PH I ASSESS OF POTENTIAL INTERACTIONS BETWEEN IV COCAINE, ETHANOL, DISULFIRAM

PH I 评估 IV 可卡因、乙醇、双硫仑之间的潜在相互作用

• 批准号: 7378204
• 负责人: JOHN D ROACHE
• 金额: $ 2.01万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378204
• 关键词: PH; ASSESS; POTENTIAL; INTERACTIONS; BETWEEN

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: This is a Phase I human laboratory clinical pharmacology study to assess potential interactions between intravenous cocaine and intravenous ethanol administration in cocaine-dependent subjects treated with oral disulfiram. The primary objective of this study is to determine safety of alcohol use in cocaine-dependent subjects that used cocaine after treatment with disulfiram. This will be achieved by measuring adverse events and changes in cardiovascular and psychiatric responses from baseline. RESEARCH PLAN: This is a double-blind, placebo-controlled inpatient Phase I clinical study to determine the cardiovascular and psychiatric safety of alcohol use in cocaine-dependent subjects who had used cocaine after treatment with disulfiram. The study will employ a gradual "dose run-up" approach testing the safety and clinical tolerance of IV cocaine and ethanol alone, before and after treatment with disulfiram, before finally combining all three agents for the final test of safety. Study agent (disulfiram/placebo) will be administered double-blind, but the cocaine and ethanol doses will be single-blind and use double-dummy procedures. The study will be conducted under NIDA contract at two sites (San Antonio and UCLA). METHODS: Subjects who are cocaine dependent, but who are otherwise healthy and not seeking treatment, will be screened for eligibility and admitted for a 17-day stay on the residential research unit at University Hospital. On seven designated infusion days, subjects will be admitted to the GCRC for the conduct of experimental infusion sessions including demonstration of initial clinical tolerance (on day -3) to the infusion of cocaine, 30 mg IV. The next two infusion days will establish the baseline cardiovascular responses of subjects to IV cocaine and ethanol infusions (on days -2 and -1, respectively). Subsequently, subjects will be randomized into one of two treatment groups and initiate oral dosage treatment with 250 mg disulfiram or placebo once a day for 7 days. Three days after initiation of daily treatment with either disulfiram (N=8) or placebo (N=4), subjects will receive IV infusions as follows: (1) IV saline on day 4; (2) 30 mg IV cocaine on day 5; (3) IV dose of ethanol on day 6; (4) on day 7, 30 mg IV cocaine followed by IV ethanol 5 minutes later. Thereafter, the double-blind dose of disulfiram/placebo treatment will cease but subjects will remain at University Hospital until discharge one week later on day 14. Subjects will be requested to return for safety follow-up one and two weeks after discharge. CLINICAL RELEVANCE: Many pharmaceutical agents have been tested for efficacy in the treatment of cocaine dependence, but none have been proven effective as yet. Recently, there have been three efficacy and three laboratory safety trials conducted evaluating the possible use of disulfiram to treat cocaine dependence. All of these have been positive and NIDA is eager to proceed with a major, Phase III cross-national clinical trial examining the efficacy of disulfiram in the treatment of primary cocaine dependence. However, the FDA will not approve such a study until a Phase I clinical trial has examined the safety of the 3-way drug interaction. The safety question raised by the FDA is a clinical characterization of the cardiac and cardiovascular risk in cocaine-dependent individuals when hypotension resulting from a disulfiram-ethanol reach into is induced in the presence of cardiac acceleration produced by cocaine. The proposed study is essential to the further development of disulfiram or any like agent for the treatment of cocaine dependence.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目的：这是一项人体实验室第一阶段临床药理学研究，旨在评估口服双硫仑治疗的可卡因依赖者中静脉注射可卡因和静脉注射乙醇之间的潜在相互作用。这项研究的主要目的是确定可卡因依赖受试者在双硫仑治疗后使用可卡因的酒精使用安全性。这将通过测量不良事件以及心血管和精神反应从基线开始的变化来实现。研究计划：这是一项双盲、安慰剂对照的住院患者I期临床研究，旨在确定在使用双硫仑治疗后使用可卡因的受试者中，酒精使用对心血管和精神安全的影响。这项研究将采用循序渐进的“剂量递增”方法，在双硫兰治疗前后，单独测试静脉注射可卡因和乙醇的安全性和临床耐受性，最后将这三种药物结合起来进行最终的安全性测试。研究试剂(双硫仑/安慰剂)将双盲给予，但可卡因和乙醇剂量将单盲并使用双模拟程序。这项研究将根据NIDA的合同在两个地点(圣安东尼奥和加州大学洛杉矶分校)进行。方法：可卡因依赖的受试者，但在其他方面是健康的，没有寻求治疗，将接受资格筛选，并在大学医院的住宿研究单元住院17天。在指定的七个输液日，受试者将被允许进入GCRC进行实验性输液环节，包括展示(在第三天)对静脉注射30 mg可卡因的初步临床耐受性。接下来的两个输液日将建立受试者对静脉注射可卡因和乙醇的基线心血管反应(分别在第二天和第一天)。随后，受试者将被随机分成两个治疗组之一，开始口服剂量治疗，每天一次，250毫克，或安慰剂，持续7天。在开始每日服用双硫兰(N=8)或安慰剂(N=4)三天后，受试者将接受如下静脉输注：(1)第4天静脉注射生理盐水；(2)第5天静脉注射30毫克可卡因；(3)第6天静脉注射乙醇；(4)第7天静脉注射30 mg可卡因，5分钟后静脉注射乙醇。此后，双硫仑/安慰剂双盲治疗将停止，但受试者将留在大学医院，直到一周后第14天出院。受试者将被要求在出院后一周和两周后返回接受安全跟进。临床意义：许多药物已经被测试在治疗可卡因依赖方面的有效性，但到目前为止还没有一种被证明有效。最近，已经进行了三项有效性和三项实验室安全性试验，评估双硫仑治疗可卡因依赖的可能性。所有这些都是阳性的，NIDA渴望进行一项大型的第三阶段跨国临床试验，检查双硫仑在治疗初级可卡因依赖方面的疗效。然而，FDA不会批准这样的研究，直到I期临床试验检查了3向药物相互作用的安全性。FDA提出的安全问题是，在可卡因产生的心脏加速存在的情况下，双硫仑-乙醇诱导低血压时，可卡因依赖者的心脏和心血管风险的临床特征。这项拟议的研究对于进一步开发用于治疗可卡因依赖的双硫兰或任何类似药物至关重要。