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

摘要 狂饮，一名男子饮用五种或五种以上的标准饮料，或一名女子饮用四种或四种以上的饮料 在大约两个小时的时间内导致醉酒，这是一种危险的行为，17%的美国人这样做 包括近30%的18-34岁成年人。酗酒与多种后果有关 以及发展为对酒精的身体依赖的风险。酗酒的治疗包括心理社会治疗 干预措施，但总的来说，经常酗酒的人不太可能寻求和接受治疗。 目前还没有FDA批准的治疗酗酒的药物。 临床前证据表明，酗酒的神经生物学与药物开发有关。 最近的研究表明，激活大脑黑素皮质素系统可以有效地减少酗酒 老鼠模型。此外，由于内源性阿片类药物β-内啡肽抑制黑素皮质素的作用， 黑素皮质素激活剂和阿片类拮抗剂的组合具有减少酗酒的协同效应 喝酒。考虑到最近成功的临床试验和FDA对 ™治疗肥胖症。Contrave™是安非他酮(一种黑素皮质素激活剂)和纳曲酮的组合 (阿片类拮抗剂)，靶剂量分别为360 mg和32 mg。因此，我们假设 激活黑素皮质素系统+/-阿片类拮抗剂将显著减少人类的酗酒。 本提议的主要目标是进行概念验证、第二阶段a翻译试验，以 评估激活黑素皮质素系统+/-阿片受体阻滞剂以减少酗酒的有效性和耐受性 喝酒。60名经常酗酒的男性和女性(男性每月至少5次，男性每月3次 前3个月的女性)将被招募并随机接受安慰剂+安慰剂、安非他酮XL 300 每日1次+安慰剂或安非他酮300 mg/d+纳曲酮50 mg/d。试验为期12周，为期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)以及不良反应。将提供医疗管理以鼓励在以下方面取得进展 饮酒目标，并提高保持率和遵从性。 综上所述，本方案是一项创新和转化性的临床试验，源于令人兴奋的临床前试验。 对使用黑素皮质素激活剂治疗可以减少酗酒的假设进行测试的发现 并测试这一作用是否被阿片类拮抗剂增强。药效信号的证据 良好的耐受性将成为进行动力充足的第二/第三阶段试验的基础。最新进展 一种治疗酗酒的有效药物疗法将是一项重大的临床进步，并将 预计将扩大对这一常见和极具破坏性问题的识别和治疗。

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.