The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-Administration in Heavy Drinkers

GLP-1 激动剂艾塞那肽对酗酒者自我饮酒的影响

• 批准号: 9792373
• 负责人: ERIC G. DEVINE
• 金额: $ 25.37万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9792373
• 关键词: Adult; Agonist; Alcohol consumption; Alcoholic Beverages; Alcoholic beverage heavy drinker; Alcohols; American; Animals; Area; Attenuated; Behavior; Blood Glucose; Brain; Caring; Cause of Death; Cessation of life; Clinical Research; Cocaine; Consumption; Crossover Design; Desire for food; Development; Disulfiram; Dose; Economic Burden; Ethanol; Exposure to; FDA approved; Food; GLP-I receptor; Gastric Emptying; Glucagon; Glucose; Goals; Hormones; Hour; Human; Hypoglycemia; Ingestion; Injections; Kinetics; Label; Laboratories; Liver; Measures; Mediating; Methods; Mission; Modeling; Monitor; Mutant Strains Mice; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Nature; Neuraxis; Nicotine; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Population; Population Heterogeneity; Property; Publishing; Questionnaires; Randomized; Randomized Controlled Trials; Regulation; Relapse; Reporting; Research; Rewards; Rodent; Safety; Sampling; Self Administration; Study Subject; System; Testing; Time; United States; Visual; absorption; acamprosate; addiction; alcohol abuse therapy; alcohol craving; alcohol effect; alcohol seeking behavior; alcohol use disorder; analog; breath alcohol measurement; clinical investigation; cost; craving; deprivation; drinking; drug development; drug discovery; exenatide; glucagon-like peptide 1; hepatic gluconeogenesis; human subject; liraglutide; novel; novel therapeutics; personalized care; phase II trial; pre-clinical; preclinical study; preference; success; treatment trial; trial comparing; Adult; Agonist; Alcohol consumption; Alcoholic Beverages; Alcoholic beverage heavy drinker; Alcohols; American; Animals; Area; Attenuated; Behavior; Blood Glucose; Brain; Caring; Cause of Death; Cessation of life; Clinical Research; Cocaine; Consumption; Crossover Design; Desire for food; Development; Disulfiram; Dose; Economic Burden; Ethanol; Exposure to; FDA approved; Food; GLP-I receptor; Gastric Emptying; Glucagon; Glucose; Goals; Hormones; Hour; Human; Hypoglycemia; Ingestion; Injections; Kinetics; Label; Laboratories; Liver; Measures; Mediating; Methods; Mission; Modeling; Monitor; Mutant Strains Mice; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Nature; Neuraxis; Nicotine; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Population; Population Heterogeneity; Property; Publishing; Questionnaires; Randomized; Randomized Controlled Trials; Regulation; Relapse; Reporting; Research; Rewards; Rodent; Safety; Sampling; Self Administration; Study Subject; System; Testing; Time; United States; Visual; absorption; acamprosate; addiction; alcohol abuse therapy; alcohol craving; alcohol effect; alcohol seeking behavior; alcohol use disorder; analog; breath alcohol measurement; clinical investigation; cost; craving; deprivation; drinking; drug development; drug discovery; exenatide; glucagon-like peptide 1; hepatic gluconeogenesis; human subject; liraglutide; novel; novel therapeutics; personalized care; phase II trial; pre-clinical; preclinical study; preference; success; treatment trial; trial comparing

