measurement. In the phantom study, as the level of the ASIR changed from 0% to 100% under identical scanning conditions, the noise value and dose were proportionally reduced. In our animal experiment, the noise value was lowest when the ASIR level was 50%, unlike in the phantom study. The dose was reduced as in the phantom study.

Assessment of an organ-based tube current modulation in thoracic computed tomography.

PubMed

Matsubara, Kosuke; Sugai, Mai; Toyoda, Asami; Koshida, Haruka; Sakuta, Keita; Takata, Tadanori; Koshida, Kichiro; Iida, Hiroji; Matsui, Osamu

2012-03-08

Recently, specific computed tomography (CT) scanners have been equipped with organ-based tube current modulation (TCM) technology. It is possible that organ-based TCM will replace the conventional dose-reduction technique of reducing the effective milliampere-second. The aim of this study was to determine if organ-based TCM could reduce radiation exposure to the breasts without compromising the image uniformity and beam hardening effect in thoracic CT examinations. Breast and skin radiation doses and the absorbed radiation dose distribution within a single section were measured with an anthropomorphic phantom and radiophotoluminescent glass dosimeters using four approaches to thoracic CT (reference, organ-based TCM, copper shielding, and the combination of the above two techniques, hereafter referred to as the combination technique). The CT value and noise level were measured using the same calibration phantom. Organ-based TCM and copper shielding reduced radiation doses to the breast by 23.7% and 21.8%, respectively. However, the CT value increased, especially in the anterior region, using copper shielding. In contrast, the CT value and noise level barely increased using organ-based TCM. The combination technique reduced the radiation dose to the breast by 38.2%, but greatly increased the absorbed radiation dose from the central to the posterior regions. Moreover, the CT value increased in the anterior region and the noise level increased by more than 10% in the entire region. Therefore, organ-based TCM can reduce radiation doses to breasts with only small increases in noise levels, making it preferable for specific groups of patients, such as children and young women.

The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene

PubMed Central

Yoo, Hong Sik; Cichocki, Joseph A.; Kim, Sungkyoon; Venkatratnam, Abhishek; Iwata, Yasuhiro; Kosyk, Oksana; Bodnar, Wanda; Sweet, Stephen; Knap, Anthony; Wade, Terry; Campbell, Jerry; Clewell, Harvey J.; Melnyk, Stepan B.; Chiu, Weihsueh A.; Rusyn, Ivan

2015-01-01

Exposure to the ubiquitous environmental contaminant trichloroethylene (TCE) is associated with cancer and non-cancer toxicity in both humans and rodents. Peroxisome proliferator-activated receptor-alpha (PPARα) is thought to be playing a role in liver toxicity in rodents through activation of the receptor by the TCE metabolite trichloroacetic acid (TCA). However, most studies using genetically altered mice have not assessed the potential for PPARα to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPARα in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Pparα-null, and humanized PPARα (hPPARα) mice were exposed intragastrically to 400 mg/kg TCE in single-dose (2, 5 and 12 h) and repeat-dose (5 days/week, 4 weeks) studies. Interestingly, following either a single- or repeat-dose exposure to TCE, levels of TCA in liver and kidney were lower in Pparα-null and hPPARα mice as compared with those in wild type mice. Levels of trichloroethanol (TCOH) were similar in all strains. TCE-exposed male mice consistently had higher levels of TCA and TCOH in all tissues compared with females. Additionally, in both single- and repeat-dose studies, a similar degree of induction of PPARα-responsive genes was observed in liver and kidney of hPPARα and wild type mice, despite the difference in hepatic and renal TCA levels. Additional sex- and strain-dependent effects were observed in the liver, including hepatocyte proliferation and oxidative stress, which were not dependent on TCA or TCOH levels. These data demonstrate that PPARα status affects the levels of the putative PPARα agonist TCA following TCE exposure. Therefore, interpretations of studies using Pparα-null and hPPARα mice need to consider the potential contribution of genotype-dependent toxicokinetics to observed differences in toxicity, rather than attributing such differences only to receptor-mediated toxicodynamic effects. PMID:26136231

The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene.

