RTI-336 as a Treatment for Methamphetamine Dependence

描述(申请人提供)：甲基苯丙胺(冰毒)是一种高度上瘾的兴奋剂，急性暴露会导致多巴胺(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求、快感丧失和其他在冰毒戒断期间常见的戒断症状。一种治疗策略是开发和测试使DA正常化(增加)的化合物，以确定使用这些药物治疗是否减少冰毒的使用。为了确定多巴胺转运体(DAT)选择性抑制剂，RTI International合成了许多3-苯基托烷类似物。其中，临床前研究表明，RTI-336可产生类可卡因的辨别性刺激效应，减少大鼠的可卡因自我给药，并对恒河猴的可卡因自我给药产生剂量依赖性的抑制。RTI-336最近获得了IND批准(75,778)，用于健康男性志愿者的初步安全测试，计划于2009年2月完成。在这一努力之后，RTI-336将在一项涉及可卡因依赖志愿者的第一阶段试验中进行评估。目前的申请首次提出了一项建议，即评估这种非常有希望的候选药物在不寻求治疗的冰毒依赖志愿者中的初步疗效。提出了以下具体目标：1.建立口服RTI-336(1、12或20 mg)与安慰剂相比的剂量-效应关系，以减弱冰毒(0和30 mg，IV)的积极主观效应；2.确定RTI-336单独和与冰毒联合使用的滥用倾向。这项拟议的工作代表着一项具有相当大公共卫生意义的重要研究努力，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。所获得的知识可能最终支持开发和实施针对冰毒依赖的循证治疗，这是一个具有巨大公共健康影响的药物滥用问题。 公共卫生相关性：在人类中，长期接触甲基苯丙胺会导致多巴胺减少，这可能会导致药物渴求、快感丧失和其他在甲基苯丙胺戒断期间常见的戒断症状。一种治疗策略是开发和测试使多巴胺正常化(增加)的化合物，以确定使用这些药物治疗是否减少甲基苯丙胺的使用。目前的申请首次提出了一项建议，即评估RTI-336在不寻求治疗的冰毒依赖志愿者中的初步疗效。

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.