Modulation of Opioid Effects by Garlic Supplements

描述(申请人提供)：大蒜补充剂被癌症患者广泛使用，因为其声称的免疫增强和抗癌作用。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以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激活。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(P-Gylcoprotein，Pgp)的活性，Pgp在肠道药物吸收中起着重要的把关作用。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有很高的不良相互作用的可能性。这项建议的主要目标是评估大蒜补充剂和羟考酮之间临床显著相互作用的可能性-羟考酮是一种常用的口服阿片类药物，用于治疗癌症疼痛。我们推测大蒜提取物可诱导肠道和肝脏细胞色素P3A4同工酶和PGP，降低阿片类药物的生物利用度，减弱阿片类药物的镇痛效果。我们建议在健康受试者中进行一项安慰剂对照的交叉试验，以调查两种精选商业大蒜补充剂(干大蒜粉和大蒜油)的急性(2天)和慢性(4周)治疗是否会影响临床相关剂量羟考酮的药代动力学以及止痛反应和副作用。将通过咪达唑仑和地高辛的表型试验证实对CYP3A4和Pgp活性的调节。羟考酮及其来自细胞色素P3A4途径的代谢物的药代动力学将被表征。羟考酮的止痛作用将通过实验疼痛范式-冷加压试验中的主观反应来衡量。一系列专门为阿片类药物效应设计的生物行为仪器将被应用于：1)躯体和认知-情感副作用和情绪障碍的主观测量，2)认知功能的测量(视觉-运动协调、记忆、言语推理)，以及3)生理反应(瞳孔收缩、呼吸)。这一结果将指导进一步研究药物与大蒜的不良相互作用在癌症化疗和姑息治疗中的作用。

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.