Mecamylamine for the Treatment of Alcohol Dependence

描述（由申请人提供）：酒精依赖是最普遍的精神疾病，也是社会面临的最昂贵的医疗保健问题之一。虽然有三种药物被美国食品和药物管理局（FDA）批准用于治疗酒精中毒，但这三种药物都有局限性，因此开发新药具有很高的临床重要性。尼古丁和酒精依赖与高共病率、尼古丁和酒精使用的协同效应以及共同的神经生物学有关。事实上，在尼古丁依赖中起重要作用的乙酰胆碱烟碱受体（nAChR）也可能在酒精依赖中起关键作用。临床前和人体实验室研究表明，一种已知可以阻断尼古丁受体的药物，盐酸美加明（Inversine），可以减少酒精的使用和渴望。我们进行了一项初步研究，评估美加明对酒精依赖者（其中约60%为吸烟者）使用乙醇的影响。我们的初步数据表明，吸烟状态和药物组之间存在显著的相互作用，对酒精使用结果重度饮酒日的影响很大;在结果饮酒日中，与安慰剂治疗的非吸烟者相比，用美加明治疗的非吸烟者的结果更好。无受试者自发报告戒烟。这项研究是第一个已知的酒精依赖患者的治疗研究。研究方法：184名酒精依赖者将被随机分配接受标准剂量的美加明（每天10 mg）或匹配的安慰剂，每天共12周。结果包括乙醇摄入量的时间线跟踪方法，渴望的强迫性饮酒量表，精神痛苦和副作用负担。此外，我们还将评估那些不打算戒烟的吸烟者的吸烟行为。我们假设，与安慰剂相比，美加明将随着时间的推移显着减少大量饮酒的天数，并且这种效果将受到吸烟状态的调节，使得这种效果在非吸烟者中更强。我们还将评估吸烟的结果，并将这项研究作为未来研究的平台。这是第一项评估美卡拉明作为酒精依赖潜在药物的研究。

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.