Mecamylamine for the Treatment of Alcohol Dependence

描述(申请人提供)：酒精依赖是最普遍的精神障碍，也是社会面临的最昂贵的医疗保健问题之一。虽然美国食品和药物管理局(FDA)批准了三种治疗酒精中毒的药物，但这三种药物都有局限性，因此开发新的药物具有很高的临床意义。尼古丁和酒精依赖是由高共病发生率、尼古丁和乙醇使用的协同效应以及共同的神经生物学联系在一起的。事实上，在尼古丁依赖中起重要作用的乙酰胆碱尼古丁受体(NAChR)在酒精依赖中也可能起到关键作用。临床前和人体实验室研究表明，一种已知的阻断尼古丁受体的药物，盐酸甲乙胺(Inverine)，可以减少酒精使用和渴望。我们进行了一项初步研究，评估甲氨基甲胺对酒精依赖者酒精使用的影响，其中约60%是吸烟者。我们的初步数据表明，吸烟状况和药物组对饮酒结果有显著的交互作用，酗酒天数的影响大；结果饮酒天数有显著的趋势，不吸烟者接受甲氨基甲胺治疗的结果比不吸烟者接受安慰剂治疗的结果更好。没有受试者自发地报告戒烟。这项研究是已知的第一项针对酒精依赖患者的治疗研究。方法：184名酒依赖患者将被随机分配到两组，一组每天服用标准剂量的甲氨基己胺(每天10毫克)，另一组每天服用相应的安慰剂，总共持续12周。结果包括时间线反馈法测量的酒精摄入量，强迫性饮酒量表测量的渴求，精神痛苦和副作用负担。此外，我们还将评估没有尝试戒烟的吸烟者的吸烟行为。我们假设甲氨基甲胺与安慰剂相比，随着时间的推移将显著减少大量饮酒的天数，而且这种影响将被吸烟状况所缓和，因此在不吸烟的人中效果会更强。我们还将评估吸烟使用结果，并以这项研究为平台进行未来的研究。这是第一次评估甲氨基甲胺作为潜在的酒精依赖药物治疗剂的研究。

DESCRIPTION (provided by applicant): Alcohol dependence is the most prevalent psychiatric disorder, and also one of the most costly health care problems faced by society. Although there are three medications approved by the Food and Drug Administration (FDA) to treat alcoholism all three have limitations, so the development of new medications is of high clinical importance. Nicotine and alcohol dependence are linked by a high rate of comorbidity, a synergistic effect of nicotine and ethanol use and a common neurobiology. In fact, acetylcholine nicotinic receptors (nAChR), which are important in nicotine dependence may also play a crucial role in alcohol dependence. Preclinical and human laboratory studies have suggested that a drug known to block nicotine receptors, mecamylamine hydrochloride (Inversine), decreases alcohol use and craving. We conducted a pilot study evaluating the effects of mecamylamine on ethanol use in alcohol dependent individuals, approximately 60% of whom were smokers. Our preliminary data suggests that there is a significant interaction between smoking status and medication group on the alcohol use outcome heavy drinking days with a large effect size; there is a trend toward significance in the outcome drinking days where non-smokers treated with mecamylamine had better outcomes compared to non-smokers treated with placebo. No subjects spontaneously reported quitting smoking. This study is first known treatment study in alcohol dependent patients. Methods: One hundred and eighty-four individuals with alcohol dependence will be randomly assigned to receive either a standard dose of mecamylamine (10 mg daily) or a matching placebo every day for a total of twelve weeks. Outcomes include ethanol intake as measured by the Time Line Followback Method, craving as measured by the Obsessive Compulsive Drinking Scale, psychiatric distress and side effect burden. In addition, we will evaluate smoking behavior in smokers who are not trying to abstain from smoking. We hypothesize that mecamylamine will significantly reduce heavy drinking days over time compared to placebo, and that this effect will be moderated by smoking status such that the effect will be stronger in non-smokers. We will also evaluate smoking use outcomes and use this study as a platform to conduct future studies. This is the first study conducted to evaluate mecamylamine as a potential pharmacotherapeutic agent for alcohol dependence.