Monoamine Antagonist Therapies for Methamphetamine Abuse

描述（由申请人提供）：在过去几年中，美国和世界范围内甲基苯丙胺的使用有所增加，导致相关医疗问题的频率和严重程度增加。然而，尚未发现具有医学上可接受的有效性和副作用平衡的药物。虽然大脑化学递质多巴胺在安非他明的愉悦增强和精神刺激作用中起着重要作用，但递质去甲肾上腺素和血清素也对这些作用有很大贡献。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对甲基苯丙胺的作用和依赖性非常重要。然而，这些神经递质系统还没有被广泛的药物干预的目标进行测试。本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、5-羟色胺作用或两者的药物是否可以有利地改变甲基苯丙胺的中枢神经系统（CNS）作用、心血管作用和/或药代动力学。拟用于人体试验的药物有哌唑嗪、赛庚啶和喹替沙星。滥用甲基苯丙胺的志愿者将接受六次治疗，间隔2-3天。在每个阶段的甲基苯丙胺或甲基苯丙胺安慰剂给药前，将以随机、双盲设计单次口服一种治疗药物（安慰剂、低剂量、高剂量）。志愿者在每六个阶段的研究中仅接受一种治疗药物。甲基苯丙胺将静脉内（iv）给药，给药方案为人类耐受良好，但其本身可产生易于测量的效应。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-HT 2A受体（赛庚啶）或两者（喹替佐米）的药物是否会改变甲基苯丙胺的自我报告/表现效应。在具体目标2中，我们将确定这些药物的急性预处理是否会改变甲基苯丙胺相对于单独使用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甲基苯丙胺的浓度-效应（药效学）关系。在给予治疗药物（或安慰剂）和甲基苯丙胺（或安慰剂）之前和之后，自我报告（ARCI、POMS、VAS）、认知表现（DSST、Stroop）和心脏效应（例如，心输出量和心律失常）测量。将采集血样，以确定药物对甲基苯丙胺血清浓度的影响。这些措施将提供一个广泛的药理作用概况，并有助于了解这些药物的有益作用是如何被不良副作用所阻碍的。这些新的数据集可以提供有关如何使用现有药物的基本信息，并设计更好的药物来治疗目前无法治愈的成瘾。 公共卫生相关性：这些研究与公共卫生直接相关，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疗影响的药物和理想药物的特征。这些研究将确定治疗药物的有益作用和副作用的最有效平衡。这些研究还将确定甲基苯丙胺药理学的特征，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.