Human Laboratory Screening of Lorcaserin in Smokers with Alcohol Use Disorder

患有酒精使用障碍的吸烟者中氯卡色林的人体实验室筛查

• 批准号: 9752761
• 负责人: Eric D Claus
• 金额: $ 21.47万
• 依托单位: THE MIND RESEARCH NETWORK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-10 至 2021-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752761
• 关键词: Addictive Behavior; Agonist; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcohols; Attenuated; Behavior; Behavioral; Cigarette; Cigarette Smoker; Clinical; Consumption; Cross-Over Studies; Cross-Over Trials; Data; Development; Dopamine; Double-Blind Method; Drug Receptors; Evaluation; FDA approved; Face; Health; Human; Impulsivity; Intervention; Investigation; Joints; Laboratories; Ligands; Measures; Motivation; National Institute on Alcohol Abuse and Alcoholism; Nicotine; Nicotine Dependence; Outcome; Outcome Measure; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase II Clinical Trials; Placebos; Play; Population; Pre-Clinical Model; Protocols documentation; Randomized Controlled Trials; Regulation; Relapse; Rewards; Risk; Role; Screening procedure; Selective Serotonin Reuptake Inhibitor; Self Administration; Serotonergic System; Serotonin; Serotonin Receptor 5-HT2C; Smoker; Smoking; Subgroup; Substance Use Disorder; Testing; Time; Translating; United States Food and Drug Administration; Weight maintenance regimen; addiction; alcohol abuse therapy; alcohol response; alcohol use disorder; base; behavior measurement; cancer risk; cigarette smoke; cigarette smoking; clinical risk; cost effective; craving; drinking; high risk; human data; indexing; individualized medicine; interest; new therapeutic target; nicotine use; novel; pre-clinical; preclinical study; randomized trial; response; screening; serotonin receptor; side effect; smoking cessation

PROJECT SUMMARY Pharmacotherapy development remains a critical objective for reducing health and societal burdens associated with alcohol use disorder (AUD). Developing targeted treatments for specific AUD subgroups is a key aim under the NIAAA medication development strategy. Among those with AUD, cigarette smokers comprise a sizable and critical subgroup with disproportionally high long-term health risks, making it a key priority to advance therapies for concurrent AUD and cigarette smoking. The serotonin (5-hydroxtytryptamine; 5-HT) system is broadly implicated in addictive behaviors, in part reflecting the role of 5-HT in modulating dopamine function. Preclinical studies of 5-HT receptor drugs have shown that targeted modulation of the 5-HT2C receptor (implicated in 5-HT-related inhibition of DA function) alters the consumption and reinstatement of addictive drugs, including alcohol and nicotine. Additionally, preclinical evidence shows that 5-HT2C receptor agonists attenuate behavioral indices of impulsivity. Of the selective 5-HT2C receptor agonists, lorcaserin has superior near-term potential for repurposing as an AUD therapy, having been approved by the Food and Drug Administration for weight management. A recent Phase II clinical trial supported efficacy of lorcaserin for smoking cessation; however, no human trials have examined lorcaserin's effects on alcohol-related outcomes or measures of impulsivity. Human laboratory medication trials offer a time- and cost-effective option for validating preclinical findings prior to larger randomized controlled trials, and for testing candidate treatment mechanisms. This application proposes a human laboratory screening trial to evaluate lorcaserin as a novel candidate therapy for smokers with AUD. The effects of lorcaserin vs. placebo will be evaluated in a double- blind, within-subjects, crossover study with human laboratory endpoints. This study will provide initial human data on the effects of a 5-HT2C receptor agonist in relation to alcohol-related outcomes, informing its potential for further evaluation as a candidate treatment for AUD.

项目摘要 药物治疗的发展仍然是减少相关健康和社会负担的关键目标 酒精使用障碍（AUD）为特定的AUD亚组开发靶向治疗是一个关键目标 根据NIAAA药物开发战略。在AUD患者中，吸烟者占 长期健康风险极高的重要亚组，因此， 同时存在AUD和吸烟的先进疗法。血清素（5-羟色胺; 5-HT） 5-HT系统广泛地参与成瘾行为，部分反映了5-HT在调节多巴胺中的作用 功能5-HT受体药物的临床前研究已经表明，靶向调节5-HT受体的活性是一种有效的方法。 5-HT 2C受体（与5-HT相关的DA功能抑制有关）改变DA的消耗和恢复 包括酒精和尼古丁在内的成瘾药物。此外，临床前证据表明，5-HT 2C受体 激动剂减弱冲动的行为指数。在选择性5-HT 2C受体激动剂中，氯卡色林具有 上级近期潜力，可重新用作AUD治疗，已获得食品和药物管理局的批准 体重管理的管理。最近的一项II期临床试验支持氯卡色林对 戒烟;然而，没有人体试验研究过氯卡色林对酒精相关结果的影响 或者冲动的衡量标准人体实验室药物试验提供了一个时间和成本效益的选择， 在大型随机对照试验之前验证临床前发现，并用于测试候选治疗 机制等本申请提出了一种人类实验室筛选试验，以评估氯卡色林作为一种新的抗肿瘤药物。 AUD吸烟者的候选治疗。氯卡色林与安慰剂的作用将在一项双重评估中进行评估， 设盲、受试者内、交叉研究，具有人体实验室终点。这项研究将提供初步的人类 关于5-HT 2C受体激动剂与酒精相关结局的作用的数据，告知其潜在的 作为AUD的候选治疗进行进一步评估。