Efficacy and Safety of the Melanocortin Activator Bupropion in Treating Binge Drinking

黑皮质素激活剂安非他酮治疗酗酒的功效和安全性

• 批准号: 9167020
• 负责人: James C. Garbutt
• 金额: $ 18.05万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167020
• 关键词: Adult; Adverse event; Affect; Age; Age-Years; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animals; Antidepressive Agents; Appetitive Behavior; Attention; Biological Markers; Blood alcohol level measurement; Body Weight decreased; Brain; Bupropion; Cessation of life; Clinical; Clinical Management; Clinical Trials; Consumption; Controlled Clinical Trials; Development; Disease; Dose; Double-blind trial; Employment; FDA approved; Family; Foundations; Frequencies; Gamma-glutamyl transferase; Gender; Goals; Health; Heavy Drinking; Hour; Human; Individual; Intervention; Intoxication; Length; Linear Models; Medical; Naltrexone; Narcotic Antagonists; Neurobiology; Neurons; Obesity; Opioid; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physical Dependence; Placebo Control; Placebos; Population; Pro-Opiomelanocortin; Randomized; Recruitment Activity; Recurrence; Reporting; Risk; Risk Behaviors; Risk Factors; Safety; Sample Size; Severities; Signal Transduction; System; Testing; Time; Traffic accidents; Translational trial; United States; Violence; Woman; Work; arm; beta-Endorphin; binge drinking; carbohydrate-deficient transferrin; clinical care; common treatment; drinking; economic cost; endogenous opioids; follow-up; innovation; man; melanocortin receptor; men; mouse model; novel strategies; pre-clinical; primary outcome; problem drinker; psychosocial; translational clinical trial; young adult

Abstract Binge drinking, the consumption of five or more standard drinks for a man or four or more drinks for a woman in about a two hour period leading to intoxication, is a risky behavior practiced by17% of the U.S. population including nearly 30% of adults 18-34 years of age. Binge drinking is associated with multiple consequences and risk of progression to physical dependence on alcohol. Treatment of binge drinking includes psychosocial interventions but, overall, individuals that regularly binge drink are less likely to seek and to receive treatment. There is no FDA approved medication for binge drinking. Preclinical evidence is laying out a neurobiology of binge drinking with relevance for medication development. Recent work has shown that activating the brain melanocortin system potently reduces binge drinking in a mouse model. Furthermore, because the endogenous opioid β-endorphin inhibits melanocortin actions, a combination of a melanocortin activator and an opioid antagonist has a synergistic effect to reduce binge drinking. This latter finding is intriguing given the recent successful clinical trial and FDA approval of Contrave™ for obesity. Contrave™ is a combination of bupropion (a melanocortin activator) and naltrexone (an opioid antagonist) with a target dose of 360 mg and 32 mg respectively. Therefore we hypothesize that activation of melanocortin systems +/- opioid antagonism will significantly reduce binge drinking in humans. The primary objective of the present proposal is to conduct a proof-of-concept, Phase IIa translational trial to assess for efficacy and tolerability of activating melanocortin systems +/- opioid blockade to reduce binge drinking. 60 men and women with recurrent binge drinking (at least 5 episodes a month for men and 3 for women in the prior 3 months) will be recruited and randomized to either placebo + placebo, bupropion XL 300 mg/d + placebo or bupropion XL 300 mg/d + naltrexone 50 mg/d. The trial will last 12 weeks with a 3 month follow-up to assess stability of change. Primary outcomes include frequency and intensity of binge drinking and changes in biomarkers of heavy drinking (gamma-glutamyl transferase and carbohydrate deficient transferrin) as well as adverse events. Medical Management will be provided to encourage progress towards drinking goals and to enhance retention and compliance. In summary, the present proposal is an innovative and translational clinical trial derived from exciting preclinical findings to test the hypothesis that treatment with a melanocortin activator can reduce binge drinking in humans and to test whether this action is augmented by an opioid antagonist. Evidence for an efficacy signal with good tolerability would form the foundation to conduct a well-powered Phase II/III trial. The development of an effective pharmacotherapy for binge drinking would be a significant clinical advance and one that would be expected to expand the identification and treatment of this common and highly destructive problem.

摘要 狂饮，男性饮用五杯或更多标准酒，女性饮用四杯或更多标准酒 在大约两个小时的时间内导致中毒，是一种危险的行为，有17%的美国人口 包括近30%的18-34岁的成年人。酗酒会带来多种后果 和发展为身体依赖酒精的风险。酗酒的治疗包括社会心理治疗 但是，总体而言，经常酗酒的人不太可能寻求和接受治疗。 没有FDA批准的药物用于酗酒。 临床前证据正在展示与药物开发相关的酗酒神经生物学。 最近的研究表明，激活大脑黑皮质素系统可以有效地减少酗酒， 小鼠模型此外，由于内源性阿片样物质β-内啡肽抑制黑皮质素的作用， 黑皮质素激活剂和阿片样物质拮抗剂的组合对减少暴食具有协同作用 喝酒考虑到最近成功的临床试验和FDA批准的 Contrave™治疗肥胖症。Contrave™是安非他酮（一种黑皮质素激活剂）和纳洛酮的组合 (an阿片类拮抗剂），目标剂量分别为360 mg和32 mg。因此，我们假设， 黑皮质素系统的激活+/-阿片样物质拮抗作用将显著减少人类的狂饮。 本提案的主要目标是进行概念验证、IIa期转化试验， 评估激活黑皮质素系统+/-阿片类药物阻断减少暴食的疗效和耐受性 喝酒60名反复酗酒的男性和女性（男性每月至少5次， 前3个月的女性）并随机分配至安慰剂+安慰剂、安非他酮XL 300 mg/d +安慰剂或安非他酮XL 300 mg/d +纳洛酮50 mg/d。试验将持续12周，其中3个月 跟踪评估变化的稳定性。主要结果包括酗酒的频率和强度 以及大量饮酒的生物标志物（γ-谷氨酰转移酶和碳水化合物缺乏）的变化 转铁蛋白）以及不良事件。将提供医疗管理，以鼓励取得进展， 饮酒的目标，并提高保留和遵守。 总之，本提案是一项创新和转化的临床试验，来自令人兴奋的临床前研究。 研究结果验证了使用黑皮质素激活剂治疗可以减少酗酒的假设 并测试这种作用是否被阿片类拮抗剂增强。疗效信号的证据 具有良好耐受性的药物将为开展具有良好功效的II/III期试验奠定基础。发展 一个有效的药物治疗酗酒将是一个重大的临床进步， 预计将扩大对这一常见和高度破坏性问题的识别和治疗。