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卫生保健问题之一。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重要性。尼古丁和酒精依赖是由高共病率、尼古丁和乙醇使用的协同效应和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）可能在酒精依赖中也起着至关重要的作用。临床前和人体实验室研究表明，一种已知能阻断尼古丁受体的药物盐酸甲胺（逆维辛）可以减少酒精的使用和渴望。我们进行了一项初步研究，评估了甲胺对酒精依赖个体使用乙醇的影响，其中约60%的人是吸烟者。我们的初步数据表明，吸烟状况和用药组对重度饮酒日的酒精使用结果有显著的相互作用，且效应量较大；在饮酒的日子里，用甲胺治疗的非吸烟者比用安慰剂治疗的非吸烟者有更好的结果。没有受试者自发地报告戒烟。这项研究是首次对酒精依赖患者进行治疗研究。方法：184名酒精依赖患者将被随机分配接受标准剂量的甲美胺（每天10毫克）或匹配的安慰剂，每天共12周。结果包括时间线追踪法测量的乙醇摄入量，强迫性饮酒量表测量的渴望程度，精神痛苦和副作用负担。此外，我们将评估那些不试图戒烟的吸烟者的吸烟行为。我们假设，与安慰剂相比，随着时间的推移，甲胺胺将显著减少重度饮酒天数，并且这种效果将被吸烟状况所缓和，因此在非吸烟者中效果会更强。我们还将评估吸烟使用的结果，并将本研究作为开展未来研究的平台。这是第一个评估甲胺作为酒精依赖的潜在药物治疗剂的研究。

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.