Project Summary More than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States and the estimated annual economic burden of AUD is $249 billion. Approximately 88,000 Americans die from alcohol-related causes each year; untreated AUD is the fourth most preventable cause of death in the US. Four medications have been FDA-approved for treating AUD, but none of these medications have proven to be effective across the heterogeneous groups of drinkers. Treating addiction more effectively is goal with national importance and accelerating drug development for AUD is one of the priorities for NIAAA. This proposal is intended to answer this call for accelerating drug development by exploring the potential of a glucagon-like peptide-1 (GLP-1) agonist, exenatide, as a candidate medication for the treatment of AUD. There is now substantial preclinical evidence that GLP-1 agonists can attenuate behaviors that model both the consumption and seeking of several commonly abused substances including alcohol, cocaine, and nicotine. The GLP-1 agonists Exendin-4 and liraglutide have been shown to reduce alcohol consumption by rodents and attenuate alcohol-induced place preference. Treatment with Exendin-4 blocks increases in alcohol intake following periods of alcohol deprivation, suggesting that this drug may decrease the likelihood of relapse. There is also evidence that Exendin-4 induced reductions in alcohol consumption do not occur in mutant mice who are missing central nervous system GLP-1 receptors. There are no published clinical studies testing the effects of GLP-1 agonists on alcohol consumption. This study is intended to accelerate medication development for AUD by testing a commercially-available and well-tolerated agent at a fraction of the cost of new drug discovery. None of the FDA-approved AUD medications or off-label AUD medications target this GLP-1 pathway, making exenatide a promising compound for AUD drug development. The specific aims of this study are to test the effects of exenatide on 1) alcohol self-administration and craving among heavy drinkers, 2) alcohol absorption, and 3) blood glucose levels during a drinking task. The effects of 5mcg dose of exenatide or sham injection will be evaluated in a human laboratory using an alcohol self-administration method. In this within-subjects crossover design, 36 heavy drinkers will be randomized to exposure order (exenatide or sham injection) prior to completing two alcohol self-administration trials. Subjects will receive a priming drink of alcohol and will have access to 8 drinks over a 2-hour period. We anticipate that subjects will consume less alcohol following the administration of exenatide compared to when they receive a sham injection. Significant exenatide-induced reductions in drinking will be considered to be an indication that this drug may have value as an AUD medication. This study may provide a rationale for phase II RCTs testing exenatide with a treatment-seeking AUD population. These results may also help to spur further clinical investigation of the effects of exenatide and other available GLP-1 agonists on the factors implicated in the regulation of alcohol consumption.

项目摘要 在美国，超过1600万成人患有酒精饮用障碍（AUD）和估计 AUD的年度经济负担为2490亿美元。大约88,000名美国人死于与酒精有关的 每年原因；未经处理的AUD是美国第四大最可预防的死亡原因。四种药物 已被FDA批准用于治疗AUD，但这些药物都没有被证明是有效的 饮酒者的异质群体。更有效地对待成瘾是具有国家重要性的目标，并且 加速AUD的药物开发是NIAAA的优先事项之一。该建议旨在回答 通过探索胰高血糖素样肽-1（GLP-1）的潜力来加速药物开发的呼吁 激动剂，艾替尼，作为AUD治疗的候选药物。现在有大量的临床前 GLP-1激动剂可以衰减对消费和寻求的行为的证据 几种通常滥用的物质，包括酒精，可卡因和尼古丁。 GLP-1激动剂Exendin-4 已经证明利拉格林可以减少啮齿动物的饮酒量，并减轻酒精诱导的 放置偏好。在酒精期间，用Exendin-4块治疗酒精摄入量增加 剥夺表明这种药物可能会降低复发的可能性。也有证据表明 Exendin-4诱导的饮酒量减少不会发生在缺失中心的突变小鼠中 神经系统GLP-1受体。没有公开的临床研究测试GLP-1激动剂的影响 关于饮酒。这项研究旨在通过测试A加速AUD的药物开发 在新药发现成本的一小部分中，商业上可用且耐受良好的代理商。没有 由FDA批准的AUD药物或标签外AUD药物以这种GLP-1途径为目标，使Etenatide成为 有希望的AUD药物开发的化合物。这项研究的具体目的是测试 1）饮酒自我给药和渴望在重饮者中，2）酒精吸收和3） 饮酒任务期间的血糖水平。 5MCG剂量的艾鉴定或假注射的影响将是 在人类实验室中使用酒精自我管理方法进行评估。在这个受试者内部跨界 设计，36位重型饮酒者将在接触订单中随机分配（体床或假注射） 完成两个酒精自我管理试验。受试者将收到一杯酒精饮料，并将有 在2小时内获得8杯酒。我们预计受试者在此之后会消耗少量酒精 与接受假注射相比，艾替肽的给药。大量阳离子引起的 减少饮酒将被认为是一种迹象，表明该药物可能具有AUD的价值 药物。这项研究可能为通过寻求治疗的II期RCTS测试Etenatide提供理由 澳元人口。这些结果也可能有助于刺激艾替肽影响的进一步临床研究 以及其他可用的GLP-1激动剂，内容涉及与饮酒有关的因素。