A Controlled Trial of NAC for Cocaine Dependence

NAC 治疗可卡因依赖的对照试验

• 批准号: 7237865
• 负责人: Robert James Malcolm
• 金额: $ 43.61万
• 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 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7237865
• 关键词: Acetaminophen; Acetylcysteine; Acidic Amino Acid Transport Systems; Adverse effects; Advertisements; Allergic Reaction; Behavioral; Binding; Cell membrane; Chemistry; Clinic; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Cognitive Therapy; Communities; Condition; Coupled; Creatinine; Cues; Cysteine; Cystic Fibrosis; Cystine; Daily; Data; Dialysis procedure; Dose; Double-Blind Method; Drops; Electrocardiogram; Electroencephalogram; Ensure; Equilibrium; Female; Frequencies; Glutamates; Hematology; Human; Individual; Laboratories; Manuals; Measurement; Measures; Molecular; National Institute of Drug Abuse; Nucleus Accumbens; Numbers; Oral; Oral cavity; Outcome Measure; Overdose; Patient Self-Report; Personal Satisfaction; Pharmaceutical Preparations; Pharmacological Treatment; Phase II Clinical Trials; Physical Dialysis; Physical assessment; Physicians; Placebos; Population Study; Preclinical Drug Evaluation; Prefrontal Cortex; Procedures; Prodrugs; Randomized; Rate; Recruitment Activity; Relative (related person); Research; Research Personnel; Safety; Score; Severities; Skin; Slide; Sodium; Standards of Weights and Measures; Stimulus; Stratification; Suggestion; Synapses; Time; Treatment outcome; United States Food and Drug Administration; Urine; Ventral Tegmental Area; Visual; Week; Withdrawal; Withdrawal Symptom; addiction; analog; antiporter; base; craving; day; experience; extracellular; in vivo; instrument; intraperitoneal; male; placebo controlled study; pre-clinical; preclinical study; programs; psychosocial; racial and ethnic; relating to nervous system; response; trend

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）：尽管进行了二十多年的研究，但仍没有有效的药物治疗可卡因依赖。临床前研究已经阐明了伏核、腹侧被盖区和前额皮质中谷氨酰胺能和多巴胺能回路的重要性。这些研究表明，重复服用可卡因会减少突触谷氨酸。大多数突触谷氨酸来自非囊泡释放，特别是来自半胱氨酸/谷氨酸逆向转运蛋白。该交换器是质膜结合的钠依赖性阴离子氨基酸转运蛋白，其将细胞外胱氨酸交换为细胞内谷氨酸。重复服用可卡因会损害胱氨酸谷氨酸交换器，降低细胞外谷氨酸水平。半胱氨酸的反向透析可恢复伏隔核中降低的基础谷氨酸水平。全身给予半胱氨酸前体药物，如 N-乙酰半胱氨酸 (NAC) 也可使细胞外谷氨酸正常化，并阻止可卡因的行为恢复。 MAC 已获得 FDA 批准用于治疗囊性纤维化和对乙酰氨基酚过量。 我们研究了 13 名未寻求治疗的可卡因依赖受试者，他们每天口服两次 600 毫克 NAC，并测量了副作用、耐受性、自我报告的可卡因渴望、可卡因戒断症状和提示反应性的电生理测量。 NAC 和安慰剂之间的副作用数量没有差异 (p=0.29)。渴望评级表明，当受试者接受 NAC 治疗时，渴望下降 (p=0.05)，而安慰剂受试者的渴望并未显着下降。根据可卡因严重程度评估的测量，NAC 显​​着减轻了可卡因戒断症状 (p<0.05)。在提示反应范式中，受试者对可卡因和中性幻灯片表现出类似的反应；在安慰剂条件下，受试者对可卡因的反应水平高于中性刺激（p=0.052）。 令人信服的临床前分子和行为研究支持使用 NAC 来治疗可卡因依赖。我们有初步的人体实验室数据表明 NAC 可以减少渴望、可卡因戒断症状以及可能的皮肤电导提示反应性。我们已收到 FDA 的 IND 申请，开展 NAC 联合认知行为疗法 (CBT) 治疗可卡因依赖的双盲 II 期试验。该提案的主要目标包括：1) 通过自我报告和评估，确定口服两种剂量的 NAC（1200、2400 毫克）联合 CBT 与安慰剂和 CBT 治疗可卡因依赖（N=282）的疗效。通过定量尿液药物筛查进行验证； 2) 确定 NAC 与安慰剂的安全性； 3) 研究服用 NAC 或安慰剂的受试者的可卡因渴望/提示反应和戒断症状。