STUDIES OF THE OPIATE SYSTEM IN CHOLESTATIC LIVER DISEASE

阿片系统在胆汁淤积性肝病中的研究

• 批准号: 3855410
• 负责人: E A JONES
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3855410
• 关键词: blood chemistry; cholestasis; clinical trials; disease /disorder model; drug administration routes; enkephalins; human subject; human therapy evaluation; human tissue; inhibitor /antagonist; laboratory rat; liver disorder chemotherapy; liver pharmacology; medical complication; naloxone; narcotic antagonists; neuropeptide receptor; opiate alkaloid; opioid receptor; primary biliary cirrhosis; pruritis; skin disorder chemotherapy

A new system for continuously quantitating scratching activity, independent of gross limb movements, has been devised. This system permits objective quantitative studies of the effectiveness of therapies for the pruritus of cholestasis to be undertaken. Using this system naloxone infusions have been shown to decrease a scratching activity index by about 50% in patients with pruritus due to primary biliary cirrhosis, suggesting that the opiate system may be implicated in the mediation of the pruritus of cholestasis. Support for the hypothesis that the status of the opiate system is altered in cholestasis has been provided by showing that rats with acute cholestasis due to bile duct resection exhibit antinociception (as assessed by the tail flick assay) and that this pathophysiologic state can be stereoselectively reversed by naloxone. Furthermore, increased levels of total opioid activity and methionine enkephalin have been demonstrated in plasma in this model of cholestasis. These findings are consistent with the syndrome of cholestasis being associated with increased opiatergic tone mediated by endogenous opioids. As opiates, such as morphine, are known to induce pruritus, the mechanism of the pruritus of cholestasis could be increased opiatergic tone. A double blind trial of naloxone infusions for the pruritus of chronic cholestasis is nearing completion. An open trial of the orally bioavailable opiate antagonist nalmefene for this complication of cholestasis is also in progress. In six patients oral nalmefene was associated with a clinical amelioration of pruritus in all, an improvement in visual analogue scores in 5 and a decrease in scratching activity index in 4. In additional studies of the opiate system in cholestasis, bile duct resected rats have been shown to exhibit a naloxone- reversible decrease in the ACTH response to stress.

一个新的系统，用于连续定量抓挠活动，独立 肢体运动的一种方式。 该系统允许客观 皮肤瘙痒症治疗有效性的定量研究 胆汁淤积症。 使用该系统，纳洛酮输注具有 已显示可使患者的抓挠活动指数降低约50 伴有原发性胆汁性肝硬化引起的瘙痒，这表明阿片类药物 系统可能涉及胆汁淤积瘙痒的介导。 支持阿片系统状态改变的假设 在胆汁淤积中的作用， 由于胆管切除术引起的胆汁淤积表现出抗伤害感受（如评估的 通过甩尾测定），并且这种病理生理状态可以 立体选择性逆转纳洛酮。 此外， 总阿片活性和甲硫氨酸脑啡肽已被证明， 血浆中的胆汁淤积。 这些研究结果是一致 胆汁郁积证与阿片紧张性增加有关 由内源性阿片类物质介导。 众所周知，阿片类药物，如吗啡， 引起瘙痒，胆汁淤积性瘙痒的机制可能是 增加鸦片的张力。 纳洛酮输注治疗糖尿病的双盲试验 慢性胆汁淤积症的瘙痒已经接近完成。 公开审理 口服生物可利用的阿片拮抗剂纳美芬 胆汁淤积的并发症也在进行中。 6例患者口服 纳美芬与所有瘙痒症的临床改善相关， 5例患者的视觉模拟评分改善， 活动指数4. 在对阿片系统的其他研究中， 胆汁淤积，胆管切除大鼠已显示出纳洛酮- ACTH对应激反应的可逆性降低。