Methamphetamine Pharmacotherapy Development Center

描述（由申请人提供）：甲基苯丙胺滥用是一个普遍存在的问题，目前没有有效的药物治疗。 该项目将测试调节肾上腺素能功能的药物作为甲基苯丙胺依赖治疗的安全性和有效性。在一系列协调的住院实验室和门诊治疗研究中，我们将对肾上腺素能化合物的效用进行系统研究。我们建议检查的具体化合物是α-2激动剂可乐定，β受体阻滞剂卡维地洛，α-1拮抗剂哌唑嗪和去甲肾上腺素再摄取抑制剂托莫西汀。作为我们研究的一部分，我们将开发新的检测技术，并利用群体药代动力学/药效学模型来提供我们试验期间非法甲基苯丙胺消耗量的定量估计。我们假设，量化候选药物治疗对非法药物摄入的影响将大大提高我们评估药物有效性和治疗结果的能力。 复吸是情绪、渴望、压力和戒断心理学复杂变化的一个功能。替代标记物在确定药物反应中可能是必不可少的。在我们的研究中，我们将评估使用细胞因子IL-6、C-反应蛋白和肿瘤坏死因子-α作为压力的替代标记物来预测复发、测量药物效果和确定结果的效用。 协调具体的实验，以便一个实验的结果通知后续研究的设计。在我们的实验室部分，我们将）评估我们的候选药物和甲基苯丙胺之间的相互作用，2）在受控条件下开发和验证我们的方法来量化非法药物摄入量，3）评估甲基苯丙胺-细胞因子相互作用。这些研究的结果用于将四种肾上腺素能药物中的两种从住院实验室推进到安慰剂对照的门诊治疗试验。在这些门诊试验中，我们将1）评估这些候选药物的临床疗效，2）在真实的世界条件下验证定量甲基苯丙胺摄入方法，3）确定我们的免疫标记物预测复发的效用。 我们专注的、基于机械的研究为方法开发和疗效评估提供了机会，如果没有合作中心，这些机会是无法实现的。

DESCRIPTION (provided by applicant): Methamphetamine abuse is a widespread problem for which there is currently no effective pharmacotherapy. This project will test the safety and efficacy of medications that modulate adrenergic function as treatments for methamphetamine dependence. In a coordinated series of inpatient laboratory and outpatient treatment studies, we will perform a systematic investigation of the utility of adrenergic compounds. The specific compounds that we propose examining are the alpha-2 agonist clonidine, the beta-blocker carvedilol, the alpha-l antagonist prazosin, and the norepinephrine reuptake inhibitor atomoxetine. As part of our research, we will develop new assay techniques and utilize population pharmacokinetic/pharmacodynamic modeling to provide a quantitative estimate of the amounts of illicit methamphetamine consumed during our trials. We postulate that quantifying the effects of candidate pharmacotherapies on illicit drug intake will substantially improve our ability to assess the effectiveness of our medications and therapeutic outcomes. Relapse to drug use occurs as a function of complex alterations in mood, craving, stress and withdrawal symptomatology. Surrogate markers can be essential in determining drug response. In our studies we will assess the utility of using the cytokines IL-6, C-reactive protein and tumor necrosis factor-alpha as surrogate makers of stress to predict relapse, measure drug effect, and determine outcome. Specific experiments are coordinated so that results from one experiment informs the design of subsequent, studies. In our laboratory component we will) assess interactions between our candidate drugs and methamphetamine, 2) develop and validate under controlled conditions our method to quantify illicit drug intake, and 3) evaluate methamphetamine-cytokine interactions. Results from these studies are used to advance two of the four adrenergic drugs from the inpatient laboratory to placebo-controlled outpatient treatment trials. In these outpatient trials we will 1) assess the clinical efficacy of these candidate drugs, 2) validate the quantitative methamphetamine ingestion method under real world conditions, and 3) determine the utility of our immune markers to predict relapse. Our focused, mechanistically-based studies present opportunities for methods development and efficacy evaluations that could not be practically achieved without a collaborative center.