N-acetylcysteine for Relapse Prevention to Cocaine Use

描述（由申请人提供）：本申请提出了一项双盲临床试验，以评估n -乙酰半胱氨酸（NAC）作为治疗可卡因依赖的复发预防剂的疗效。寻求治疗的可卡因依赖者，年龄在18岁至70岁之间，所有族裔和种族背景的男性和女性，将获得知情同意并进行筛选，以获得满意的纳入和排除标准。这项研究有两个可行的假设。首先，NAC将减少可卡因使用的复发，这是基于一组可卡因依赖个体在开始用药前至少7天确认戒断可卡因的多次事件测量。其次，NAC组在停药后的4周随访期间将显示出比安慰剂持续的疗效。研究NAC治疗可卡因成瘾的有效性的基本原理最初是基于动物数据，该数据指出慢性操作性暴露于可卡因后会引起谷氨酸能脑回路的扰动。NAC改善了谷氨酸能缺陷，抑制了可卡因和线索诱导的可卡因寻求行为的恢复。最近的临床前研究有力地表明，NAC作为一种预防复发的药物，在短暂的可卡因戒断后是最有效的。在动物实验中，这些积极作用在停用NAC后持续数周。在我们最近的NAC试验中，有一小部分受试者戒断了几天，我们的两种NAC治疗剂量的复发时间都比安慰剂长得多。我们将招募在两个类似的强化门诊项目中接受可卡因依赖治疗的受试者。经知情同意后经uds确认禁欲的潜在受试者将被筛选。在第一阶段，受试者将进入为期一周的开放标签安慰剂阶段，继续监测禁欲，并促进坚持每天两次服用开放标签安慰剂，并参加诊所就诊。在第二阶段，受试者将被随机分配，以平衡性别、共病酒精依赖、吸烟状况和过去30天内基线可卡因使用严重程度（<或≥11天）。为了验证假设一，受试者将参加一项为期八周的试验，每天两次服用1200毫克NAC，或每天两次服用相同外观和气味的安慰剂，持续八周，每周就诊三次。奖励措施将针对药物依从性和诊所出勤率。受试者将参加认知行为疗法（CBT），这是一种标准化的手册驱动的支持性心理治疗，经常用于成瘾药物试验。多个时间对事件的测量将绘制出8周内的禁欲生存分析。为了验证假设二，NAC将在第八周结束时停止，受试者将在接下来的一个月内每周返回。据我们所知，NAC作为人类可卡因成瘾复发预防药物的疗效尚未得到评估。

DESCRIPTION (provided by applicant): This application proposes a double-blind clinical trial to evaluate the efficacy of N-acetylcysteine (NAC) as a relapse prevention agent for the treatment of cocaine dependence. Treatment-seeking cocaine dependent males and females, ages 18 to 70 and of all ethnic and racial backgrounds, will be given informed consent and screened for satisfactory inclusion and exclusion criteria. The study has two working hypotheses. First, NAC will decrease relapse to cocaine use, based on multiple time-to-event measures of relapse in a group of cocaine-dependent individuals with at least 7 days of confirmed abstinence from cocaine before medication initiation. Second, the NAC group will show sustained efficacy over placebo in the 4-week follow-up period after medication is discontinued. The rationale for investigating the efficacy of NAC in the treatment of cocaine addiction was initially based on animal data that pointed to perturbations of glutamatergic brain circuitry after chronic operant exposure to cocaine. NAC ameliorated glutamatergic deficits and inhibited cocaine and cue induced reinstatement of cocaine seeking behaviors. Recent preclinical work strongly suggests that NAC will be most effective as a relapse prevention agent after a brief period of abstinence from cocaine. In animals, these positive effects persist for several weeks after cessation of NAC. In a small subset of subjects entering our recent NAC trial with a few days of abstinence, both of our NAC treatment doses showed substantially longer times to relapse than placebo. We will recruit subjects being treated for cocaine dependence in two similar intensive outpatient programs. Potential subjects with UDS-confirmed abstinence after informed consent will be screened. In Stage 1, subjects will enter a one week open-label placebo phase to continue to monitor abstinence and promote adherence to taking open-label placebo twice daily and attend clinic visits. In Stage 2, subjects will be "urn" randomized to balance for gender, co-morbid alcohol dependence, smoking status and severity of baseline cocaine use (< or >11 days use) in the past 30 days. To test hypothesis one, subjects will participate in an eight week trial of 1200 mg of NAC twice daily or equal-appearing and smelling placebo twice daily for eight weeks with three clinic visits per week. Incentives will be directed at medication adherence and clinic attendance. Subjects will attend cognitive behavior therapy (CBT), a standardized manual driven supportive psychotherapy frequently used in addiction medication trials. Multiple time-to-event measures will plot abstinence survival analyses over the eight weeks. To test hypothesis two, NAC will be discontinued at the end of week eight and subjects will return weekly for one additional month. To our knowledge, NAC has not been evaluated for efficacy as a relapse prevention medication for cocaine addiction in humans.