Cocaine Pharmacotherapy Targeting Dopamine & GABA

描述（由申请人提供）：该药物开发中心（MDU）的主题是开发新的GABA增强药物，并使用遗传方法将成功的可卡因药物治疗（如双硫仑和GABA再摄取阻滞剂噻加宾）与可卡因依赖患者亚组进行最佳匹配-我们正在进行两项门诊随机临床试验和一系列五项实验室筛选研究，以寻找新的GABA增强剂。第一个项目是一项随机、安慰剂对照、为期12周的临床试验，在双硫仑和GABA再摄取阻滞剂噻加宾的试验中检查150名可卡因依赖性美沙酮稳定患者。这些患者将根据功能性多巴胺β羟化酶（DBH）多态性进行分层，仅在具有导致低OBH水平和相对较高多巴胺（DA）水平的遗传单倍型的患者中预测对双硫仑的治疗反应。第二个项目包括140个抑郁症。最近戒断，可卡因依赖患者在一个随机，安慰剂对照，12周复发试验与四个治疗组：安慰剂，舍曲林。舍曲林+噻加宾和舍曲林+加巴喷丁。本试验包括最初2周的住院禁欲。这两个项目中的患者将接受GABA相关多态性的遗传筛查，作为未来研究中对GABA增强剂治疗反应的潜在预测因素。第三个项目将在实验室中使用可卡因对人类进行给药，以筛选五种GABA增强剂作为药物治疗的潜在效用。这三个项目涉及在临床试验和人体实验室中检查九种不同的潜在可卡因药物疗法。这些临床试验提供了双硫仑或DA再摄取阻滞剂舍曲林与GABA增强剂-噻加宾和加巴喷丁降低DA的有趣对比。总体而言，该中心将对300多名患者进行研究，并在门诊II期试验或人体实验室研究中使用8种不同的药物。

DESCRIPTION (provided by applicant): This Center for Medications Development (MDU) has a theme of developing new GABA enhancing medications and using genetic approaches to optimally match successful cocaine pharmacotherapies such as disulfiram and the GABA reuptake blocker tiagabine to subgroups of cocaine dependent patients- We are conducting two outpatient randomized clinical trials and a series of five laboratory screening studies for new GABA enhancers. The first project is a randomized, placebo-controlled, 12-week clinical trial examining 150 cocaine-dependent methadone-stabilized patients in a trial of disulfiram and the GABA reuptake blocker tiagabine. These patients will be stratified based on a functional dopamine beta hydroxylase (DBH) polymorphism with the prediction of a treatment response to disulfiram only in those with the genetic haplotype that leads to low OBH levels and relatively higher dopamine (DA) levels. The second project includes 140 depressed. recently abstinent, cocaine-dependent patients in a randomized, placebo-controlled, 12-week relapse trial with four treatment groups: placebo, sertraline. sertraline + tiagabine and sertraline + gabapentin. This trial includes an initial 2 weeks of inpatient abstinence. The patients in both projects will undergo genetic screening of GABA related polymorphisms as potential predictors of treatment response to GABA enhancers in future studies. The third project will use cocaine administration to humans in a laboratory in order to screen five GABA enhancers for their potential utility as pharmacotherapies. These three projects involve examination of nine different potential cocaine pharmacotherapies in clinical trials and the human laboratory. These clinical trials offer an interesting contrast in DA enhancement by disulfiram or the DA reuptake blocker sertraline versus DA reduction by the GABA enhancers - tiagabine and gabapentin. Overall, over 300 patients will be studied in this Center and eight different agents in either outpatient Phase II trials or human laboratory studies.