GABAERGIC & GLUTAMATERGIC AGENTS--COCAINE USE IN METHADONE MAINTENANCE

本部分药物开发单位(MDU)概述了在美沙酮维持的受试者中使用可卡因进行武器治疗的II期筛选研究，这些药物通过GABA能或吕他玛能机制发挥作用。这些研究将分两部分进行，GABA能药在L-2年试验，谷氨酸能药在3-5年试验。我们小组在完成使用美沙酮的可卡因受试者的药物治疗试验方面有很长的历史，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多巴胺奖励通路，这被认为是可卡因成瘾特性的基础，而调节GABA和谷氨酸系统的药物可以降低可卡因在动物模型中的增强特性。为这些初步研究选择的GABA能药是：L)GABA激动剂巴氯芬；和2)选择性GABA再摄取抑制剂替加宾。进入第一阶段研究的谷氨酸能药物是：L)N-甲基-D-天冬氨酸受体拮抗剂阿卡米松和2)突触前谷氨酸释放抑制剂拉莫三嗪。在整个五年期间，每项研究将招募60名受试者，总共120名受试者。受试者将被随机分配到五种细胞中的一种：安慰剂或两种不同剂量的巴氯芬或替加宾(研究1)或氨基己酸酯或拉莫三嗪(研究2)，分别对GABA能和谷氨酸能药物进行总共8或12周的积极治疗。在活跃的试验结束时，药物将在两周内逐渐减少。主要结果将是自我报告可卡因的使用，每周三次可卡因代谢物苯甲酰ecGonine的尿毒理学和治疗保留。希望我们能证明一种或多种可卡因制剂在阿片类药物维持的受试者中使用的有效性和安全性，如果获得令人鼓舞的结果，将计划进行二期对照研究，从这些二期筛选试验中确定有希望的候选药物。

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.