Safety and initial efficacy of lisdexamfetamine for methamphetamine dependence

赖右苯丙胺治疗甲基苯丙胺依赖的安全性和初步疗效

• 批准号: 8229870
• 负责人: Rajkumar Jyotishchandra Sevak
• 金额: $ 1.42万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8229870
• 关键词: Adult; Amphetamines; Attention deficit hyperactivity disorder; Attenuated; Behavioral; Cardiovascular system; Characteristics; Child; Clinical; Clinical Trials; County; Dependence; Development; Dextroamphetamine; Dose; Drug Formulations; Drug abuse; Effectiveness; Epidemiology; Evaluation; FDA approved; Funding; Future; Health; Human; Hydrolysis; Individual; Ingestion; Intravenous; Laboratories; Laboratory Research; Laboratory Study; Los Angeles; Maintenance; Measures; Mechanics; Methamphetamine; Methamphetamine dependence; Nature; Oral; Overdose; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Placebos; Prodrugs; Property; Psychostimulant dependence; Public Health; Questionnaires; Reinforcement Schedule; Research; Resistance; Safety; Self Administration; Severities; Symptoms; Tablets; Testing; Toxic effect; Withdrawal; addiction; base; capsule; cost; design; improved; indexing; methamphetamine abuse; neurochemistry; novel; research study

DESCRIPTION (provided by applicant): Methamphetamine (MA) dependence is a major public health concern; however, a widely accepted pharmacotherapy has not yet been identified. The results of several clinical trials indicate that d-amphetamine, a medication that shares neurochemical, behavioral and pharmacological effects with MA, reduces street use of stimulants and severity of withdrawal in amphetamine-dependent patients. Unfortunately, clinicians may not favor d-amphetamine, because of its high abuse potential. Indeed, d-amphetamine is reportedly abused, primarily by crushing the tablets in order to snort the drug. It is likely then, the potential for the clinical utility of d- amphetamine may be enhanced by the development of abuse-deterrent formulations, that are resistant to tampering to extract the active stimulant. One such product, lisdexamfetamine (LDX) is the first FDA-approved pro-drug stimulant, that is a therapeutically inactive molecule. After oral ingestion, however, it is converted to d-amphetamine, which is responsible for the drug's activity. A recent study of abuse liability showed that at doses of LDX and d- amphetamine that contain equivalent molar amounts of free amphetamine base, LDX produced significantly less "drug liking" than did d-amphetamine. This finding suggests that LDX has low stimulant properties, and little abuse potential, highlighting its suitability as a candidate medication for MA dependence. However, the safety of administering LDX with MA, and the ability of LDX to modify the abuse-related behavioral effects of MA have yet to be tested. We propose to conduct human laboratory evaluations of the safety and initial efficacy of LDX as a pharmacotherapy for MA dependence. The first specific aim is to evaluate the safety and tolerability of administering LDX in combination with intravenous MA in humans. MA-dependent individuals will receive ascending doses of intravenous (i.v.) MA while maintained on increasing doses of LDX (Exp. 1). Cardiovascular indices will be used to determine the safety of the LDX-MA combinations while subjective measures will be used to characterize the behavioral effects. The results of this experiment will guide the selection of the dose to be tested in Exp.2. The second specific aim is to determine whether LDX maintenance attenuates the reinforcing effects of MA. To accomplish this aim, we will assess MA self-administration, during LDX maintenance, in a progressive-ratio schedule of reinforcement (Exp. 2). The reinforcing effects of drugs, including MA, are central to their abuse potential. An effective pharmacotherapy for stimulant dependence should reduce MA self-administration. If successful, the findings from the proposed study will provide crucial scientific information on the safety and initial efficacy of LDX that could be useful for larger clinical trials evaluating efficacy of LDX for MA dependence. The results of this study will also help elucidate the optimal conditions (e.g., dose) under which LDX might be expected to be effective. PUBLIC HEALTH RELEVANCE: The proposal offers to provide important scientific and clinical information on the safety and initial efficacy of lisdexamfetamine (LDX) as a putative pharmacotherapy for methamphetamine (MA) dependence. The proposed human laboratory research will elucidate the optimal conditions (e.g., dose) under which LDX might be expected to be safe and effective. Because a widely accepted medication for treating MA dependence is not yet available, and the cost associated with clinical trials is substantial, human laboratory research can provide an economical and efficient approach for determining preliminary efficacy of LDX for MA dependence.

描述（由申请人提供）：甲基苯丙胺（MA）依赖是一个主要的公共卫生问题;然而，尚未确定广泛接受的药物治疗。几项临床试验的结果表明，d-苯丙胺，一种与MA具有神经化学，行为和药理作用的药物，减少了街头使用兴奋剂和苯丙胺依赖患者戒断的严重程度。不幸的是，临床医生可能不赞成d-安非他明，因为它的高滥用潜力。实际上，据报告，d-安非他明也被滥用，主要是通过压碎药片以掩盖药物。因此，可能的是，d-安非他明的临床应用的潜力可以通过开发滥用威慑制剂来增强，所述滥用威慑制剂抵抗篡改以提取活性兴奋剂。 一种这样的产品，利右苯丙胺（LDX）是第一个FDA批准的前药兴奋剂，这是一种治疗上无活性的分子。然而，口服摄入后，它会转化为d-安非他明，这是药物活性的原因。最近一项关于滥用倾向的研究表明，在含有等摩尔量游离安非他明碱的LDX和d-安非他明剂量下，LDX产生的“药物喜好”明显低于d-安非他明。这一发现表明，LDX具有低刺激特性，几乎没有滥用的可能性，突出了其作为MA依赖候选药物的适用性。然而，LDX与MA一起给药的安全性以及LDX改变MA的滥用相关行为效应的能力还有待测试。 我们建议对LDX作为MA依赖性药物治疗的安全性和初步疗效进行人体实验室评价。第一个具体目的是评估在人体中LDX与静脉内MA联合给药的安全性和耐受性。MA依赖性个体将接受递增剂量的静脉内（i. v.）MA同时维持增加剂量的LDX（实验。1）。心血管指数将用于确定LDX-MA复方制剂的安全性，而主观指标将用于表征行为效应。该实验的结果将指导实验2中待测剂量的选择。第二个具体目标是确定LDX维持是否减弱MA的强化作用。为了实现这一目标，我们将评估MA自我管理，在LDX维持期间，在一个渐进的比例强化时间表（实验1）。2）。包括MA在内的药物的强化作用是其滥用潜力的核心。一个有效的药物治疗兴奋剂依赖应减少MA自我管理。如果成功，拟议研究的结果将提供有关LDX安全性和初步疗效的关键科学信息，这些信息可能有助于评估LDX对MA依赖的疗效的大型临床试验。这项研究的结果也将有助于阐明最佳条件（例如，剂量），在此剂量下LDX可能预期有效。 公共卫生关系：该提案提供了关于利右苯丙胺（LDX）作为甲基苯丙胺（MA）依赖的推定药物治疗的安全性和初步疗效的重要科学和临床信息。拟议的人类实验室研究将阐明最佳条件（例如，剂量），在此剂量下LDX可能是安全有效的。由于目前还没有一种广泛接受的治疗MA依赖的药物，并且与临床试验相关的成本很高，因此人体实验室研究可以提供一种经济有效的方法来确定LDX对MA依赖的初步疗效。