New Pharmacotherapy for Alcohol and Co-morbid Disorders

酒精和共病疾病的新药物疗法

• 批准号: 8318743
• 负责人: NASSIMA AIT-DAOUD
• 金额: $ 88.25万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318743
• 关键词: 3-aminobutyric acid; Abstinence; Address; Adopted; Adverse event; Aftercare; Alcohol dependence; Alcohols; Aminobutyric Acids; Antismoking; Behavioral; Cessation of life; Clinical; Clinical Trials; Consumption; Cotinine; Disease; Dopamine; Dose; Double-Blind Method; Employee Strikes; Excitatory Amino Acids; Exhibits; Glutamates; Heavy Drinking; Individual; Knowledge; Manuals; Measures; Mediating; Medicine; Methodology; Midbrain structure; Mission; Monitor; Morbidity - disease rate; Nicotine; Nicotine Dependence; Nucleus Accumbens; Pathway interactions; Patient Self-Report; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebos; Quality of life; Randomized; Relapse; Reporting; Research Support; Schedule; Serum; Smoke; Smoker; Smoking; Societies; Sum; Testing; Therapeutic Effect; Time; Titrations; Ventral Tegmental Area; Withdrawal; alcohol relapse; arm; behavior measurement; clinical effect; cohort; craving; design; drinking; drinking behavior; efficacy testing; follow-up; gamma-Aminobutyric Acid; improved; inhibitor/antagonist; innovation; kainate; mesolimbic system; mortality; neuronal cell body; novel; novel strategies; prevent; psychosocial; public health relevance; response; self help; smoking cessation; smoking relapse; topiramate

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.

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型药理学策略。酒精和尼古丁的强化作用是通过皮质-中脑边缘多巴胺（CMDA）系统介导的，同时使用这两种药物可增强其药理作用。我们提出了一个更好的方法来控制多巴胺（DA）的影响，同时间接调制DA的释放和功能表达。多巴胺从腹侧被盖区的细胞体释放和通过皮质-中脑边缘系统表达其增强作用都受到GABA传出神经的调节，这些传出神经受谷氨酸介导的兴奋性氨基酸通路的紧张性控制。因此，可以合理地假设，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中脑DA的释放及其通过从丘脑核投射到皮质的途径的功能表达来减少尼古丁和酒精的增强作用。我们最近的概念验证证明了这种新方法的前景，即托吡酯与安慰剂相比显著改善了酒精依赖性吸烟者的戒烟率并降低了血清可替宁水平。托吡酯在酒精依赖个体中的一个重要临床作用似乎是其抗戒断作用促进逐渐减少饮酒。因此，由于托吡酯的这种独特的抗戒断作用，我们建议采用与治疗酒精依赖个体相同的方法，如吸烟者的常见做法，即设定目标戒烟日期（TQD），在该日期之后可以测量对任一药物的复发。我们提出了一个为期18周的双盲临床试验，随访3个月，其中酒精依赖的吸烟者将接受简短的行为依从性增强治疗（BBCET）加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，大剂量托吡酯（高达250毫克/天），或低剂量托吡酯（高达125毫克/天），以防止复发大量饮酒和吸烟。3个治疗组中的每个治疗组应包含98名个体，总N为294。TQD将在治疗第6周开始时进行。我们的主要目标是确定低剂量和高剂量托吡酯是否比安慰剂更有效，可以减少酗酒天数的百分比，并提高通过自我报告和CO监测相结合确定的持续戒烟率。TQD和治疗的最后4周。我们也将能够确定是否低剂量的托吡酯是有效的，因为高剂量，因此，与较低的不良反应。我们的次要目的是测试托吡酯在TQD后和治疗的最后4周内是否比安慰剂更有效地改善生活质量和减少渴望，以及这种改善是否会在随访阶段持续。 公共卫生关系：在美国，依赖酒精的吸烟者可能是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会增加戒烟的可能性，还会减少饮酒行为。很少有药物治疗研究寻求既能有效治疗酒精依赖又能有效治疗尼古丁依赖的药物。我们提供的证据表明，托吡酯，促进3-氨基丁酸（GABA）和抑制剂AMPA/红藻氨酸β-氨基丁酸能活性，不仅减少大量饮酒，但也减少了吸烟的酒精依赖人群中的尼古丁消耗。我们现在建议测试托吡酯的疗效，在一项试验中，重点是治疗酒精依赖的吸烟者伴随。拟议试验的独特之处在于，它将包括专门针对增强戒烟的行为措施，在其一般方法中平等地解决两种共病疾病的治疗，并通过使用目标戒烟日期直接与其设计中的戒烟研究报告进行比较。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，以防止社会中的发病率和死亡率。