A Controlled Trial of NAC for Cocaine Dependence

NAC 治疗可卡因依赖的对照试验

• 批准号: 6956202
• 负责人: Robert James Malcolm
• 金额: $ 41.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956202
• 关键词: acetylcysteine; behavioral /social science research tag; clinical research; clinical trial phase II; cocaine; cognitive behavior therapy; combination therapy; craving; cues; drug abuse chemotherapy; drug addiction; drug addiction antagonist; drug adverse effect; drug screening /evaluation; drug withdrawal; human subject; human therapy evaluation; patient oriented research; questionnaires; urinalysis

DESCRIPTION (provided by applicant): There is no effective pharmacological treatment for cocaine dependence despite over two decades of research. Pre-clinical studies have elucidated the importance of glutaminergic and dopaminergic circuits among the nucleus accumbens, ventral tegmental area, and prefrontal cortex. These studies have indicated that repeated cocaine administration reduces synaptic glutamate. Most synaptic glutamate arises from nonvesicular release, and specifically from the cysteine/glutamate antiporter. This exchanger is a plasma membrane-bound sodium dependent anionic amino acid transporter that exchanges extra cellular cystine for intra cellular glutamate. Repeated cocaine administration impairs the cystine glutamate exchanger, lowering extracellular glutamate levels. Reverse dialysis of cysteine restores diminished basal glutamate levels in the nucleus accumbens. Systemic administration of cysteine pro drugs such as N-acetylcysteine (NAC) also normalizes extracellular glutamate and blocks behavioral reinstatement by cocaine. MAC is FDA-approved for the treatment of cystic fibrosis and acetaminophen overdose. We studied 13 non-treatment seeking cocaine dependent subjects who were given 600 mg of NAC orally twice daily and measured side effects, tolerability, self-reported cocaine craving, cocaine withdrawal symptoms, and electrophysiologic measures of cue reactivity. Number of side effects did not differ between NAC and placebo (p=0.29). Craving ratings suggested that when subjects were treated with NAC, cravings dropped (p=0.05) while placebo subjects did not show a significant drop in craving. NAC significantly reduced cocaine withdrawal symptoms as measured by the Cocaine Severity Assessment (p<0.05). In the cue reactivity paradigm, subjects showed comparable responses to both cocaine and neutral slides; in the placebo condition, subjects showed a higher level of responding to cocaine relative to neutral stimuli (p=0.052). Convincing pre-clinical molecular and behavioral studies support the use of NAC to treat cocaine dependence. We have preliminary human laboratory data suggesting that NAC reduces craving, cocaine withdrawal symptoms, and possibly skin conductance cue reactivity. We have received an IND from the FDA to conduct a double blind, phase II trial of NAC plus cognitive-behavioral therapy (CBT) in the treatment of cocaine dependence. The primary objective to this proposal include: 1) to determine the efficacy of two doses (1200, 2400 mg) of NAC orally with CBT as compared to placebo and CBT in treating cocaine dependence (N=282) as measured by self-report and validated by quantitative urine drug screens; 2) to determine the safety of NAC vs. placebo; and 3) to study cocaine craving/cue reactivity and withdrawal symptoms in subjects taking NAC or placebo.

描述（由申请人提供）：尽管研究了二十年，但仍没有有效的可卡因依赖药理治疗方法。临床前的研究阐明了伏隔核，腹侧盖区和前额叶皮层对谷氨酰胺能和多巴胺能回路的重要性。这些研究表明，重复的可卡因给药减少了突触谷氨酸。大多数突触谷氨酸源是非抗性释放，特别是来自半胱氨酸/谷氨酸抗植物。该交换剂是质膜结合的钠依赖性阴离子氨基酸转运蛋白，可将细胞外的胱氨酸交换为细胞内谷氨酸。可卡因的重复给药会损害胱氨酸谷氨酸交换器，从而降低细胞外谷氨酸水平。半胱氨酸的反向透析恢复了伏隔核中基底谷氨酸水平降低。半胱氨酸Pro药物（例如N-乙酰半胱氨酸（NAC））的全身性给药也使细胞外谷氨酸归一化，并阻止可卡因的行为恢复。 MAC经FDA批准用于治疗囊性纤维化和对乙酰氨基酚的过量。 我们研究了13个寻求可卡因依赖性受试者的非治疗方法，他们每天两次口服600 mg NAC，并测量的副作用，耐受性，自我报告的可卡因渴望，可卡因戒断症状以及提示反应性的电生理学测量值。 NAC和安慰剂之间的副作用数量没有差异（P = 0.29）。渴望等级表明，当受试者用NAC处理时，渴望下降（P = 0.05），而安慰剂受试者并未显示出明显的渴望下降。 NAC可显着减少可卡因戒断症状，​​如可卡因严重程度评估所测量（P <0.05）。在提示反应性范式中，受试者对可卡因和中性载玻片的反应都具有可比的反应。在安慰剂条件下，相对于中性刺激，受试者对可卡因的反应水平更高（p = 0.052）。 令人信服的临床前分子和行为研究支持使用NAC治疗可卡因依赖性。我们有初步的人类实验室数据，表明NAC可减少渴望，可卡因戒断症状以及可能的皮肤电导提示反应性。我们已经从FDA获得了IND，以在可卡因依赖性治疗中进行NAC加认知行为疗法（CBT）的双盲，II期试验。该提案的主要目的包括：1）确定与安慰剂和CBT在治疗可卡因依赖性（n = 282）相比，用CBT和CBT确定两种剂量（1200，2400 mg）的疗效。通过定量尿液药物筛查验证； 2）确定NAC与安慰剂的安全； 3）研究可卡因渴望/提示反应性和戒断症状的受试者或安慰剂的戒断症状。