GABAERGIC & GLUTAMATERGIC AGENTS--COCAINE USE IN METHADONE MAINTENANCE

本药物开发单元（MDU）的本节概述了在美沙酮维持受试者中使用通过GABA能或谷氨酸能机制起作用的药物进行可卡因治疗的II期筛选研究。这些研究将分两部分进行，第1 -2年测试GABA能药物，第3-5年测试谷氨酸能药物。我们的小组在可卡因使用美沙酮受试者中完成药物治疗试验的历史很长，例子包括地昔帕明，马吲哚，金刚烷胺，溴隐亭和安非他酮。临床前证据表明，GABA和谷氨酸系统可以调节被认为是可卡因成瘾性质的基础的多巴胺奖赏途径，并且调节GABA和谷氨酸系统的试剂可以降低动物模型中可卡因的强化性质。选择用于这些初步研究的GABA能药物是：1）GABAB激动剂巴氯芬;和2）选择性GABA再摄取抑制剂噻加宾。选择用于I期研究的谷氨酸能药物是：1）NMDA受体拮抗剂阿坎酸和2）突触前谷氨酸释放抑制剂拉莫三嗪。每项研究共招募60例受试者，整个5年期间共招募120例受试者。受试者将被随机分配至五个单元之一：安慰剂或两种不同剂量的巴氯芬或噻加滨（研究1）或阿坎酸或拉莫三嗪（研究2），分别进行总共8周或12周的GABA能和谷氨酸能药物的活性治疗。在积极的试验结束时，药物将在两周内逐渐减少。主要结局将是自我报告的可卡因使用情况、可卡因代谢物苯甲酰芽子碱的每周三次尿液毒理学和治疗保留。希望我们将证明这些药物中的一种或多种用于阿片类药物维持受试者中可卡因使用的有效性和安全性，并且如果获得令人鼓舞的结果，将计划II期对照研究，其中从这些II期筛选试验中鉴定出有希望的候选药物。

This section of this Medications Development Unit (MDU) outlines phase ll screening studies for armacotherapy of cocaine use in methadone- maintained subjects with agents that act through GABAergic or lutamatergic mechanisms. These studies would be carried out in two parts, with GABAergic agents being tested in Years l-2, and glutamatergic agents in Years 3-5. Our group has a long history of completing pharmacotherapy trials in cocaine-using methadone subjects, and examples have included desipramine, mazindol, amantadine, bromocriptine and bupropion. Pre- clinical evidence indicates that GABA and glutamate systems can modulate dopamine reward pathways which are thought to underlie the addictive properties of cocaine, and agents which modulate GABA and glutamate systems can reduce the reinforcing properties of cocaine in animal models. The GABAergic agents chosen for these pilot studies are: l) the GABAB agonist baclofen; and 2) the selective GABA reuptake inhibitor tiagabine. The glutamatergic agents chosen for phase I studies are: l) the NMDA receptor antagonist acamprosate and 2) the pre~synaptic glutamate release inhibitor lamotrigine. A total of 60 subjects will be recruited into each study for a total of 120 subjects over the entire five year period. Subjects will be randomized to one of five cells: placebo or two different doses of either baclofen or tiagabine (Study 1) or acamprosate or lamotrigine (Study 2) for a total of 8 or 12 weeks of active treatment for GABAergic and glutamatergic agents respectively. At the end of the active trials, medications would be tapered over a two week period. Primary outcomes will be self-reported cocaine use, three times weekly urine toxicology for the cocaine metabolite benzoylecgonine and treatment retention. It is hoped that we will demonstrate the efficacy and safety one or more of these agents for cocaine use in opiate-maintained subjects, and if encouraging results are obtained, phase ll controlled studies would be planned with promising candidates identified from these phase ll screening trials.