RTI-336 as a Treatment for Methamphetamine Dependence

描述（由申请人提供）：甲基苯丙胺（冰毒）是一种高度上瘾的兴奋剂，急性接触会导致多巴胺（DA）释放并刺激中脑奖励中心。在人类中，长期接触冰毒会导致DA减少，这可能会导致药物渴望、快感缺乏和其他戒断症状，这在冰毒戒断期间很常见。一种治疗策略是开发和测试使DA正常化（增加）的化合物，以确定用这些药物治疗是否能减少冰毒的使用。为了鉴定多巴胺转运体（DAT）选择性抑制剂，RTI International合成了许多3-苯基tropane类似物。其中，临床前研究表明，RTI-336在大鼠中产生可卡因样判别刺激效应，减少可卡因自我给药，在恒河猴中产生剂量依赖性的可卡因自我给药抑制。RTI-336最近获得了ind批准（75,778），可在健康男性志愿者中进行初步安全试验，计划于2009年2月完成。在此之后，RTI-336将在一项涉及可卡因依赖志愿者的一期试验中进行评估。目前的申请首次提出了一项建议，以评估这种非常有前途的候选药物在非寻求治疗的甲基安非他命依赖志愿者中的初步疗效。提出以下具体目标：1。与安慰剂相比，建立口服RTI-336（1,12或20mg）减弱甲基苯丙胺诱导（0和30mg， IV）阳性主观效应的能力的剂量效应关系；2. 确定RTI-336单独使用及与冰毒联合使用时的滥用责任。拟议的工作代表了一项重要的研究工作，具有相当大的公共卫生意义，因为它将评估一种专门针对DAT抑制治疗冰毒依赖的化合物。获得的知识可能最终支持开发和实施以证据为基础的治疗冰毒依赖的方法，冰毒依赖是一种具有巨大公共卫生影响的药物滥用问题。

DESCRIPTION (provided by applicant): Methamphetamine (METH) is a highly addictive stimulant and acute exposure causes dopamine (DA) release and stimulates midbrain reward centers. In humans, long-term METH exposure leads to DA reductions, which may contribute to drug craving, anhedonia, and other withdrawal symptoms common during METH abstinence. One therapeutic strategy is to develop and test compounds that normalize (increase) DA to determine if treatment with these drugs reduces METH use. In an effort to identify a dopamine transporter (DAT) selective inhibitor, a number of 3-phenyltropane analogs were synthesized by RTI International. Among these, preclinical studies have shown that RTI-336 produced cocaine-like discriminative stimulus effects and reduced cocaine self-administration in rats, and produced dose-dependent suppression of cocaine self-administration in rhesus monkeys. RTI-336 recently received IND-approval (75,778) for preliminary safety testing in healthy male volunteers, and is scheduled to be completed by February 2009. Subsequent to this effort, RTI-336 will be evaluated in a phase I trial involving cocaine-dependent volunteers. The current application puts forth, for the first time, a proposal to evaluate the preliminary efficacy of this very promising candidate medication in non-treatment-seeking METH-dependent volunteers. The following Specific Aims are proposed: 1. To establish dose-effect relationships for the ability of oral RTI-336 (1, 12 or 20 mg) as compared to placebo, to attenuate METH-induced (0 and 30 mg, IV) positive subjective effects; 2. To determine the abuse liability of RTI-336 alone and in combination with METH. The proposed work represents an important research effort with considerable public health significance in that it will evaluate a compound targeted specifically at DAT inhibition for the treatment of METH dependence. The knowledge gained may ultimately support development and implementation of evidence-based treatments for METH dependence, a drug abuse problem with tremendous public health impact. PUBLIC HEALTH RELEVANCE: In humans, long-term methamphetamine exposure leads to dopamine reductions, which may contribute to drug craving, anhedonia, and other withdrawal symptoms common during methamphetamine abstinence. One therapeutic strategy is to develop and test compounds that normalize (increase) dopamine to determine if treatment with these drugs reduces methamphetamine use. The current application puts forth, for the first time, a proposal to evaluate the preliminary efficacy of RTI-336 in non-treatment-seeking METH-dependent volunteers.