Modulation of Opioid Effects by Garlic Supplements

描述（由申请人提供）：大蒜补充剂因其声称的免疫增强和抗癌作用而被癌症患者广泛使用。流行病学证据和实验室研究表明，饮食中的大蒜或大蒜提取物可能通过多种生化和细胞机制来预防或阻止癌症，包括抑制肿瘤的促进和增殖，以及通过抑制生物活化酶和诱导解毒酶来抑制致癌物的活化。大蒜尤其以其在肠道和肝脏中诱导细胞色素P450酶而闻名，这构成了药物的主要解毒系统。此外，最近的报道表明，大蒜还可以调节外排膜转运蛋白p -糖蛋白（Pgp）的活性，Pgp在肠道药物吸收中起着重要的看门人作用。因此，大蒜补充剂与用于治疗癌症和相关医学并发症的药物之间很有可能发生不良相互作用。本提案的主要目的是评估大蒜补充剂和羟考酮（一种常用的用于治疗癌症疼痛的口服阿片类药物）之间临床显著相互作用的可能性。我们假设大蒜提取物诱导肠道和肝脏CYP3A4同工酶和Pgp，降低阿片类药物的生物利用度，减弱阿片类药物镇痛的有效性。我们建议在健康受试者中进行一项安慰剂对照交叉试验，以调查两种选择的商业大蒜补充剂（干大蒜粉和大蒜油）急性（2天）和慢性（4周）治疗是否会影响临床相关剂量的羟考酮的药代动力学、镇痛反应和副作用。CYP3A4和Pgp活性的调节将通过咪达唑仑和地高辛的表型试验来证明。羟考酮及其代谢产物源自CYP3A4途径的药代动力学将被表征。羟考酮镇痛将测量主观反应在一个实验性的疼痛范式-冷压力测试。专门为阿片类药物效应设计的一系列生物行为工具将用于获得：1)躯体和认知情感副作用和情绪障碍的主观测量，2)认知功能（视觉运动协调，记忆，言语推理）的测量，以及3)生理反应（瞳孔收缩，呼吸）。该结果将指导进一步研究大蒜在癌症化疗和姑息治疗中的不良药物相互作用的责任。

DESCRIPTION (provided by applicant): Garlic supplements are widely used by cancer patients for their purported immune enhancement and anticancer effects. Epidemiological evidence and laboratory studies suggest that dietary garlic or garlic extracts may prevent or halt cancer through multiple biochemical and cellular mechanisms, including inhibition of tumor promotion and proliferation, as well as suppression of carcinogen activation through inhibition of bioactivating enzymes and induction of detoxification enzymes. Garlic is particularly known for its induction of cytochrome P450 enzymes in the intestine and liver, which constitute a major detoxification system for drugs. In addition, recent reports suggest that garlic can also modulate the activity of the efflux membrane transporter P-gylcoproptein (Pgp), which plays an important gatekeeper's role in intestinal drug absorption. Hence, there is a high potential for undesirable interactions between garlic supplements and drugs used in the treatment of cancer and related medical complications. The main objective of this proposal is to assess the likelihood of a clinically significant interaction between garlic supplements and oxycodone-a commonly used oral opioid for the treatment of cancer pain. We hypothesize that garlic extract induces intestinal and hepatic CYP3A4 isoenzyme and Pgp, lowers opioid bioavailability, and attenuates the effectiveness of opioid analgesia. We propose a placebo-controlled, crossover trial in healthy human subjects to investigate whether acute (2 days) and chronic (4-weeks) treatment with 2 select commercial garlic supplements (dried garlic powder and garlic oil) would affect the pharmacokinetics as well as the analgesic response and side effects of a clinically relevant dose of oxycodone. Modulation of CYP3A4 and Pgp activities will be demonstrated by phenotyping tests with midazolam and digoxin. Pharmacokinetics of oxycodone and its metabolites derived from CYP3A4 pathways will be characterized. Oxycodone analgesia will be measured by subjective responses in an experimental pain paradigm-cold pressor test. A battery of biobehavioral instruments that have been specifically designed for opioid effects will be applied to obtain: 1) subjective measures of somatic and cognitive-affective side effects and mood disturbance, 2) measures of cognitive function (visual-motor coordination, memory, verbal reasoning), and 3) physiological responses (pupil constriction, respiration). The results will guide further studies on the liability of adverse herb-drug interactions with garlic in chemotherapy and palliative treatment of cancer.