Phase I Safety Interaction Trial of Ibudilast with Methamphetamine

说明(申请人提供)：甲基苯丙胺(MA)依赖造成毁灭性的个人和公共健康后果，特别是在美国西部和中西部(SAMHSA应用统计办公室，2005年)。行为疗法帮助一些人减少或消除药物的使用(Lee和Rawson，2008)，但没有被批准用于治疗MA滥用的药物(vocci和Appl，2007)。开发一种或多种药物以减少MA滥用，当与循证行为和咨询干预措施一起实施时，将具有明显的公共卫生意义。如PA-07-333，用于治疗安非他明和安非他明样相关疾病的药物开发中所指出的，本申请寻求资金以进行伊布司特(又名：安非他明)的初步安全相互作用试验。AV411)，这是一种非选择性的磷酸二酯酶抑制剂，具有减弱中枢神经系统胶质细胞激活的活性。最近的研究表明，胶质细胞可能在调节包括MA(Vijayaraghavan 2009)在内的滥用药物的奖赏特性中起重要作用，并且MA诱导的胶质细胞激活可能通过胶质细胞分泌促炎细胞因子而导致MA的神经毒性和相关的认知功能障碍(Narita，Suzuki等人)。2008年)。因此，我们建议测试一种新的药物治疗MA依赖的方法：通过抑制MA诱导的胶质细胞激活来改善MA相关的认知功能障碍/退化。这项拟议的研究是一项I期临床试验，将利用随机双盲、安慰剂对照的受试者内交叉设计，在12名未寻求治疗的MA依赖志愿者中确定MA的安全性和耐受性以及主观和强化效果，这些志愿者接受了伊布司特(20 mg Bid和50 mg Bid)和安慰剂的治疗。这项研究将针对以下具体目标：(1)确定异丁司特(20 mg Bid或50 mg Bid)是否改变静脉注射甲基苯丙胺的心血管反应；(2)确定异丁司特(20 mg Bid或50 mg Bid)是否改变静脉注射甲基苯丙胺的主观效应；(3)确定异丁司特(50 Mg Bid)是否改变静脉注射甲基苯丙胺的增强效应；以及(4)确定异丁司特是否改变静脉注射甲基苯丙胺的药代动力学。还将进行探索性神经认知和药物遗传学分析。在加州大学洛杉矶分校和加州大学洛杉矶分校的团队在努力开发MA滥用和/或依赖的药物疗法方面拥有广泛的专业知识。这项研究的结果将提供在评估异丁司特治疗MA依赖的有效性的第二阶段临床试验之前所需的安全交互作用数据。 与公共健康相关：在洛杉矶县，与酒精等其他物质相比，甲基苯丙胺在接受公共资助的治疗中所占的比例更高，因此，对于寻求戒除甲基苯丙胺的依赖者来说，有很大的公共卫生需求可以优化行为疗法的结果。这项试验将收集描述潜在新疗法异丁司特(一种非选择性磷酸二酯酶抑制剂)的安全性的数据，在静脉注射30毫克甲基苯丙胺的情况下，分两次剂量(20毫克BID和50毫克BID)。在门诊环境下推进异丁司特的试验之前，这些相互作用数据是必要的。

DESCRIPTION (provided by applicant): Methamphetamine (MA) dependence causes devastating personal and public health consequences, particularly in the Western and Midwestern United States (SAMHSA Office of Applied Statistics 2005). Behavioral therapies help some persons reduce or eliminate their use of the drug (Lee and Rawson 2008), but there are no medications approved for the treatment of MA abuse (Vocci and Appel 2007). The development of one or more medications to reduce MA abuse when implemented with evidence-based behavioral and counseling interventions would have obvious public health significance. As noted in PA-07-333, Medications Development for the Treatment of Amphetamine and Amphetamine-Like Related Disorders, this application seeks funding to conduct an initial safety interaction trial of ibudilast (a.k.a. AV411), a non-selective phosphodiesterase inhibitor that has activity as an attenuator of CNS glial activation. Recent research suggests that glial cells may be important in modulating the rewarding properties of drugs of abuse including MA (Vijayaraghavan 2009) and that MA-induced glial activation may contribute to MA's neurotoxicity and associated cognitive dysfunction via glial cell secretion of pro-inflamatory cytokines (Narita, Suzuki et al. 2008). Therefore, we propose testing a novel approach to pharmacologic treatment of MA dependence: amelioration of MA-related cognitive dysfunction/degeneration via suppression of MA-induced glial activation. The proposed study is a Phase I clinical trial that will utilize a randomized double-blind, placebo-controlled within-subject crossover design to determine safety and tolerability and subjective and reinforcing effects of MA in 12 non-treatment seeking MA-dependent volunteers treated with ibudilast (20mg BID and 50mg BID) and placebo. The study will address the following Specific Aims: (1) to determine whether ibudilast (20 mg BID or 50 mg BID) alters the cardiovascular response to IV methamphetamine; (2) to determine whether ibudilast (20 mg BID or 50 mg BID) alters the subjective effects of IV methamphetamine; (3) to determine whether ibudilast (50 mg BID) alters the reinforcing effects of IV methamphetamine; and (4) to determine whether ibudilast alters the pharmacokinetics of IV methamphetamine. Exploratory neurocognitive and pharmaco- genetic analyses will also be performed. The team assembled at UCLA and Harbor-UCLA has extensive expertise in efforts to develop pharmacotherapies for MA abuse and/or dependence. Results of this study will provide the safety-interaction data required before a Phase II clinical trial to assess the efficacy of ibudilast for treatment of MA dependence can be performed. PUBLIC HEALTH RELEVANCE: In Los Angeles County, methamphetamine accounts for more admissions to publicly funded treatments than any other substance, including alcohol and so there is a significant public health need for medications that could optimize outcomes of behavioral therapies for dependent individuals seeking abstinence from methamphetamine. This trial will collect data describing the safety of a potential new treatment, ibudilast (a non-selective phosphodiesterase inhibitor), at two doses (20 mg BID and 50 mg BID) in the presence of 30 mg methamphetamine delivered intravenously. These interaction data are necessary before moving forward with trials of ibudilast in outpatient settings.