Tiagabine and Disulfiram for Cocaine Dependence

噻加宾和双硫仑治疗可卡因依赖

• 批准号: 7648021
• 负责人: FREDERICK Gerard MOELLER
• 金额: $ 12.58万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648021
• 关键词: Abstinence; Accounting; Alleles; Anxiety; Area; Attenuated; Behavior; Behavior Therapy; Brain; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognitive Therapy; Cues; Data; Disulfiram; Dopamine; Dopamine-beta-monooxygenase; Dose; Double-Blind Method; Enzymes; Euphoria; GABA Agonists; GABA transporter; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genotype; Haplotypes; Homozygote; Hour; Intervention; Methadone; Methods; Neurons; Norepinephrine; Nucleus Accumbens; Opioid; Outcome; Paranoia; Participant; Patient Self-Report; Patients; Peripheral; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Plasma; Population; Principal Investigator; Psychological reinforcement; Randomized; Randomized Clinical Trials; Rate; Regulation; Relative (related person); Role; Safety; Screening procedure; Synapses; Testing; Treatment Efficacy; Treatment outcome; Urinalysis; Week; Work; aged; attenuation; base; day; design; experience; gabapentin; gamma-Aminobutyric Acid; inhibitor/antagonist; neurotransmission; noradrenergic; programs; prospective; response; reuptake; tiagabine; uptake

Comorbid cocaine dependence among methadone maintained patients interferes with treatment outcomes. Disulfiram (DPH inhibitor) and Tiagabine (GAT-1 blocker) have shown promising results in the treatment of cocaine dependence. While inhibition of DpH activity is hypothesized to increase dopamine neurotransmission primarily in the neocortexand 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-1021CDT) predict the treatment efficacy of disulfiram and tiagabine among newly admitted methadone treated patients. DBH-1021CDT regulates plasma D0H levels by influencing DBH gene expression. Based on our pilot studies, we hypothesize that carriers of the low-DpH associated T allele will have significant reductions in cocaine use, because they are more susceptible to inhibition of D0Hby disulfiram. In contrast, carriers of the high-DpH associatedC 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 expectedto provide a better understanding of the role of the DpH inhibitor disulfiram and the selective GABA reuptake inhibitor tiagabine on cocaine using behavior among distinct DBH-1021CDT genotypes.

美沙酮维持患者中共病可卡因依赖干扰治疗结果。 双硫仑（DPH抑制剂）和噻加宾（GAT-1阻滞剂）在治疗糖尿病中显示出有希望的结果。 可卡因依赖虽然DpH活性的抑制被假设为增加多巴胺 神经传递主要是在新皮层和加强焦虑的经验，可卡因的使用， GABA再摄取的选择性抑制被假设为主要在以下情况中减弱多巴胺神经传递： 伏隔核并减少可卡因使用的强化作用。本提案的目的是 确定多巴胺β功能多态性的前瞻性筛查在多大程度上 羟化酶（DBH-1021 CDT）预测双硫仑和噻加宾在新生儿中的治疗效果 接受美沙酮治疗的病人DBH-1021 CDT通过影响DBH调节血浆D 0 H水平 基因表达。基于我们的初步研究，我们假设低DpH相关T等位基因的携带者 可卡因的使用将显著减少，因为他们更容易受到D 0 H的抑制， 双硫仑相反，高DpH相关C等位基因携带者可卡因使用量几乎没有减少 双硫仑，但由于噻加宾的对比作用， 减少多巴胺的释放。这项为期14周的双盲、安慰剂对照随机临床试验将 为150名可卡因依赖性阿片类药物依赖患者提供治疗。年龄在18-65岁之间的参与者将 随机接受双硫仑250 mg/天、噻加宾24 mg/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）。主要结果将是减少阿片类药物和可卡因的使用，通过自我报告进行评估 并通过每周三次的尿检确认这项研究有望提供一个更好的 了解DpH抑制剂双硫仑和选择性GABA再摄取抑制剂噻加宾的作用 不同DBH-1021 CDT基因型之间可卡因使用行为的影响。