PubMed

Yoo, Hong Sik; Cichocki, Joseph A; Kim, Sungkyoon; Venkatratnam, Abhishek; Iwata, Yasuhiro; Kosyk, Oksana; Bodnar, Wanda; Sweet, Stephen; Knap, Anthony; Wade, Terry; Campbell, Jerry; Clewell, Harvey J; Melnyk, Stepan B; Chiu, Weihsueh A; Rusyn, Ivan

2015-10-01

Exposure to the ubiquitous environmental contaminant trichloroethylene (TCE) is associated with cancer and non-cancer toxicity in both humans and rodents. Peroxisome proliferator-activated receptor-alpha (PPARα) is thought to be playing a role in liver toxicity in rodents through activation of the receptor by the TCE metabolite trichloroacetic acid (TCA). However, most studies using genetically altered mice have not assessed the potential for PPARα to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPARα in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Pparα-null, and humanized PPARα (hPPARα) mice were exposed intragastrically to 400 mg/kg TCE in single-dose (2, 5 and 12 h) and repeat-dose (5 days/week, 4 weeks) studies. Interestingly, following either a single- or repeat-dose exposure to TCE, levels of TCA in liver and kidney were lower in Pparα-null and hPPARα mice as compared with those in wild type mice. Levels of trichloroethanol (TCOH) were similar in all strains. TCE-exposed male mice consistently had higher levels of TCA and TCOH in all tissues compared with females. Additionally, in both single- and repeat-dose studies, a similar degree of induction of PPARα-responsive genes was observed in liver and kidney of hPPARα and wild type mice, despite the difference in hepatic and renal TCA levels. Additional sex- and strain-dependent effects were observed in the liver, including hepatocyte proliferation and oxidative stress, which were not dependent on TCA or TCOH levels. These data demonstrate that PPARα status affects the levels of the putative PPARα agonist TCA following TCE exposure. Therefore, interpretations of studies using Pparα-null and hPPARα mice need to consider the potential contribution of genotype-dependent toxicokinetics to observed differences in toxicity, rather than attributing such differences only to receptor-mediated toxicodynamic effects. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study.

PubMed

Provenzano, Robert; Besarab, Anatole; Wright, Steven; Dua, Sohan; Zeig, Steven; Nguyen, Peter; Poole, Lona; Saikali, Khalil G; Saha, Gopal; Hemmerich, Stefan; Szczech, Lynda; Yu, K H Peony; Neff, Thomas B

2016-06-01

Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2). Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. Short treatment duration and small sample size. In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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.

In vitro gas production of foliage from three browse tree species treated with different dose levels of exogenous fibrolytic enzymes.

PubMed

López, D; Vázquez-Armijo, J F; López-Villalobos, N; Lee-Rangel, H A; Salem, A Z M; Borquez-Gastelum, J L; Domínguez-Vara, I A; Rojo-Rubio, R

2016-10-01

The aim of this study was to evaluate the effect of different dose levels of exogenous fibrolytic enzymes (EFE) on in vitro ruminal fermentation kinetics and energy utilization of foliages from three browse trees (Pithecellobium dulce, Heliocarpus velutinus and Guazuma ulmifolia). Mixture of EFE product was added to the leaves of the three browse tree species at three dose levels: 0 (control), 3.5 and 7.0 mg/g of DM. Chemical composition of the foliages, including plant secondary metabolites such as total phenolics (TP), saponins (SAP) and aqueous fraction (AF), was determined. In addition, in vitro assaying of ruminal gas production kinetics was determined for the three browse three foliages treated with EFE. P. dulce had the highest crude protein content (p < 0.05), whereas G. ulmifolia had the highest content of neutral detergent fibre and SAP (p < 0.05) and H. velutinus had the lowest content of TP (p < 0.05). The interaction between tree species and dose level of EFE was significant (p < 0.05) for gas production (GP) at 24 h of incubation, parameters b and c of the accumulated GP curve, short-chain fatty acids (SCFA) and metabolizable energy (ME). The lowest (p < 0.01) extent of accumulated GP as well as the b and c values occurred in G. ulmifolia at 0 mg EFE/g DM. P. dulce had the highest (p < 0.05) values for ME and SCFA at the highest dose of EFE. Tree species and dose level had significant (p < 0.05) effects on all parameters describing in vitro ruminal fermentation kinetics and energy utilization. Addition of EFE improved the fermentation kinetics of the browse species considered in this study. Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.

Determining the behavioural dose-response relationship of marine mammals to air gun noise and source proximity.

