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Sökning: WFRF:(Fukasawa Takashi)

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  • Mukonzo, K, et al. (författare)
  • A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
  • 2009
  • Ingår i: British journal of clinical pharmacology. - 1365-2125. ; 68:5, s. 690-9
  • Tidskriftsartikel (refereegranskat)abstract
    • center dot Efavirenz is metabolized by highly polymorphic enzymes, CYP2B6 and CYP3A. The effect of the different variant alleles on efavirenz population pharmacokinetics has not yet been fully explored. center dot CYP2B6*6 influences efavirenz steady-state pharmacokinetics. Together with sex it explains 11% of the between-subject variability in apparent oral clearance, but predictions could potentially be improved if additional alleles causing reduced drug metabolism were identified. center dot ABCB1 (3435C -> T) may have effect on efavirenz single-dose and steady-state pharmacokinetics. WHAT THIS STUDY ADDS center dot A new polymorphism in ABCB1 gene (rs3842) and CYP2B6*11 in addition to sex and CYP2B6*6 genotype predict efavirenz single-dose pharmacokinetics. center dot A combined population pharmacogenetic/pharmacokinetic modelling approach allows determination and simulation of determinant factors for efavirenz single-dose pharmacokinetics based on data on gender, biochemical variables and genetic factors in relevant genes (a total of 30 SNPs in CYP2B6, ABCB1 and CYP3A4 genes) in Ugandan population. AIMS Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using nonmem. METHODS Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS Apparent oral clearance (95% confidence interval) was 4 l h l-1 (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
  • Takahashi, Masaya, et al. (författare)
  • Relative Influences of Sickness Absence and Presence on Job Stress Factors, Chronic Fatigue, and Sleep Disturbances
  • 2007
  • Ingår i: The XIII th European Concress of Work and Organizational Psychology, EAWOP, May 9-12 2007, Stockholm.
  • Konferensbidrag (populärvet., debatt m.m.)abstract
    • Objective: Being at work when sick has received wide attention because of its probable costs to both employees and employers. Limited data is available for the roles of sickness absence in the health effects of sickness presence. We examined job stress factors, chronic fatigue, sleep disturbances among factory workers while considering their status of both sickness absence and presence.Methods: A total of 211 employees (mean age 45 years; 193 men) working at a pulp and chemical factory completed and returned a questionnaire asking sickness absence and presence during the previous one year, job stress factors, chronic fatigue, sleep disturbances, and background information (response rate = 97%). Participants were divided into four groups according to whether or not they took sickness absence and/or sickness presence. We compared these four groups for the above dependent variables by analysis of covariance and a multiple logistic regression model to adjust for the possible effects of gender and age.Results: Workers reporting no sickness absence but presence (12% of the participants) showed the highest levels of quantitative workload, variance in workload, depressive symptoms, and chronic fatigue, and the lowest job satisfaction among the groups, though not significant compared to the sickness absence plus presence group (8%). No significant group differences were observed for the other factors of job stress or insomnia symptoms. But the no sickness absence but presence workers reported the greatest sleepiness at work.Conclusions: Going to work despite being sick may be associated with adverse stress reactions. Nevertheless, our findings favor the hypothesis that taking a sickness absence appropriately may have some effects to alleviate the presence-related reactions.
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