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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的酗酒，男性饮酒五杯或以上，女性饮酒四杯或以上在大约两小时内导致中毒，是 17% 的美国人的危险行为包括近 30% 的 18-34 岁成年人，酗酒会带来多种后果。酗酒的治疗包括心理社会治疗。干预措施，但总体而言，经常酗酒的人寻求和接受治疗的可能性较小。目前尚无 FDA 批准的治疗酗酒的药物。临床前证据阐明了酗酒的神经生物学与药物开发的相关性。最近的研究表明，激活大脑黑皮质素系统可以有效减少酗酒小鼠模型。此外，由于内源性阿片类β-内啡肽抑制黑皮质素作用，黑皮质素激活剂和阿片类拮抗剂的组合具有减少暴饮暴食的协同作用鉴于最近成功的临床试验和 FDA 的批准，后一个发现很有趣。 Contrave™ 治疗肥胖症。Contrave™ 是安非他酮（一种黑皮质素激活剂）和纳曲酮的组合。（阿片类拮抗剂），目标剂量分别为 360 mg 和 32 mg。黑皮质素系统的激活+/-阿片类药物拮抗作用将显着减少人类的酗酒。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+/-阿片类药物阻断的功效和耐受性以减少暴饮暴食 60 名经常酗酒的男性和女性（男性每月至少 5 次，男性每月至少 3 次）前 3 个月内的女性）将被招募并随机接受安慰剂 + 安慰剂安非他酮 XL 300 mg/d + 安慰剂或安非他酮 XL 300 mg/d + 纳曲酮 50 mg/d 该试验将持续 12 周，为期 3 个月。评估变化稳定性的后续行动包括酗酒的频率和强度。以及大量饮酒的生物标志物的变化（γ-谷氨酰转移酶和碳水化合物缺乏转铁蛋白）以及不良事件将被提供以鼓励进展。饮酒目标并提高保留率和依从性。总之，本提案是一项创新的转化性临床试验，源自令人兴奋的临床前研究研究结果检验了黑皮质素激活剂治疗可以减少酗酒的假设人类并测试阿片类拮抗剂是否增强了这种作用，以证明功效信号的证据。良好的耐受性将为开展强有力的 II/III 期试验奠定基础。找到一种有效的药物疗法来治疗酗酒将是一项重大的临床进步，预计将扩大对这一常见且极具破坏性问题的识别和治疗。