CLINICAL ASSESSMENT OF HERB-DRUG INTERACTION

草药-药物相互作用的临床评估

• 批准号: 7377677
• 负责人: Bill Gurley
• 金额: $ 8.57万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377677
• 关键词: CLINICAL; ASSESSMENT; HERB; DRUG; INTERACTION

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Forty subjects divided into two independent groups, each containing equal numbers of males and females (aged 22-40 years), will provide informed consent and be enrolled. The first group of subjects (n = 20) will be used to evaluate the effect of chronic herb supplementation on hepatic and/or intestinal CYP3A4, CYP1A2, and CYP2D6 activity (e.g. midazolam, MDZ; caffeine, CFE; and debrisoquin, DB). The second group (n = 20) will be used to assess whether or not herbal supplements can modulate P-gp activity (e.g. Digoxin, DGX). Subjects in each of the two groups will undergo separate, randomized appraisals of herb, rifampin, and clarithromycin administration on CYP and P-gp activity. Subjects in each group will be randomized to one of six supplementation sequences. For inclusion in the study, subjects must be in good health and currently not on any chronic medication or dietary supplement. Candidates will report to the General Clinical Research Center (GCRC) located on the 6th floor of the John L. McClellan Memorial Veterans Hospital in Little Rock for screening procedures. All candidates will be screened with the aid of medical histories, blood chemistries and urinalyses. Exclusion criteria include: smoking, chronic alcohol intake, obesity (>120% ideal body weight), oral contraceptive use, abnormal thyroid function, elevated serum transaminases, pregnancy, and lactation. Prior to enrollment, subjects will be phenotyped with debrisoquine (DB) to screen for poor CYP2D6 metabolizers. Subjects exhibiting poor metabolizer phenotypes (urinary DB recovery ratio ? 0.25) will be excluded from participation. Subjects will be asked to fast overnight (~8 hours) prior to the days of clearance and/or phenotype measurement. On the study days, all subjects will report to the General Clinical Research Center at the John L. McClellan Memorial Veterans Hospital in Little Rock, AR. Midazolam (Versed10 mg oral solution, Roche Laboratories, Nutley, NJ), and digoxin (Lanoxicaps¿, two 0.2 mg capsules, Glaxo-Wellcome, Research Triangle Park, NC) will be obtained from commercial sources while debrisoquine (5 mg oral solution) and caffeine (100 mg oral solution) will be prepared at the UAMS College of Pharmacy. On each day of drug administration, serial serum and/or whole blood samples, or urinary metabolite/parent ratios will be used for phenotype characterization. An advantage of this approach is that subjects serve as their own control. By comparing the difference in baseline and post-treatment clearance/phenotype indices within each subject, the influence of herbal supplementation on CYP and P-gp activity is best characterized. The degree of change calculated as the difference in clearance between baseline and post-treatment indices will allow more effective comparisons. For example, the aftereffect of ginkgo biloba on P-gp is best determined by comparing differences in baseline and 28-day DGX clearances. This approach also controls for the large intersubject variability inherent in probe drug clearance comparisons

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。40名受试者被分为两个独立的组，每个组包含相同数量的男性和女性（年龄在22-40岁），将提供知情同意并入组。第一组受试者（n = 20）将被用来评估慢性草药补充对肝脏和/或肠道CYP3A4、CYP1A2和CYP2D6活性的影响（如咪达唑仑，MDZ；咖啡因，CFE；和德布喹，DB）。第二组（n = 20）将用于评估草药补充剂是否可以调节P-gp活性（例如地高辛，DGX）。两组的受试者将分别进行随机评估，分别使用草药、利福平和克拉霉素对CYP和P-gp活性的影响。每组的受试者将被随机分配到六个补充序列中的一个。纳入研究的受试者必须身体健康，目前未服用任何慢性药物或膳食补充剂。候选人将向位于小石城约翰L.麦克莱伦纪念退伍军人医院6楼的一般临床研究中心（GCRC）报告筛选程序。所有候选人将在病史、血液化学和尿液分析的帮助下进行筛选。排除标准包括：吸烟、长期饮酒、肥胖（体重超过理想体重的120%）、口服避孕药、甲状腺功能异常、血清转氨酶升高、妊娠和哺乳期。在入组之前，受试者将使用碎片喹（DB）进行表型分析，以筛选CYP2D6代谢不良者。表现出不良代谢表型的受试者(尿DB回收率？0.25)将被排除在参与之外。受试者将被要求在清除率和/或表型测量前禁食一夜（~8小时）。在研究当天，所有受试者将向位于AR小石城的约翰L.麦克莱伦纪念退伍军人医院的一般临床研究中心报告。米达唑仑（Versed10毫克口服溶液，罗氏实验室，Nutley， NJ）和地高辛（Lanoxicaps¿，两种0.2毫克胶囊，葛兰素-威康公司，北卡罗来纳州研究三角洲公园）将从商业来源获得，而碎屑喹（5毫克口服溶液）和咖啡因（100毫克口服溶液）将在UAMS药学院制备。在给药的每一天，连续血清和/或全血样本，或尿液代谢物/亲本比率将用于表型表征。这种方法的一个优点是受试者可以作为他们自己的控制对象。通过比较每个受试者的基线和治疗后清除率/表型指数的差异，可以最好地表征草药补充对CYP和P-gp活性的影响。以基线和治疗后指标之间的间隙差计算的变化程度将允许更有效的比较。例如，银杏叶对P-gp的影响最好通过比较基线和28天DGX清除率的差异来确定。该方法还控制了探针药物清除率比较中固有的大受试者间变异性