New Pharmacotherapy for Alcohol and Co-morbid Disorders

描述(由申请人提供)：我们提出了一种同时治疗酒精和尼古丁依赖的新药理策略。酒精和尼古丁的增强作用是通过皮质-中脑边缘多巴胺(CMDA)系统介导的，两种药物的联合使用增强了它们的药理作用。我们提出了一种更好的方法，通过同时间接调节多巴胺的释放及其功能表达来控制多巴胺的效应。在谷氨酸介导的兴奋性氨基酸通路的紧张性调控下，腹侧被盖区胞体的DA释放及其通过皮质-中脑边缘系统表达的增强效应都受到GABA传出的调节。因此，有理由假设，一种促进皮质-中脑边缘GABA能功能并抑制谷氨酸作用的药物，应该通过抑制从伏核向皮质投射的通路抑制中脑DA的释放及其功能表达，从而减弱尼古丁和酒精的增强作用。我们最近的概念验证证明了这一新方法的前景，与安慰剂相比，托吡酯显着提高了戒烟率，并降低了酒精依赖吸烟者的血清可替宁水平。托吡酯对酒精依赖者的一个重要临床效果似乎是它的抗戒断作用促进了饮酒的逐渐减少。因此，由于托吡酯的这种独特的抗戒断作用，我们建议采用与吸烟者的常见做法相同的方法来治疗酒精依赖患者，即设定目标戒烟日期(TQD)，之后可以测量对任何一种药物的复发。我们提出了一项为期18周、为期3个月的双盲临床试验，其中酒精依赖吸烟者将接受简短的行为依从性增强治疗(BBCET)和吸烟自助手册作为他们的心理社会治疗，并将随机接受安慰剂、高剂量托吡酯(高达250毫克/天)或低剂量托吡酯(高达125毫克/天)，以防止再次酗酒和吸烟。3个治疗武器中的每一个应包含98个人，总人数为294人。TQD将发生在治疗的第6周开始。我们的主要目标是确定低剂量和大剂量托吡酯在减少重度饮酒天数的百分比和提高持续戒烟率方面是否比安慰剂更有效，这是通过自我报告和治疗后和最后4周的CO监测相结合确定的。我们还将能够确定较低剂量的托吡酯是否与较高剂量的托吡酯一样有效，因此与较低的不良反应相关。我们的次要目标是测试托吡酯在改善生活质量和减少TQD后和治疗后最后4周的渴求方面是否比安慰剂更有效，以及这种改善是否会持续到后续阶段。 公共卫生相关性：依赖酒精的吸烟者可能是美国可预防的发病率和死亡率最高的人。有令人信服的证据表明，在酒精依赖者中促进戒烟不仅增加了戒烟的可能性，还减少了饮酒行为。很少有药物治疗研究寻找既能有效治疗酒精依赖又能治疗尼古丁依赖的药物。我们提供的证据表明，托吡酯是3-氨基丁酸(GABA)的促进剂和AMPA/海人酸谷氨酸能活性的抑制剂，不仅可以减少酗酒，还可以减少吸烟的酒精依赖人群的尼古丁摄入量。我们现在建议在一项试验中测试托吡酯的疗效，该试验的重点是同时治疗酒精依赖吸烟者。拟议试验的独特之处在于，它将包括专门用于加强戒烟的行为措施，在其一般方法中同等处理这两种共病障碍的治疗，并在其设计中通过使用目标戒烟日期直接与戒烟研究的报告相比较。该项目支持NIAAA的使命，即开发治疗酒精和尼古丁依赖的有效药物，以防止社会上的发病率和死亡。

DESCRIPTION (provided by applicant): We propose a novel pharmacological strategy for treating alcohol and nicotine dependence concomitantly. The reinforcing effects of both alcohol and nicotine are mediated through the cortico-mesolimbic dopamine (CMDA) system, and the concomitant use of both drugs enhances their pharmacological effects. We propose a better approach to control dopamine (DA) effects by contemporaneous indirect modulation of DA release and its functional expression. Both DA release from its cell bodies in the ventral tegmental area and the expression of its reinforcing effects through the cortico-mesolimbic system are modulated by GABA efferents under the tonic control of glutamate-mediated excitatory amino acid pathways. Thus, it is reasonable to hypothesize that a medication that facilitates cortico-mesolimbic GABAergic function and inhibits glutamate action should diminish both nicotine's and alcohol's reinforcing effects by inhibiting the release of midbrain DA and its functional expression through pathways projecting from the nucleus accumbens to the cortex. The promise of this novel approach is exemplified by our recent proof-of-concept demonstration that topiramate compared with placebo significantly improved smoking abstinence rates and decreased serum cotinine levels among alcohol- dependent smokers. An important clinical effect of topiramate in alcohol-dependent individuals appears to be that its anti-withdrawal effects promote the gradual tapering of drinking. Hence, due to this unique anti- withdrawal effect of topiramate, we propose to adopt the same methodology for treating alcohol-dependent individuals, as is common practice with smokers, of setting a target quit date (TQD) after which relapse to either drug can be measured. We propose an 18-week, double-blind clinical trial with a 3-month follow-up, in which alcohol-dependent smokers will receive brief behavioral compliance enhancement treatment (BBCET) plus a smoking self-help manual as their psychosocial treatment, and will be randomized to receive placebo, high-dose topiramate (up to 250 mg/day), or low-dose topiramate (up to 125 mg/day) to prevent relapse to heavy drinking and smoking. Each of the 3 treatment arms shall contain 98 individuals, with a total N of 294. The TQD will occur at the beginning of the 6th week of treatment. Our primary objective is to determine whether both low- and high-dose topiramate will be more efficacious than placebo at reducing the percentage of heavy drinking days and increasing the continuous abstinence rate for smoking determined by a combination of self-report and CO monitoring after the TQD and in the last 4 weeks of treatment. We also will be able to determine whether a lower dose of topiramate is as efficacious as the higher dose and, therefore, is associated with a lower adverse profile. Our secondary objectives are to test whether topiramate will be more efficacious than placebo at improving quality of life and reducing craving after the TQD and in the last 4 weeks of treatment and whether this improvement will be sustained in the follow-up phase. PUBLIC HEALTH RELEVANCE: Smokers who are dependent on alcohol have perhaps the highest rate of preventable morbidity and mortality in the U.S. There is compelling evidence that promoting smoking cessation among those with alcohol dependence not only increases the likelihood of abstinence from smoking but also reduces drinking behavior. Few pharmacotherapy studies have sought medicines that are efficacious at treating both alcohol and nicotine dependence. We have provided evidence that topiramate, a facilitator of 3-aminobutyric acid (GABA) and an inhibitor of AMPA/kainate glutaminergic activity, not only decreased heavy drinking but also diminished nicotine consumption among a cohort of alcohol-dependent individuals who smoked. We now propose to test the efficacy of topiramate in a trial that focuses on treating alcohol-dependent smokers concomitantly. The uniqueness of the proposed trial is that it will include behavioral measures specifically focused to enhance smoking abstinence, address the treatment of both comorbid disorders equally in its general approach, and be directly comparable to the reporting of smoking cessation studies in its design by using a target quit date. This project supports NIAAA's mission to develop efficacious medications for the treatment of alcohol and nicotine dependence to prevent morbidity and deaths in society.