Lacosamide effects on alcohol self administration and craving in heavy drinkers

拉科酰胺对重度饮酒者的酒精自我管理和渴望的影响

• 批准号: 9434501
• 负责人: ERIC G. DEVINE
• 金额: $ 25.78万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9434501
• 关键词: Adult; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; American; Anticonvulsants; Back; Behavior Therapy; Caring; Cause of Death; Cessation of life; Clinical Research; Control Animal; Crossover Design; Digit structure; Disease; Disulfiram; Dose; Economic Burden; Epilepsy; FDA approved; Focal Seizure; Goals; Heavy Drinking; Hour; Human; Intelligence; Label; Laboratories; Lead; Measures; Methodology; Mission; Modeling; Movement; Mus; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Nucleus Accumbens; Obsessive compulsive behavior; Pathway interactions; Pharmaceutical Preparations; Pharmacogenetics; Pharmacologic Actions; Pharmacotherapy; Phase; Placebos; Play; Population; Population Heterogeneity; Proteins; Questionnaires; Randomized; Randomized Controlled Trials; Regulation; Reporting; Research; Rodent; Role; Self Administration; Self-Administered; Short-Term Memory; Sodium Channel; Testing; Time; TimeLine; Treatment outcome; United States; Visual; acamprosate; addiction; alcohol abuse therapy; alcohol craving; alcohol effect; alcohol seeking behavior; alcohol use disorder; analog; clinical investigation; cognitive function; collapsin response mediator protein-2; cost; craving; drinking; drug development; experience; improved; knock-down; novel; personalized care; phase II trial; pre-clinical; problem drinker; success; trial comparing; voltage

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 approved by the FDA to date for treating AUD, but none of these medications have proven to be effective across the heterogeneous groups of people with this disorder. Treating addiction more effectively has become a national priority and accelerating drug development for AUD is one of the priorities for NIAAA. The present proposal is intended to answer this call for accelerating drug development by exploring the potential of a novel anticonvulsant, lacosamide, as a candidate medication for the treatment of AUD. This drug, which is FDA-approved for the treatment of seizure disorders, has unique pharmacological actions that include enhancement of slow sodium channel inactivation and inhibition of collapsin response mediator protein-2 (CRMP-2). Alcohol consumption in mice that had knockdown of CRMP-2 within the nucleus accumbens was decreased from levels seen in control animals. In rodent studies, lacosamide administration has produced reductions in `excessive' drinking and has experimentally-induced decreased expression of the CRMP-2 protein. These findings implicate CRMP-2 as playing a role in the regulation of alcohol consumption. None of the FDA-approved AUD medications or medications commonly used off-label to treat AUD target this CRMP-2 pathway, making lacosamide a promising compound for AUD drug development. The aims of this study are to: 1) test the effects of lacosamide on alcohol self-administration and craving, 2) assess the effects of lacosamide on the reinforcing stimulant effects of a priming drink of alcohol, 3) test the effects of 5 days of lacosamide administration on cognitive function, and 4) test the effects of lacosamide on alcohol consumption and craving during a 5-day period of exposure. The effects of 5-days of lacosamide (300mg) or placebo will be evaluated in a human laboratory using an alcohol self-administration methodology. In this within-subjects crossover design, heavy drinkers (N=24) will be randomized to the order of exposure (lacosamide or placebo) prior to completing two alcohol self-administration trials. Subjects will receive a priming drink of alcohol and will have access to 8 alcoholic drinks over a 2-hour period. We anticipate that subjects will consume less alcohol during an alcohol self-administration trial when receiving lacosamide compared to when they are receiving placebo. Significant lacosamide-induced reductions in the quantity of alcohol self-administered 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 clinical studies testing lacosamide with a treatment-seeking AUD population. These results may also help to spur further pre-clinical investigation into the role played by CRMP-2 in regulating both alcohol consumption and alcohol seeking behaviors.

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 迄今已获得FDA的批准用于治疗AUD，但这些药物都没有被证明是 在患有这种疾病的异质群体中有效。更有效地对待成瘾 成为NIAAA的优先事项之一，成为国家优先事项，并加速AUD的药物开发。这 目前的建议旨在通过探索潜力来回答此呼吁，以加速药物开发 一种新型的抗惊厥药，lacosamide，作为AUD治疗的候选药物。这种药物，就是 FDA批准用于治疗癫痫发作，具有独特的药理作用，包括 慢速钠通道失活和抑制折叠蛋白反应介质蛋白2的增强 （CRMP-2）。伏伏核中CRMP-2敲低的小鼠的饮酒是 从对照动物中看到的水平下降。在啮齿动物研究中，lacosamide的给药已产生 减少“过量”饮酒，并通过实验引起的CRMP-2表达降低 蛋白质。这些发现暗示CRMP-2是在饮酒的调节中发挥作用。没有 FDA批准的AUD药物或通常在标签外的药物治疗AUD目标 途径，使Lacosamide成为AUD药物开发的有希望的化合物。这项研究的目的是： 1）测试Lacosamide对饮酒自我给药和渴望的影响，2）评估Lacosamide的影响 关于酒精灌注饮料的增强刺激作用，3）测试5天的lacosamide的作用 对认知功能进行管理，4）测试Lacosamide对饮酒和渴望的影响 在5天的暴露期间。将评估5天的5天（300mg）或安慰剂的影响 人类实验室使用酒精自给自足的方法。在这个受试者内部的跨界设计中， 饮酒者（n = 24）将在完成之前随机分配到曝光顺序（lacosamide或安慰剂） 两项酒精自我管理试验。受试者将获得酒精饮料，并可以使用8 酒精饮料在2小时内。我们预计在酒精期间，受试者的酒精会减少 与接受安慰剂相比，接受lacosamide的自我管理试验。重要的 lacosamide诱导的自我管理饮酒量减少将被认为是 表明该药物可能具有AUD药物的价值。这项研究可能为II期提供理由 临床研究对寻求治疗的AUD人群测试Lacosamide。这些结果也可能有助于 促进了对CRMP-2在调节两种饮酒中所起的作用的进一步临床前研究 和饮酒的行为。