Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

The effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects (n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz were measured by LC-MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ∼2.5-fold) and decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-∞) of efavirenz (by ∼1.6- and ∼2.5-fold respectively) (p < 0.001). Rifampin treatment substantially increased the Cmax and AUC0-12h of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz, metabolic ratio (AUC0-72h of metabolites to AUC0-72h efavirenz) and the amount of metabolites excreted in urine (Ae0-12hr) (all, p < 0.01). Female subjects had longer elimination half-life (1.6-2.2-fold) and larger weight-adjusted distribution volume (1.6-1.9-fold) of efavirenz than male subjects (p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo. The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme

Women with Fibromyalgia Have Lower Levels of Calcium, Magnesium, Iron and Manganese in Hair Mineral Analysis

Little is known about hair mineral status in fibromyalgia patients. This study evaluated the characteristics of hair minerals in female patients with fibromyalgia compared with a healthy reference group. Forty-four female patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria were enrolled as the case group. Ageand body mass index-matched data were obtained from 122 control subjects enrolled during visit for a regular health check-up. Hair minerals were analyzed and compared between the two groups. The mean age was 43.7 yr. General characteristics were not different between the two groups. Fibromyalgia patients showed a significantly lower level of calcium (775 µg/g vs 1,093 µg/g), magnesium (52 µg/g vs 72 µg/g), iron (5.9 µg/g vs 7.1 µg/g), copper (28.3 µg/g vs 40.2 µg/g) and manganese (140 ng/g vs 190 ng/g). Calcium, magnesium, iron, and manganese were loaded in the same factor using factor analysis; the mean of this factor was significantly lower in fibromyalgia group in multivariate analysis with adjustment for potential confounders. In conclusion, the concentrations of calcium, magnesium, iron, and manganese in the hair of female patients with fibromyalgia are lower than of controls, even after adjustment of potential confounders

Contribution of N-Glucuronidation to Efavirenz Elimination In Vivo in the Basal and Rifampin-Induced Metabolism of Efavirenz▿

In this study, the contribution of efavirenz N-glucuronidation to efavirenz elimination in vivo was assessed. In a two-period placebo-controlled crossover trial design, a single 600-mg oral dose of efavirenz was administered to healthy volunteers (n = 10) pretreated with placebo pills or 600 mg/day rifampin orally for 10 days. Urine and plasma concentrations of efavirenz and 8-hydroxyefavirenz were measured by the liquid chromatography-tandem mass spectrometry method after enzymatic hydrolysis with β-glucuronidase (conjugated and unconjugated) and without enzymatic hydrolysis (unconjugated). Pharmacokinetic parameters of efavirenz within the placebo- or rifampin-treated group obtained after enzymatic hydrolysis did not show any statistically significant difference compared with those obtained without enzymatic hydrolysis (P > 0.05; paired t test, two-tailed). The amount of efavirenz excreted over 12 h was significantly larger after enzymatic hydrolysis in both the placebo (P = 0.007) and rifampin (P = 0.0001) treatment groups, supporting the occurrence of direct N-glucuronidation of efavirenz, but the relevance of this finding is limited because the amount of efavirenz excreted as unchanged or conjugated in urine is less than 1% of the dose administered. In both the placebo- and rifampin-treated groups, plasma concentrations of 8-hydroxyefavirenz and the amount excreted over 12 h were significantly larger (P < 0.00001) after enzymatic hydrolysis than without enzymatic hydrolysis. These findings suggest that although the occurrence of direct efavirenz N-glucuronidation is supported by the urine data, the abundance of efavirenz N-glucuronide in plasma is negligible and that the contribution of the N-glucuronidation pathway to the overall clearance of efavirenz seems minimal

Serum Gamma-glutamyl Transferase Concentration Within the Reference Range is Related to the Coronary Heart Disease Risk Prediction in Korean Men: Analysis of the Korea National Health and Nutrition Examination Survey (V-1, 2010 and V-2, 2011)

Background: Limited data exist on the association of serum gamma-glutamyl transferase (GGT) level within the reference range with the increased risk of coronary heart disease (CHD) prediction in men. The study examined the association between serum GGT concentration within the reference range and the CHD risk prediction in Korean men. Methods: The study employed data from Korean National Health and Nutrition Examination Survey (V-1, 2010 and V-2, 2011) where a total of 1301 individuals were analyzed. A 10-year CHD risk prediction was computed using the Framingham Risk Score (FRS) modified by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). Results: Positive correlations were established between log-transformed GGT concentration and FRS (r = 0.237, P < 0.001). After adjustment of body mass index, the amount of alcohol intake and low-density lipoprotein-cholesterol, the odds ratio (95% confidence interval) for intermediate risk and beyond of 10-year CHD prediction (10-year risk ≥10%) with lowest quartile of participants was 1.21 (0.78-1.87) for second quartiles, 1.39 (0.88-2.21) for third quartiles and 2.03 (1.23-3.34) for highest quartiles. Conclusions: Higher serum GGT within its reference range was significantly correlated with a 10-year CHD risk prediction estimation using NCEP ATP III in Korean men

