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疗法（如双硫仑和GABA再摄取阻断剂替加滨）与可卡因依赖患者的亚组进行最佳匹配。我们正在进行两项门诊随机临床试验和一系列五项新的GABA增强药物的实验室筛选研究。第一个项目是一项随机、安慰剂对照、为期12周的临床试验，对150名可卡因依赖美沙酮稳定的患者进行了双硫仑和GABA再摄取阻滞剂硫加滨的试验。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，并预测仅在具有导致低OBH水平和相对较高多巴胺（DA）水平的遗传单倍型的患者中对双硫仑的治疗反应。第二个项目包括140个洼地。最近，戒断，可卡因依赖患者在一个随机，安慰剂对照，12周复发试验四个治疗组：安慰剂，舍曲林。舍曲林+替加滨和舍曲林+加巴喷丁。该试验包括最初2周的住院戒断。这两个项目的患者将在未来的研究中进行GABA相关多态性的遗传筛选，作为对GABA增强剂治疗反应的潜在预测因子。第三个项目将在实验室对人体施用可卡因，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审查九种不同的潜在可卡因药物疗法。这些临床试验提供了一个有趣的对比：双硫仑或氨基丁酸再摄取阻滞剂舍曲林增强氨基丁酸与硫加滨和加巴喷丁增强氨基丁酸降低氨基丁酸。总体而言，该中心将研究300多名患者，并在门诊II期试验或人体实验室研究中研究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.