PubMed

Dunlop, Rebecca A; Noad, Michael J; McCauley, Robert D; Scott-Hayward, Lindsay; Kniest, Eric; Slade, Robert; Paton, David; Cato, Douglas H

2017-08-15

The effect of various anthropogenic sources of noise (e.g. sonar, seismic surveys) on the behaviour of marine mammals is sometimes quantified as a dose-response relationship, where the probability of an animal behaviourally 'responding' (e.g. avoiding the source) increases with 'dose' (or received level of noise). To do this, however, requires a definition of a 'significant' response (avoidance), which can be difficult to quantify. There is also the potential that the animal 'avoids' not only the source of noise but also the vessel operating the source, complicating the relationship. The proximity of the source is an important variable to consider in the response, yet difficult to account for given that received level and proximity are highly correlated. This study used the behavioural response of humpback whales to noise from two different air gun arrays (20 and 140 cubic inch air gun array) to determine whether a dose-response relationship existed. To do this, a measure of avoidance of the source was developed, and the magnitude (rather than probability) of this response was tested against dose. The proximity to the source, and the vessel itself, was included within the one-analysis model. Humpback whales were more likely to avoid the air gun arrays (but not the controls) within 3 km of the source at levels over 140 re. 1 µPa 2  s -1 , meaning that both the proximity and the received level were important factors and the relationship between dose (received level) and response is not a simple one. © 2017. Published by The Company of Biologists Ltd.

Radiation dose reduction in a neonatal intensive care unit in computed radiography.

PubMed

Frayre, A S; Torres, P; Gaona, E; Rivera, T; Franco, J; Molina, N

2012-12-01

The purpose of this study was to evaluate the dose received by chest x-rays in neonatal care with thermoluminescent dosimetry and to determine the level of exposure where the quantum noise level does not affect the diagnostic image quality in order to reduce the dose to neonates. In pediatric radiology, especially the prematurely born children are highly sensitive to the radiation because of the highly mitotic state of their cells; in general, the sensitivity of a tissue to radiation is directly proportional to its rate of proliferation. The sample consisted of 208 neonatal chest x-rays of 12 neonates admitted and treated in a Neonatal Intensive Care Unit (NICU). All the neonates were preterm in the range of 28-34 weeks, with a mean of 30.8 weeks. Entrance Surface Doses (ESD) values for chest x-rays are higher than the DRL of 50 μGy proposed by the National Radiological Protection Board (NRPB). In order to reduce the dose to neonates, the optimum image quality was achieved by determining the level of ESD where level noise does not affect the diagnostic image quality. The optimum ESD was estimated for additional 20 chest x-rays increasing kVp and reducing mAs until quantum noise affects image quality. Copyright © 2012 Elsevier Ltd. All rights reserved.

Monoaminergic Psychomotor Stimulants: Discriminative Stimulus Effects and Dopamine Efflux

PubMed Central

Desai, Rajeev I.; Paronis, Carol A.; Martin, Jared; Desai, Ramya

2010-01-01

The present studies were conducted to investigate the relationship between discriminative stimulus effects of indirectly acting monoaminergic psychostimulants and their ability to increase extracellular levels of dopamine (DA) in the nucleus accumbens (NAcb) shell. First, the behavioral effects of methamphetamine (MA), cocaine (COC), 1-[2-[bis(4-fluorophenyl-)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), d-amphetamine, and methylphenidate were established in rats trained to discriminate intraperitoneal injections of 0.3 mg/kg MA from saline. In other studies, in vivo microdialysis was used to determine the effects of MA, COC, and GBR 12909 on extracellular DA levels in the NAcb shell. Results show that all drugs produced dose-related and full substitution for the discriminative stimulus effects of 0.3 mg/kg MA. In microdialysis studies, cumulatively administered MA (0.3–3 mg/kg), COC (3–56 mg/kg), and GBR 12909 (3–30 mg/kg) produced dose-dependent increases in DA efflux in the NAcb shell to maxima of approximately 1200 to 1300% of control values. The increase in DA levels produced by MA and COC was rapid and short-lived, whereas the effect of GBR 12909 was slower and longer lasting. Dose-related increases in MA lever selection produced by MA, COC, and GBR 12909 corresponded with graded increases in DA levels in the NAcb shell. Doses of MA, COC, and GBR 12909 that produced full substitution increased DA levels to approximately 200 to 400% of control values. Finally, cumulatively administered MA produced comparable changes in DA levels in both naive and 0.3 mg/kg MA-trained rats. These latter results suggest that sensitization of DA release does not play a prominent role in the discriminative stimulus effects of psychomotor stimulants. PMID:20190012

