Tiagabine and Disulfiram for Cocaine Dependence

噻加宾和双硫仑治疗可卡因依赖

• 批准号: 6830601
• 负责人: Gerardo Gonzalez
• 金额: $ 17.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830601
• 关键词: clinical trials; cocaine; cognitive behavior therapy; disulfiram; dopamine; dopamine beta monooxygenase; drug abuse chemotherapy; drug addiction; enzyme activity; gamma aminobutyrate; genetic polymorphism; genetic screening; genotype; human subject; human therapy evaluation; methadone; neural transmission; neurons; neurotransmitter antagonist; norepinephrine; patient oriented research; pharmacogenetics

Comorbid cocaine dependence among methadone maintained patients interferes with treatment outcomes. Disulfiram (DbetaH inhibitor) and Tiagabine (GAT-1 blocker) have shown promising results in the treatment of cocaine dependence. While inhibition of DbetaH activity is hypothesized to increase dopamine neurotransmission primarily in the neocortex and to intensify the dysphoric experience of cocaine use, the selective inhibition of GABA reuptake is hypothesized to attenuate dopamine neurotransmission primarily in the nucleus accumbens and to reduce the reinforcing effects of cocaine use. The objective of this proposal is to determine to what extend does prospective screening for a functional polymorphism of dopamine beta hydroxylase (DBH-1021C->T) predict the treatment efficacy of disulfiram and tiagabine among newly admitted methadone treated patients. DBH -1021C->T regulates plasma DbetaH levels by influencing DBH gene expression. Based on our pilot studies, we hypothesize that carriers of the low-DbetaH associated T allele will have significant reductions in cocaine use, because they are more susceptible to inhibition of DbetaH by disulfiram. In contrast, carriers of the high-DpH associated C allele will have little reduction in cocaine use with disulfiram, but may have significant reductions with tiagabine, because of tiagabine's contrasting action in reducing dopamine release. This 14-week double-blind, placebo controlled randomized clinical trial will provide treatment for 150 cocaine-dependent opioid dependent patients. Participants, aged 18-65 years, will be randomized to receive disulfiram 250mg/day, tiagabine 24mg/day, or placebo while concurrently receiving treatment with methadone. All participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment). The primary outcomes will be reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses. The proposed study is expected to provide a better understanding of the role of the DbetaH inhibitor disulfiram and the selective GABA reuptake inhibitor tiagabine on cocaine using behavior among distinct DBH -1021C->T genotypes.

美沙酮的合并可卡因依赖性维持患者会干扰治疗结果。二硫仑（DBETAH抑制剂）和tiagabine（GAT-1阻滞剂）在可卡因依赖性治疗方面表现出了令人鼓舞的结果。 While inhibition of DbetaH activity is hypothesized to increase dopamine neurotransmission primarily in the neocortex and to intensify the dysphoric experience of cocaine use, the selective inhibition of GABA reuptake is hypothesized to attenuate dopamine neurotransmission primarily in the nucleus accumbens and to reduce the reinforcing effects of cocaine use.该提案的目的是确定什么扩展可以对多巴胺β羟化酶（DBH-1021C-> t）的功能性多态性进行前瞻性筛查预测，可预测新近接收的由新近接受的美酮治疗患者中二硫酸和tiagabine的治疗功效。 DBH -1021C-> t通过影响DBH基因表达来调节血浆DBETAH水平。基于我们的试点研究，我们假设相关的低 - 二甲虫的载体将显着降低可卡因的使用，因为它们更容易受到二硫酸的抑制作用。相比之下，高DPH相关的C等位基因的载体将很少减少可卡因与二硫兰酯的使用，但由于Tiagabine在减少多巴胺释放方面的对比作用，可能会大幅减少tiagabine。这项为期14周的双盲，安慰剂对照的随机临床试验将为150名可卡因依赖性阿片类药物患者提供治疗。年龄在18-65岁的参与者将被随机分配以每天250毫克的二硫酸含量，每天24mg/天或安慰剂，同时接受美沙酮治疗。所有参与者每周接受1小时的心理治疗（认知行为治疗）。正如自我报告评估的，主要结果将减少阿片类药物和可卡因的使用，并通过每周三次的尿液线路确认。拟议的研究有望更好地了解dbetah抑制剂二硫酸酯和选择性GABA再摄取抑制剂tiagabine在可卡因上使用不同DBH -1021C-> T基因型中的行为。