Herb-Opioid Interactions

性状（由申请人提供）：贯叶连翘提取物，具有 作为一种非处方的天然抗抑郁药而广受欢迎。 直到最近，SJW被认为耐受性良好，相对安全。 在过去的一年里，据报道， SJW和几种窄治疗指数药物，特别是环孢素茚地那韦， 和地高辛。现在认识到相互作用涉及两个 药物处置机制：细胞色素P450 3A 4酶和主动外排 泵，P-糖蛋白，均导致血液或血浆中 损害受影响患者治疗效果的药物浓度 药天然和合成阿片类药物是治疗阿片类药物的一线药物。 癌症和癌症引起的严重疼痛的姑息治疗 治疗众所周知，抑郁症是一种共病状态， 严重和控制不良的癌症相关疼痛。鉴于广泛的 承认圣约翰草是一种“情绪增强剂”和天然抗抑郁药， 接受阿片类止痛药的癌症疼痛患者很可能会转向这种草药 用于缓解抑郁症状的制剂。本报告的总体目标 研究建议是调查是否发生重大的相互作用， 两种广泛使用的阿片类镇痛药-羟考酮和芬太尼和圣约翰草 通过健康志愿者的实验室研究提取。研究 将评估与以下物质相互作用的潜在临床意义 尊重阿片类镇痛的疗效和副作用，并提供科学的 深入了解任何观察到的潜在药代动力学机制 交互.本研究的羟考酮组旨在1）研究 诱导CYP 3A 4介导的N-去甲基化，这是主要的解毒作用 2）解决SJW对羟考酮的诱导作用， 肠和肝CYP 3A 4通过静脉内和口服给药， CYP 3A特异性体内催化探针-咪达唑仑。芬太尼的手臂 研究将1）评估SJW对脑摄取和外排动力学的影响 芬太尼的药代动力学-药效学（PK-PD）模型， 在阿片类药物静脉输注期间和之后随时间的反应，以及 2)评价芬太尼镇痛效果及副作用， SJW预处理可能是由于在BBB诱导Pgp所致。 研究的第三组将评估SJW是否具有镇痛特性， 它本身，或能够促进阿片类镇痛。总体而言，拟议 研究将提供一个明确的评估的潜力和临床 SJW和阿片类药物之间不良相互作用的意义 癌症疼痛治疗

DESCRIPTION (provided by applicant):Extract of SJW; Hypericum perforatum, has gained widespread popularity as an over-the-counter, natural antidepressant. Until recently, SJW was thought to be well tolerated and relatively safe. Within the past year, adverse metabolic interactions have been reported between SJW and several narrow therapeutic index drugs, notably cyclosporine indinavir, and digoxin. The interactions are now recognized to involve induction of two drug disposition mechanisms: cytochrome P450 3A4 enzyme and the active efflux pump, P-glycoprotein, both leading to profound reductions in blood or plasma drug concentration that compromises the therapeutic efficacy of the affected drug. Natural and synthetic opioids are the first-line agents for the palliative treatment of severe pain that results from cancer and cancer treatment. It is well recognized that depression is a co-morbid condition of severe and poorly controlled cancer-related pain. Given the widespread recognition of St. Johns wort as a "mood enhancer" and natural antidepressant, cancer pain patients receiving opioid analgesics may well turn to this herbal preparation for relief of depressive symptoms. The overall objective of this research proposal is to investigate if significant interactions occur between two widely used opioid analgesics - oxycodone and fentanyl and St. John wort extract through laboratory-based studies in healthy volunteers. The studies will assess the potential clinical significance of the interactions with respect to opioid analgesia efficacy and side effects, and provide scientific insights into the pharmacokinetic mechanisms underlying any observed interactions. The oxycodone arm of the study is designed to 1) investigate the induction of CYP3A4-mediated N-demethylation which is the major detoxification pathway for oxycodone, and 2) resolve the inductive effects of SJW on intestinal and hepatic CYP3A4 through intravenous and oral administrations of a CYP3A-specific, in vivo catalytic probe -midazolam. The fentanyl arm of the study will 1) assess the effects of SJW on the brain uptake and efflux kinetics of fentanyl through pharmacokinetic-pharmacodynamic (PK-PD) modeling of miotic response over time during and following intravenous infusion of the opioid, and 2) to evaluate the changes in analgesia and side effects of fentanyl upon pretreatment with SJW that may have resulted from induction of Pgp at the BBB. A third arm of the study will assess whether SJW has analgesic properties of its own, or is capable of promoting opioid analgesia. Overall, the proposed research will provide a definitive assessment of the potential and clinical significance of adverse interactions between SJW and opioids in the context of cancer pain therapy.