Monoamine Antagonist Therapies for Methamphetamine Abuse

描述(由申请人提供)：在过去的几年里，冰毒在美国和世界各地的使用有所增加，导致相关的医疗问题更加频繁和严重。然而，还没有发现在有效性和副作用之间达到医学上可接受的平衡的药物。虽然大脑化学递质多巴胺在苯丙胺令人愉悦的强化和精神运动刺激作用中发挥着重要作用，但去甲肾上腺素和5-羟色胺也对这些效应起到了重要作用。最近的证据表明，去甲肾上腺素和5-羟色胺系统之间存在的功能联系可能在甲基苯丙胺的作用和依赖中具有极其重要的作用。然而，这些神经递质系统还没有像药物干预的目标那样进行广泛的测试。这项申请提出了相关的人体研究，以确定阻断去甲肾上腺素作用和/或5-羟色胺作用的药物是否可以有利地改变中枢神经系统(CNS)效应、心血管效应和/或甲基苯丙胺的药代动力学。建议在人体上测试的药物是哌唑嗪、赛庚啶和奎硫平。滥用甲基苯丙胺的志愿者将接受六次治疗，间隔2-3天。其中一种治疗药物(安慰剂、低剂量、高剂量)的单剂量口服将以随机、双盲设计在每次给药之前给予甲基苯丙胺或甲基苯丙胺安慰剂。在每六个疗程的研究中，志愿者将只接受一种治疗药物。甲基苯丙胺将静脉注射(Iv)，剂量方案人类可以很好地耐受，但这本身就会产生容易测量的效果。在具体目标1中，我们将确定阻断(1b-肾上腺素能受体(哌唑嗪)、5-HT2a受体(赛庚啶)或两者(奎硫平)的药物是否会改变甲基苯丙胺的自我报告/执行效果。在具体目标2中，我们将确定与单独使用甲基苯丙胺相比，这些药物的急性预处理是否改变了甲基苯丙胺的心血管效应。在具体目标3中，我们将确定这些药物是否改变了甲基苯丙胺的浓度-效应(药效学)关系。在使用治疗药物(或安慰剂)和甲基苯丙胺(或安慰剂)前后，将获得自我报告(ARCI、POMS、VAS)、认知能力(DSST、Stroop)和心脏效应(例如，心输出量和心律失常)指标。将采集血液样本，以确定药物对甲基苯丙胺血清浓度的影响。这些措施将提供广泛的药理作用概况，并有助于理解这些药物的有益作用如何受到不良副作用的阻碍。这些新的数据集可以提供有关如何使用现有药物和设计更好的药物来治疗目前无法治愈的成瘾的基本信息。 公共卫生相关性：这些研究与公共健康直接相关，因为它们将确定有可能有效治疗甲基苯丙胺滥用造成的严重精神和医学影响的药物和理想药物的特点。这些研究将确定治疗药物的益处和副作用的最有效平衡。这些研究还将确定甲基苯丙胺的药理特征，这些特征可以作为未来治疗药物开发的目标。

DESCRIPTION (provided by applicant): Methamphetamine use has increased in the US and worldwide in the past years resulting in greater frequency and severity of related medical problems. Yet, no medicines with a medically-acceptable balance of effectiveness and side effects have been discovered. While the brain chemical transmitter dopamine plays a major role in the pleasurable reinforcing and psychomotor stimulant effects of amphetamines, the transmitters norepinephrine and serotonin also contribute substantially to these effects. Recent evidence suggests that the functional links that exist between norepinephrine and serotonin systems may be profoundly important in methamphetamine effects and dependence. However, these neurotransmitter systems have not been tested as extensively as targets of pharmacologic interventions. This application proposes interrelated human studies to determine whether medicines that block norepinephrine action, serotonin action, or both can favorably alter the central nervous system (CNS) effects, cardiovascular effects, and/or pharmacokinetics of methamphetamine. The proposed medicines to be tested in humans are prazosin, cyproheptadine, and quetiapine. Methamphetamine-abusing volunteers will undergo six sessions spaced 2-3 days apart. A single oral dose of one of the treatment medicines (placebo, low dose, high dose) will be given in a randomized, double-blind design before methamphetamine or methamphetamine placebo administration in each session. The volunteers will receive only one of the treatment medicines during each six-session study. Methamphetamine will be given intravenously (iv) in a dosing regimen that is well-tolerated by humans but that results in easily measurable effects by itself. In Specific Aim 1, we will determine whether medications that block (1b-adrenergic receptors (prazosin), 5-HT2A receptors (cyproheptadine), or both (quetiapine) alter the self-reported/performance effects of methamphetamine. In Specific Aim 2, we will determine whether acute pretreatment with these medications alters the cardiovascular effects of methamphetamine relative to methamphetamine alone. In Specific Aim 3, we will determine whether these medications alter the concentration-effect (pharmacodynamics) relationships of methamphetamine. Before and after administering the treatment medicines (or placebo) and methamphetamine (or placebo), self-report (ARCI, POMS, VAS), cognitive performance (DSST, Stroop), and cardiac effect (e.g., cardiac output and arrhythmia) measures will be obtained. Blood samples will be obtained to determine the effect of the medicines on methamphetamine serum concentrations. These measures will provide a broad pharmacologic effect profile and help to understand how beneficial effects of these medicines are hindered by adverse side effects. These novel datasets could provide essential information on how to use existing medicines and design better medicines to treat what is currently an untreatable addiction. PUBLIC HEALTH RELEVANCE: These studies have immediate relevance to public health because they will identify medications and characteristics of ideal medicines that have the potential to effectively treat the serious psychiatric and medical effects of methamphetamine abuse. The studies will define the most effective balance of beneficial effects and side effects of the treatment medications. These studies will also identify characteristics of methamphetamine pharmacology that can be targeted for future treatment medications development.