Monoamine Antagonist Therapies for Methamphetamine Abuse

单胺拮抗剂治疗甲基苯丙胺滥用

• 批准号: 7707036
• 负责人: W BROOKS GENTRY
• 金额: $ 35.49万
• 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/7707036
• 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; Neuraxis; Neurotransmitters; Norepinephrine; Oral; Patient Self-Report; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Physiological; Placebos; Play; Prazosin; Procedures; Public Health; Randomized; Relative (related person); Rewards; Role; Serotonin; Serotonin Receptor 5-HT2A; Serum; Severities; Site; System; Testing; Time; Treatment Protocols; 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（申请人提供）：在美国和过去几年中，甲基苯丙胺的使用量增加，导致相关医疗问题的频率和严重程度更高。然而，没有发现具有医学上有效性和副作用平衡的药物。尽管大脑化学发射机多巴胺在苯丙胺的令人愉悦的增强和心理刺激作用中起着重要作用，但发射机去甲肾上腺素和5-羟色胺也对这些作用产生了重大贡献。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在甲基苯丙胺的作用和依赖性中非常重要。但是，这些神经递质系统尚未像药理学干预措施那样广泛测试。该应用提出了相互关联的研究，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中枢神经系统（CNS）作用，心血管效应和/或甲基苯丙胺的药代动力学。在人类中要测试的拟议的药物是prazosin，cyproheptadine和quetiapine。滥用甲基苯丙胺的志愿者将进行6次间隔2-3天的会议。每次疗程中，将在随机的，双盲的设计中给出一种单一的口服治疗药物（安慰剂，低剂量，高剂量）。在每项六项课程研究中，志愿者将仅接受一种治疗药物。甲基苯丙胺将在人类宽容的剂量方案中静脉内（IV）给予（IV），但这本身会产生易于测量的效果。在特定目标1中，我们将确定阻断（1B-肾上腺素受体（prazosin），5-HT2A受体（cyproheptadine）或两者（喹硫平）是否会改变甲基苯丙胺的自我报告/性能效应。在特定目标2中，我们将确定急性对这些药物的急性预处理效果。在特定的目标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）关系将获得样品，以确定药物对甲基苯丙胺血清浓度的影响。这些新颖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处理目前不可治疗的成瘾的基本信息。 公共卫生相关性：这些研究与公共卫生有直接的相关性，因为它们将确定有效治疗甲基苯丙胺滥用的严重精神病和医学影响的理想药物的药物和特征。这些研究将定义有益作用和治疗药物副​​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，这些特征可以针对未来的治疗药物开发。