Comparison of different glucocorticoid regimens in the management of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PubMed

Ajish, T P; Praveen, V P; Nisha, B; Kumar, Harish

2014-11-01

There are recommendations regarding the total dose of hydrocortisone to be administered in the treatment of classical congenital adrenal hyperplasia (CAH) to achieve the twin objectives of glucocorticoid replacement and control of hyperandrogenism. However, there is evidence gap regarding the breakup, timing and type of the steroid regimen. Efficacy of three different glucocorticoid regimens having the same total dose of steroid, differing in either the timing or type of evening steroid administered, in achieving biochemical control of the disease was assessed. The study was done in 13 prepubertal children with classical CAH over a 6-month period with 2 months devoted to each regimen. We used a prospective cross-over design using 10-15 mg/m(2) total dose of hydrocortisone. Two-fifths of the total dose of hydrocortisone was administered in the morning and one-fifth of the total dose was administered at noon in all the regimens. The regimens differed in the timing of the evening dose of hydrocortisone, 06.00-07.00 pm in regimen 1 and 09.00-10.00 pm in regimen 2. The third regimen had the evening dose of hydrocortisone replaced by an equivalent dose of prednisolone suspension which was administered at 10.00 pm. Serum 17-hydroxyprogesterone and testosterone levels were compared to assess the efficacy of treatment regimens. The three different regimens were found to be similar in their ability to control 17-hydroxyprogesterone and testosterone levels. The percentage of patients with predefined criteria for biochemically controlled disease was similar in all the three regimens. However, there was a trend toward better control of 17-hydroxyprogesterone levels in patients receiving evening dose of prednisolone. There is no significant advantage in administering the hydrocortisone dose late at night in patients with classical CAH.

Characterization of glycidol-hemoglobin adducts as biomarkers of exposure and in vivo dose

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

Honda, Hiroshi, E-mail: honda.hiroshi@kao.co.jp; Törnqvist, Margareta; Nishiyama, Naohiro

2014-03-15

Hemoglobin adducts have been used as biomarkers of exposure to reactive chemicals. Glycidol, an animal carcinogen, has been reported to form N-(2,3-dihydroxy-propyl)valine adducts to hemoglobin (diHOPrVal). To support the use of these adducts as markers of glycidol exposure, we investigated the kinetics of diHOPrVal formation and its elimination in vitro and in vivo. Five groups of rats were orally administered a single dose of glycidol ranging from 0 to 75 mg/kg bw, and diHOPrVal levels were measured 24 h after administration. A dose-dependent increase in diHOPrVal levels was observed with high linearity (R{sup 2} = 0.943). Blood sampling at differentmore » time points (1, 10, 20, or 40 days) from four groups administered glycidol at 12 mg/kg bw suggested a linear decrease in diHOPrVal levels compatible with the normal turnover of rat erythrocytes (life span, 61 days), with the calculated first-order elimination rate constant (k{sub el}) indicating that the diHOPrVal adduct was chemically stable. Then, we measured the second-order rate constant (k{sub val}) for the reaction of glycidol with N-terminal valine in rat and human hemoglobin in in vitro experiments with whole blood. The k{sub val} was 6.7 ± 1.1 and 5.6 ± 1.3 (pmol/g globin per μMh) in rat and human blood, respectively, indicating no species differences. In vivo doses estimated from k{sub val} and diHOPrVal levels were in agreement with the area under the (concentration–time) curve values determined in our earlier toxicokinetic study in rats. Our results indicate that diHOPrVal is a useful biomarker for quantification of glycidol exposure and for risk assessment. - Highlight: • Glycidol-hemoglobin adduct (diHOPrVal) was characterized for exposure evaluation. • We studied the kinetics of diHOPrVal formation and elimination in vitro and in vivo. • Dose dependent formation and chemical stability were confirmed in the rat study. • In vivo dose (AUC) of glycidol could be estimated from diHOPrVal levels. • diHOPrVal is considered a useful exposure and in vivo dose marker of G.« less

Mebendazole paste as an anthelmintic in random source research cats.

