Herb-Opioid Interactions

描述(申请人提供)：生姜提取液；贯叶连翘 作为一种非处方药、天然抗抑郁药而广受欢迎。 直到最近，SJW还被认为耐受性良好，且相对安全。 在过去的一年里，有报道称， SJW和几种治疗指数较窄的药物，特别是环孢素吲哚那韦， 和地高辛。这种相互作用现在被认为涉及诱导两个 药物处置机制：细胞色素P450 3A4酶和主动外排 泵，P-糖蛋白，两者都会导致血液或血浆的显著减少 影响患者治疗效果的药物浓度 毒品。天然和合成阿片类药物是治疗癌症的一线药物 癌症和癌症引起的剧烈疼痛的姑息治疗 治疗。众所周知，抑郁症是一种共同的疾病， 严重且控制不佳的癌症相关疼痛。鉴于广泛存在的 圣约翰草被认为是一种“情绪增强剂”和天然的抗抑郁剂， 接受阿片类止痛药的癌症疼痛患者很可能会求助于这种草药 为缓解抑郁症状做准备。这样做的总体目标是 研究建议是调查两国之间是否存在显著的相互作用 两种广泛使用的阿片类止痛药-羟考酮、芬太尼和圣约翰麦芽汁 通过对健康志愿者的实验室研究进行提取。这些研究 将评估与之相互作用的潜在临床意义 尊重阿片类药物的镇痛效果和副作用，为临床治疗提供科学依据 对任何观察到的 互动。这项研究的羟考酮手臂旨在1)调查 诱导细胞色素P3A4介导的N-脱甲基化是主要的解毒作用 羟考酮的作用途径；2)解决四君子汤对小鼠脑损伤的诱导作用。 经静脉和口服给药的肠道和肝脏细胞色素P3A4 CYP3A特异性体内催化探针-咪达唑仑。芬太尼的手臂 研究将1)评估生姜丸对脑摄取和外流动力学的影响 芬太尼的药代动力学-药效学(PK-PD)模型 在静脉注射阿片类药物期间和之后随时间的反应，以及 2)观察芬太尼的镇痛效果及不良反应。 SJW的预处理可能是由于血脑屏障中PGP的诱导所致。 该研究的第三个分支将评估生姜丸是否具有止痛特性 它本身，或能够促进阿片类止痛。整体而言，建议的 研究将提供对潜在和临床的最终评估 SJW与阿片类药物的不良相互作用在#年的意义 癌症疼痛疗法。

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.