The Effects of the Histamine-3 Receptor Inverse Agonist Pitolisant on Alcohol Self-Administration in Heavy Drinkers

项目摘要 更多 每年一次 成因 有 这个 美国有1600多万成年人患有酒精使用障碍(AUD)，据估计 澳元的经济负担为2490亿美元。大约88,000名美国人死于与酒精有关的疾病 在美国，未经治疗的澳门氏症是第四大可预防的死因。四种药物 已经被FDA批准用于治疗AUD，但这些药物都没有被证明对 不同的饮酒者群体。更有效地治疗成瘾是具有国家重要性和 加快澳大利亚的药物开发是NIAAA的优先事项之一。这项提议意在回答 这呼吁通过探索组胺-3(H-3)受体反向的潜力来加速药物开发 激动剂/拮抗剂，垂体后叶素，作为治疗AUD的候选药物。现在有大量的 H-3受体拮抗剂和反向激动剂/拮抗剂可抑制行为的临床前证据 这既是酒精消费的模型，也是奖励的模型。这些药物已被证明可以减少酒精。 对啮齿动物的摄取，并减弱酒精诱导的位置偏爱。无论是H-3的管理 拮抗剂或拮抗剂/反向激动剂可阻断线索诱导的对酒精反应的恢复 老鼠。这些发现与酒精寻求行为可以被以下物质减弱的观点一致 对抗H-3受体激活的作用。那里 垂体后叶素 意欲 座席 澳元 目标 渴望， 日数 日数 方法。 订单 引爆 消费 诱导 这项研究可能会为二期随机对照试验提供理论依据。 与寻求治疗的澳州人一起。这些结果也可能有助于刺激进一步的临床研究。 垂体后叶素对调节饮酒相关因素的影响。 。 是否没有已发表的临床研究测试这种药物的疗效 或任何其他H-3受体反向激动剂/拮抗剂对人类饮酒的影响。这项研究是 通过测试一种商业上可获得和耐受性良好的药物来加速AUD的药物开发 而成本只有新药研发成本的一小部分。FDA批准的AUD药物或非标签药物 药物针对的是H-3受体，使垂体后叶素成为一种有希望开发的化合物。具体的 这项研究的目的是测试脑垂体后叶素对1)酒精自我给药和 2)5天暴露期间的饮酒和渴求，3)5天期间的睡眠质量 催产剂的使用，以及，4)酒精饮料的刺激作用。5- 将在人体实验室中使用酒精自我给药进行评估 在这项受试者内交叉设计研究中，36名酗酒者将被随机分成两组 (垂体后叶素或安慰剂)，在完成两个酒精自我给药试验之前。受试者将收到 在2小时内可以喝到8杯酒。我们预计受试者将 与安慰剂相比，服用催产素后的酒精含量更少。重要的催产剂- 自我饮酒量的减少将被认为是该药物 作为一种AUD药物有价值。

Project Summary More annual causes have the than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States and the estimated economic burden of AUD is $249 billion. Approximately 88,000 Americans die from alcohol-related each year; untreated AUD is t he fourth most preventable cause of death in the US. Four medications been FDA-approved for treating AUD, but none of these medications have proven to be effective across 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 the histamine-3 (H-3) receptor inverse agonist/antagonist, pitolisant, as a candidate medication for the treatment of AUD. There is now substantial preclinical evidence that H-3 receptor antagonists and inverse agonists/antagonists can suppress behaviors that model both alcohol consumption and reward. These drugs have been shown to reduce alcohol consumption by rodents and attenuate alcohol-induced place preference. The administration of either an H-3 antagonist or of an antagonist/inverse agonist can block cue-induced reinstatement of responding for alcohol in mice. These findings are consistent with idea that alcohol seeking behaviors can be attenuated by agents that counteract the actions of H-3 receptor activation. There pitolisant intended agent AUD aims craving, days days method. order priming consume induced may This study may provide a rationale for phase II RCTs testing pitolisant with a treatment-seeking AUD population. These results may also help to spur further clinical investigation of the effects of pitolisant on the factors implicated in the regulation of alcohol consumption. . are no published clinical studies testing the effects of or any other H-3 receptor inverse agonist/antagonist on human alcohol consumption. This study is to accelerate medication development for AUD by testing a commercially-available and well-tolerated at a fraction of the cost of new drug discovery. None of the FDA-approved AUD medications or off-label medications target H-3 receptors, making pitolisant a promising compound for development. The specific of this study are to test the effects of pitolisant administration on 1) alcohol self-administration and 2) alcohol consumption and craving during a 5-day period of exposure, 3) sleep quality during the 5 of pitolisant administration, and, 4) the stimulant effects of a priming drink of alcohol. The effects of 5- of pitolisant or placebo will be evaluated in a human laboratory using an alcohol self-administration In this within-subjects crossover design study, 36 heavy drinkers will be randomized to exposure (pitolisant or placebo) prior to completing two alcohol self-administration trials. Subjects will receive a drink of alcohol and will have access to 8 drinks over a 2-hour period. We anticipate that subjects will less alcohol following the administration of pitolisant compared to placebo. Significant pitolisant- reductions in the quantity of alcohol self-administered will be considered an indication that this drug have value as an AUD medication.