PubMed

Bradley, R E; Peters, L J

1982-10-01

Mebendazole paste, administered per os daily for 3 days, at dose levels of 22 mg/kg and 33 mg/kg was highly effective in removing Ancylostoma tubaeforme from naturally infected cats. The 22 mg/kg dose gave the highest efficacy (95.5% critical and 98% controlled). The same product at 11 mg/kg, 22 mg/kg, or 33 mg/kg was 100% effective in removing Toxocara cati from naturally infected cats. Both 11 mg/kg and 22 mg/kg dose levels were highly efficacious against the common tapeworm, Dipylidium caninum. No toxic side effects or clinical illness were observed in any of the cats used in this study.

Effects of 810 nm laser on mouse primary cortical neurons

NASA Astrophysics Data System (ADS)

Kharkwal, Gitika B.; Sharma, Sulbha K.; Huang, Ying-Ying; De Taboada, Luis; McCarthy, Thomas; Hamblin, Michael R.

2011-03-01

In the past four decades numerous studies have reported the efficacy of low level light (laser) therapy (LLLT) as a treatment for diverse diseases and injuries. Recent studies have shown that LLLT can biomodulate processes in the central nervous system and has been extensively studied as a stroke treatment. However there is still a lack of knowledge on the effects of LLLT at the cellular level in neurons. The present study aimed to study the effect of 810 nm laser on several cellular processes in primary cortical neurons cultured from mouse embryonic brains. Neurons were irradiated with light dose of 0.03, 0.3, 3, 10 and 30 J/cm2 and intracellular levels of reactive oxygen species, nitric oxide and calcium were measured. The changes in mitochondrial function in response to light were studied in terms of adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP). Light induced a significant increase in calcium, ATP and MMP at lower fluences and a decrease at higher fluence. ROS was induced significantly by light at all light doses. Nitric oxide levels also showed an increase on treatment with light. The results of the present study suggest that LLLT at lower fluences is capable of inducing mediators of cell signaling process which in turn may be responsible for the biomodulatory effects of the low level laser. At higher fluences beneficial mediators are reduced but potentially harmful mediators are increased thus offering an explanation for the biphasic dose response.

Effects of the Administration of 25(OH) Vitamin D3 in an Experimental Model of Chronic Kidney Disease in Animals Null for 1-Alpha-Hydroxylase.

PubMed

Torremadé, Noelia; Bozic, Milica; Goltzman, David; Fernandez, Elvira; Valdivielso, José M

2017-01-01

The final step in vitamin D activation is catalyzed by 1-alpha-hydroxylase (CYP27B1). Chronic kidney disease (CKD) is characterized by low levels of both 25(OH)D3 and 1,25(OH)2D3 provoking secondary hyperparathyroidism (2HPT). Therefore, treatments with active or native vitamin D compounds are common in CKD to restore 25(OH)D3 levels and also to decrease PTH. This study evaluates the dose of 25(OH)D3 that restores parathyroid hormone (PTH) and calcium levels in a model of CKD in CYP27B1-/- mice. Furthermore, we compare the safety and efficacy of the same dose in CYP27B1+/+ animals. The dose needed to decrease PTH levels in CYP27B1-/- mice with CKD was 50 ng/g. That dose restored blood calcium levels without modifying phosphate levels, and increased the expression of genes responsible for calcium absorption (TRPV5 and calbindinD- 28K in the kidney, TRPV6 and calbindinD-9k in the intestine). The same dose of 25(OH)D3 did not modify PTH in CYP27B1+/+ animals with CKD. Blood calcium remained normal, while phosphate increased significantly. Blood levels of 25(OH)D3 in CYP27B1-/- mice were extremely high compared to those in CYP27B1+/+ animals. CYP27B1+/+ animals with CKD showed increases in TRPV5, TRPV6, calbindinD-28K and calbindinD-9K, which were not further elevated with the treatment. Furthermore, CYP27B1+/+ animals displayed an increase in vascular calcification. We conclude that the dose of 25(OH)D3 effective in decreasing PTH levels in CYP27B1-/- mice with CKD, has a potentially toxic effect in CYP27B1+/+ animals with CKD.

Influence of high dose tumescent local anaesthesia with prilocaine on systemic interleukin (IL)-6, IL-8 and tumour necrosis factor-α.

