Monoamine Antagonist Therapies for Methamphetamine Abuse

单胺拮抗剂治疗甲基苯丙胺滥用

• 批准号: 7920200
• 负责人: W BROOKS GENTRY
• 金额: $ 35.89万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920200
• 关键词: Acute; Adrenergic Agents; Adrenergic Receptor; Adverse effects; Amphetamines; Anxiety; Arrhythmia; Blood specimen; Brain; Cardiac; Cardiac Output; Cardiovascular system; Characteristics; Chemicals; Clinical Trials; Cognitive; Cyproheptadine; Data; Data Set; Dependence; Development; Dopamine; Dose; Double-Blind Method; Drug Interactions; Drug Kinetics; Drug usage; Effectiveness; Equilibrium; Euphoria; Event; Frequencies; Future; Goals; HTR2A gene; Health; Health Hazards; Human; Hypertension; Intervention; Intravenous; Investigation; Laboratories; Laboratory Study; Lead; Link; Measurable; Measures; Medical; Medicine; Methamphetamine; Methamphetamine dependence; Neuraxis; Neurotransmitters; Norepinephrine; Oral; Patient Self-Report; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Physiological; Placebos; Play; Prazosin; Procedures; Public Health; Randomized; Regimen; Relative (related person); Rewards; Role; Serotonin; Serotonin Receptor 5-HT2A; Serum; Severities; Site; System; Testing; Time; United States Substance Abuse and Mental Health Services Administration; addiction; adrenergic; clinical effect; clinical efficacy; cognitive function; craving; design; efficacy testing; methamphetamine abuse; monoamine; noradrenergic; novel; public health relevance; quetiapine; receptor; receptor function; recidivism; response; treatment effect; volunteer

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.

描述（由申请人提供）：过去几年，甲基苯丙胺在美国和世界范围内的使用有所增加，导致相关医疗问题的频率和严重程度更高。然而，目前还没有发现一种药物能在疗效和副作用之间达到医学上可接受的平衡。当大脑化学传递素多巴胺在安非他明的愉悦强化和精神运动刺激作用中起主要作用时，传递素去甲肾上腺素和血清素也在这些作用中发挥了重要作用。最近的证据表明，去甲肾上腺素和血清素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作为药物干预的目标进行广泛的测试。本申请提出了相关的人体研究，以确定阻断去甲肾上腺素、血清素或两者作用的药物是否有利于改变甲基苯丙胺的中枢神经系统（CNS）效应、心血管效应和/或药代动力学。拟作人体试验的药物有哌唑嗪、赛庚乙胺和喹硫平。滥用甲基苯丙胺的志愿者将接受6个疗程，间隔2-3天。在每次服用甲基苯丙胺或甲基苯丙胺安慰剂之前，将采用随机双盲设计，口服一种治疗药物（安慰剂、低剂量、高剂量）。志愿者将在每六个阶段的研究中只接受一种治疗药物。甲基苯丙胺将静脉注射（iv），其给药方案为人类良好耐受，但其本身产生的效果很容易测量。在Specific Aim 1中，我们将确定阻断（1b-肾上腺素能受体）（prazosin）、5-HT2A受体（cyproheptadine）或两者（喹硫平）的药物是否会改变甲基苯丙胺的自我报告/表现效应。在特异性目标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会改变甲基苯丙胺对心血管的影响。在特异性目标3中，我们将确定这些药物是否会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，将获得自我报告（ARCI， POMS， VAS），认知表现（DSST, Stroop）和心脏效应（如心输出量和心律失常）测量。将获得血液样本，以确定药物对甲基苯丙胺血清浓度的影响。这些措施将提供一个广泛的药理学效应概况，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为如何使用现有药物和设计更好的药物来治疗目前无法治疗的成瘾提供重要信息。