Combining Medication Treatments for Alcoholism

结合药物治疗酗酒

• 批准号: 7117794
• 负责人: Bankole A Johnson
• 金额: $ 67.96万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117794
• 关键词: alcoholism /alcohol abuse; alcoholism /alcohol abuse chemotherapy; anticonvulsants; behavioral /social science research tag; clinical research; clinical trials; cognitive behavior therapy; combination chemotherapy; combination therapy; craving; disease /disorder onset; drug withdrawal; human subject; human therapy evaluation; longitudinal human study; neuropharmacology; ondansetron; patient oriented research; reinforcer; serotonin inhibitor

DESCRIPTION (provided by applicant): Recent scientific and clinical interest in combining therapeutic agents for the treatment of alcoholism are based on the fact that derangement of multiple-neurotransmitter systems are likely to underlie biological predisposition to the disease. Thus, combining effective medications working at different neurotransmitters should produce a synergistic or at least an added clinical response. We have shown that ondansetron (a serotonin-3 antagonist), compared with placebo, significantly reduces drinking and increases abstinence among EOA but not LOA, presumably by ameliorating an underlying biological (i.e. serotonergic) abnormality which is associated with early onset alcoholism. That is, treatment with the specific serotonergic agent, ondansetron, results in improved drinking outcomes only for a particular alcoholic subtype. In a preliminary clinical trial, we also have shown that topiramate (a sulfamate fructo-pyranose derivative) is superior to placebo at improving the drinking outcomes of both EOA and LOA. We have postulated that topiramate's effectiveness is associated with amelioration of the neurochemical processes due to chronic drinking which occur in both EOA and LOA: notably reduction of generalized craving symptoms due to facilitation of gamma amino butyric acid (GABA) function and inhibition of voltage-gated calcium channels. We, therefore, hypothesize that: 1) the combination of ondansetron and topiramate effects would be additive and possibly synergistic, among EOA; 2) EOA, compared with LOA, will be more responsive to treatment with ondansetron alone, and 3) that both EOA and LOA will respond to topiramate treatment. We will test the specific predictions of this hypothesis by examining the effectiveness of ondansetron (4 mcg/kg b.i.d.) and topiramate (up to 300 mg/day), each alone and in combination, in treating EOA and LOA (45 subjects/cell x 8 cells, total N=360) in a randomized, double-blind, placebo-controlled, 12-week (1 week of single-blind placebo followed by 11 weeks of double-blind condition) outpatient clinical trial. All subjects will receive manual-driven standardized Cognitive Behavioral Therapy, and follow-up at 1, 3, 6, and 9 months post-treatment. This study supports NIAAA's mission to develop effective combinative pharmacotherapies as adjuncts to psychotherapy for the treatment of alcoholism.

描述（由申请人提供）：结合治疗酒精中毒的治疗剂的最新科学和临床兴趣是基于以下事实：多神经递质系统的危险可能是对疾病的生物学倾向的基础。因此，将在不同神经递质工作的有效药物组合起来应产生协同或至少增加的临床反应。 我们已经表明，与安慰剂相比，Ondansetron（5-羟色胺-3拮抗剂）大大降低了饮酒并增加了EOA之间的戒酒，但不是LOA之间的戒酒，大概是通过改善潜在的生物学（即血清素能）异常（即与早期发作的酒精中毒相关）。也就是说，用特定的血清素能剂Ondansetron处理仅针对特定的酒精亚型可改善饮酒结果。在一项初步临床试验中，我们还表明，托吡酯（硫酸盐酸 - 吡喃糖衍生物）在改善EOA和LOA的饮酒效果方面优于安慰剂。我们假设托吡酯的有效性与EOA和LOA中发生的长期饮酒引起的神经化学过程有关：显着减少了由于促进伽马氨基酸（GABA）功能而引起的广义渴望症状，并降低了电压添加钙通道的抑制作用。因此，我们假设：1）在EOA中，ondansetron和托吡酯作用的组合将是加性的，可能是协同作用； 2）与LOA相比，EOA将对单独使用ondansetron的治疗更敏感，3）EOA和LOA都会对托吡酯治疗做出反应。 我们将通过检查ondansetron（4 mcg/kg b.i.d.）和托吡酯（最多300 mg/day）的有效性来测试该假设的具体预测，每个人单独和组合在EOA和LOA（45个受试者/细胞X 8细胞，总n = 360个）中，在一个随机的，单连接的，12周的时间内，（45个受试者x 8细胞）在145个受试者和x 8细胞中进行。双盲数周）门诊临床试验。所有受试者将接受手动驱动的标准化认知行为疗法，并在治疗后1、3、6和9个月接受随访。 这项研究支持NIAAA开发有效的组合药物疗法作为心理治疗治疗酒精中毒的辅助任务。