PubMed

Schmittner, M D; Faulhaber, J; Kemler, B; Koenen, W; Thumfart, J O; Weiss, C; Neumaier, M; Beck, G C

2010-12-01

Tumescent local anaesthesia (TLA) with high prilocaine doses leads to formation of methemoglobin (MHb) which is known to be a potent activator of pro-inflammatory endothelial cell response in vitro. As TLA is widely used for large dermatological resections, the aim of this study was to investigate the effects of high prilocaine doses on the systemic inflammatory response in vivo and its clinical relevance. This prospective study examines the influence of MHb on serum interleukin (IL)-6, IL-8 and tumour necrosis tumour necrosis (TNF)-α levels up to 72 h after application of TLA with prilocaine in doses higher than 600 mg. A total of 30 patients received prilocaine in a median dose of 1500 mg (range: 880-4160 mg) for large resections. Peak prilocaine serum concentration was reached 4 h (0.72 ± 0.07 μg/mL), the maximum concentration of MHb (7.43 ± 0.87%) and IL-6 (28.4 ± 4.1 U/L) 12 h after TLA application. TNF-α and IL-8 release were not found significantly increased. Three patients developed MHb concentrations >15%. This clinical study shows for the first time that a high prilocaine serum concentration leads in vivo to elevated systemic levels of IL-6 but not of IL-8 and TNF-α because of initial high MHb levels. Because of possible and unpredictable high MHb concentrations, TLA should only be performed with prilocaine in doses of 2.5 mg/kg. In general, new solutions of TLA are necessary to achieve adequate anaesthesia for large dermatological resections to decrease the risk of methemoglobinaemia. © 2010 The Authors. Journal compilation © 2010 European Academy of Dermatology and Venereology.

Assessing the uncertainty in a normal tissue complication probability difference (∆NTCP): radiation-induced liver disease (RILD) in liver tumour patients treated with proton vs X-ray therapy.

PubMed

Kobashi, Keiji; Prayongrat, Anussara; Kimoto, Takuya; Toramatsu, Chie; Dekura, Yasuhiro; Katoh, Norio; Shimizu, Shinichi; Ito, Yoichi M; Shirato, Hiroki

2018-03-01

Modern radiotherapy technologies such as proton beam therapy (PBT) permit dose escalation to the tumour and minimize unnecessary doses to normal tissues. To achieve appropriate patient selection for PBT, a normal tissue complication probability (NTCP) model can be applied to estimate the risk of treatment-related toxicity relative to X-ray therapy (XRT). A methodology for estimating the difference in NTCP (∆NTCP), including its uncertainty as a function of dose to normal tissue, is described in this study using the Delta method, a statistical method for evaluating the variance of functions, considering the variance-covariance matrix. We used a virtual individual patient dataset of radiation-induced liver disease (RILD) in liver tumour patients who were treated with XRT as a study model. As an alternative option for individual patient data, dose-bin data, which consists of the number of patients who developed toxicity in each dose level/bin and the total number of patients in that dose level/bin, are useful for multi-institutional data sharing. It provides comparable accuracy with individual patient data when using the Delta method. With reliable NTCP models, the ∆NTCP with uncertainty might potentially guide the use of PBT; however, clinical validation and a cost-effectiveness study are needed to determine the appropriate ∆NTCP threshold.

Assessing the uncertainty in a normal tissue complication probability difference (∆NTCP): radiation-induced liver disease (RILD) in liver tumour patients treated with proton vs X-ray therapy

PubMed Central

Kobashi, Keiji; Kimoto, Takuya; Toramatsu, Chie; Dekura, Yasuhiro; Katoh, Norio; Shimizu, Shinichi; Ito, Yoichi M; Shirato, Hiroki

2018-01-01

Abstract Modern radiotherapy technologies such as proton beam therapy (PBT) permit dose escalation to the tumour and minimize unnecessary doses to normal tissues. To achieve appropriate patient selection for PBT, a normal tissue complication probability (NTCP) model can be applied to estimate the risk of treatment-related toxicity relative to X-ray therapy (XRT). A methodology for estimating the difference in NTCP (∆NTCP), including its uncertainty as a function of dose to normal tissue, is described in this study using the Delta method, a statistical method for evaluating the variance of functions, considering the variance–covariance matrix. We used a virtual individual patient dataset of radiation-induced liver disease (RILD) in liver tumour patients who were treated with XRT as a study model. As an alternative option for individual patient data, dose-bin data, which consists of the number of patients who developed toxicity in each dose level/bin and the total number of patients in that dose level/bin, are useful for multi-institutional data sharing. It provides comparable accuracy with individual patient data when using the Delta method. With reliable NTCP models, the ∆NTCP with uncertainty might potentially guide the use of PBT; however, clinical validation and a cost-effectiveness study are needed to determine the appropriate ∆NTCP threshold. PMID:29538699

The safety of green tea and green tea extract consumption in adults - Results of a systematic review.