An algorithm for automatic 2D quadrilateral mesh generation with line constraints

Abstract Finite element method (FEM) is a fundamental numerical analysis technique widely used in engineering applications. Although state-ofthe-art hardware has reduced the solving time, which accounts for a small portion of the overall FEM analysis time, the relative time needed to build mesh models has been increasing. In particular, mesh models that must model stiffeners, those features that are attached to the plate in a ship structure, are imposed with line constraints and other constraints such as holes. To automatically generate a 2D quadrilateral mesh with the line constraints, an extended algorithm to handle line constraints is proposed based on the constrained Delaunay triangulation and QMorph algorithm. The performance of the proposed algorithm is evaluated, and numerical results of our proposed algorithm are presented.

Duplex pyrosequencing assay of the 388A>G and 521T>C SLCO1B1 polymorphisms in three Asian populations

BACKGROUND: We developed a method for detecting important SLCO1B1 polymorphisms and compared the haplotype frequencies in 3 Asian populations. METHODS: We designed a duplex pyrosequencing assay to detect simultaneously the 388A>G and 521T>C variants of SLCO1B1; this method can identify SLCO1B1*1b, SLCO1B1*5, and SLCO1B1*15. The method was validated by direct sequencing of 96 Korean subjects. In addition, duplex genotyping and the monoplex method were compared and validated with 469 Korean subjects. To characterize the haplotype frequencies based on the 2 polymorphisms, we genotyped 106 Chinese and 104 Vietnamese subjects, as well as Korean subjects, using the new method. RESULTS: The results showed 100% concordance among the monoplex and duplex pyrosequencing assays and direct sequencing method. The allele frequencies were similar in the 3 Asian populations: the most common allele was SLCO1B1*1b, while SLCO1B1*5 was rare or absent. The frequencies of functional SLCO1B1*15 alleles differed statistically between Chinese (8.2%) and Korean (14.0%) and Vietnamese (16.3%) (p<0.05, chi(2)-test). CONCLUSIONS: The duplex pyrosequencing assay appears to be an accurate, rapid, and cost-effective genotyping method to detect major SLCO1B1 important alleles in Asian populations

Efficacy and Safety of "URSA Complex" in Subjects with Physical Fatigue: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial

Background: Fatigue is a common symptom both in diseases status and in healthy subjects. Various supplements and nutraceuticals for relieving of fatigue have been used. However, there are a few studies to evaluate the efficacy and the safety of the drug for fatigue alleviation, we conducted using URSA Complex to evaluate the efficacy on physical fatigue via score changes in the checklist individual strength (CIS). Methods: The study was designed as a multicenter, randomized, double-blind, placebo-controlled trial, with subjects randomized to one of the two arms, receiving either placebo or URSA Complex administered as identical capsules. The primary efficacy endpoints of this clinical trials are the ratio of improving CIS scores < 76 points in patients at the end (4 weeks). Secondary efficacy variables are as follows one is an improvement of fatigue and the other is an improvement of the liver enzyme. Results: The fatigue recovery rate in who had improved CIS scores of < 76 points were 70.0%, 50.9% in the therapy group and placebo group, respectively (P = 0.019). The fatigue recovery rate in CIS score was higher in URSA Complex therapy group than placebo group. The difference between therapy group and placebo group was statistically significant at 4 weeks later, but not 2 weeks. Conclusions: Our results provided that the URSA Complex was effective in alleviating physical fatigue. The adverse event frequency in the therapy groups was similar to that in the placebo group

Low Levels of Sex Hormone-Binding Globulin Constitute an Independent Risk Factor for Arterial Stiffness in Korean Women

The association between sex hormone-binding globulin (SHBG) and arterial stiffness in women is not conclusive. In addition, obesity might also be involved in the relationship between SHBG and atherosclerosis. The aim of this study was to determine the relationship between SHBG and arterial stiffness in association with central obesity in women. This cross-sectional study included 381 women who participated in the health checkup programs in one hospital. The brachial-ankle pulse wave velocity (baPWV) was measured as a marker for arterial stiffness. A negative correlation was observed between SHBG levels and baPWV (rho = −0.281). The relationship was significant even after adjusting for potential confounders (beta = −0.087 in fully adjusted model). After considering the interaction between central obesity and SHBG levels, the significant association was evident only in obese women (P for interaction = 0.025). Adjustment for a 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores, instead of each cardiovascular risk factor individually, did not affect the significance of the relationship between SHBG levels and baPWV. Serum levels of SHBG were negatively associated with arterial stiffness independent of cardiovascular risk factors or 10-year ASCVD risk scores in Korean women. The relationship may be potentiated by central obesity