Phase I Safety Interaction Trial of Ibudilast with Methamphetamine

描述（由申请人提供）：甲基苯丙胺（MA）依赖会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应用统计局，2005年）。行为疗法可帮助一些人减少或消除药物使用（Lee和罗森，2008），但尚无药物获批用于治疗MA滥用（Vocci和阿佩尔，2007）。开发一种或多种药物，以减少MA滥用时，实施循证行为和咨询干预措施将具有明显的公共卫生意义。如PA-07-333中所述，用于治疗安非他明和安非他明样相关疾病的药物开发，该申请寻求资金以进行异丁司特（又名异丁司特）的初始安全性相互作用试验。AV 411），一种非选择性磷酸二酯酶抑制剂，具有作为CNS神经胶质活化衰减剂的活性。最近的研究表明，神经胶质细胞在调节包括MA在内的滥用药物的奖励特性方面可能很重要（Vijayaraghavan 2009），并且MA诱导的神经胶质活化可能通过神经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 et al. 2008）。因此，我们提出了一种新的方法来测试MA依赖的药物治疗：通过抑制MA诱导的神经胶质细胞活化来改善MA相关的认知功能障碍/退化。拟定研究是一项I期临床试验，将采用随机双盲、安慰剂对照受试者内交叉设计，在接受异丁司特（20 mg BID和50 mg BID）和安慰剂治疗的12名非寻求治疗的MA依赖性志愿者中确定MA的安全性和耐受性以及主观和强化效应。本研究将解决以下具体目的：（1）确定异丁司特是否（20 mg BID或50 mg BID）改变对IV甲基苯丙胺的心血管反应;（2）确定异丁司特是否（20 mg BID或50 mg BID）改变IV甲基苯丙胺的主观效果;（3）确定异丁司特是否（50 mg BID）改变IV甲基苯丙胺的增强作用;和（4）确定异丁司特是否改变IV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。加州大学洛杉矶分校和加州大学洛杉矶分校哈博的团队在开发MA滥用和/或依赖药物疗法方面拥有广泛的专业知识。本研究的结果将提供II期临床试验前所需的安全性相互作用数据，以评估异丁司特治疗MA依赖的疗效。 公共卫生相关性：在洛杉矶县，甲基苯丙胺比任何其他物质（包括酒精）都要多，因此，对于寻求戒除甲基苯丙胺的依赖者来说，可以优化行为治疗结果的药物具有重大的公共卫生需求。本试验将收集描述潜在新治疗异丁司特（一种非选择性磷酸二酯酶抑制剂）在存在30 mg甲基苯丙胺静脉给药的情况下两种剂量（20 mg BID和50 mg BID）的安全性的数据。这些相互作用的数据是必要的，然后再向前推进异丁司特在门诊设置的试验。

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.