PubMed

Hu, Jiang; Webster, Donna; Cao, Joyce; Shao, Andrew

2018-06-01

A systematic review of published toxicology and human intervention studies was performed to characterize potential hazards associated with consumption of green tea and its preparations. A review of toxicological evidence from laboratory studies revealed the liver as the target organ and hepatotoxicity as the critical effect, which was strongly associated with certain dosing conditions (e.g. bolus dose via gavage, fasting), and positively correlated with total catechin and epigallocatechingallate (EGCG) content. A review of adverse event (AE) data from 159 human intervention studies yielded findings consistent with toxicological evidence in that a limited range of concentrated, catechin-rich green tea preparations resulted in hepatic AEs in a dose-dependent manner when ingested in large bolus doses, but not when consumed as brewed tea or extracts in beverages or as part of food. Toxico- and pharmacokinetic evidence further suggests internal dose of catechins is a key determinant in the occurrence and severity of hepatotoxicity. A safe intake level of 338 mg EGCG/day for adults was derived from toxicological and human safety data for tea preparations ingested as a solid bolus dose. An Observed Safe Level (OSL) of 704 mg EGCG/day might be considered for tea preparations in beverage form based on human AE data. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Studies To Examine Potential Tolerability Differences between the 5-HT2C Receptor Selective Agonists Lorcaserin and CP-809101.

PubMed

Higgins, Guy A; Silenieks, Leonardo B; Patrick, Amy; De Lannoy, Ines A M; Fletcher, Paul J; Parker, Linda A; MacLusky, Neil J; Sullivan, Laura C; Chavera, Teresa A; Berg, Kelly A

2017-05-17

Lorcaserin (LOR) is a selective 5-HT 2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT 2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT 2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of functional selectivity designed to examine signaling pathways activated by both drugs in CHO (Chinese hamster ovary) cells expressing h5-HT 2C receptors failed to identify evidence for biased signaling differences between LOR and CP. Thus, both drugs showed similar profiles across PLC, PLA 2 , and ERK signaling pathways. In studies designed to examine pharmacokinetic differences between LOR and CP, while drug plasma levels correlated with increasing dose, CSF levels did not. CSF levels of LOR increased proportionally with dose; however CSF levels of CP plateaued from 6 to 12 mg/kg. Thus, the apparently improved tolerability of CP likely reflects a limit to CNS levels attained at relatively high doses.

Increased prandial insulin secretion after administration of a single preprandial oral dose of repaglinide in patients with type 2 diabetes.

PubMed

Owens, D R; Luzio, S D; Ismail, I; Bayer, T

2000-04-01

To examine the dose-related pharmacodynamics and pharmacokinetics of a single preprandial oral dose of repaglinide in patients with type 2 diabetes. A total of 16 Caucasian men with type 2 diabetes participated in two placebo-controlled double-blind randomized cross-over studies. Patients were randomized to receive a single oral dose of repaglinide (0.5, 1.0, and 2.0 mg in study 1 and 4.0 mg in study 2) or placebo (both studies) administered 15 min before the first of two sequential identical standard meals (breakfast and lunch) that were 4 h apart. During each of the study days, which were 1 week apart, blood samples were taken at frequent intervals over a period of approximately 8 h for measurement of plasma glucose, insulin, C-peptide, and repaglinide concentrations. During the first meal period (0-240 min), administration of repaglinide reduced significantly the area under the curve (AUC) for glucose concentration and significantly increased the AUC for insulin levels, C-peptide levels, and the insulin secretion rate. These results, compared with those of administering placebo, were dose dependent and log linear. The effect of repaglinide administration on insulin secretion was most pronounced in the early prandial period. Within 30 min, it caused a relative increase in insulin secretion of up to 150%. During the second meal period (240-480 min), there was no difference between repaglinide and placebo administration in the AUC for glucose concentration, C-peptide concentration, and the estimated insulin secretion rate. A single dose of repaglinide (0.5-4.0 mg) before breakfast improves insulin secretion and reduces prandial hyperglycemia dose-dependently Administration of repaglinide had no effect on insulin secretion with the second meal, which was consumed 4 h after breakfast.

Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study.

PubMed

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.

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

PubMed Central

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

2010-01-01

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