Mifepristone Treatment for Cocaine Dependence

描述（由申请人提供）：我的职业目标是研究如何将实验室和临床试验研究技术与我在神经内分泌学方面的培训相结合，以开发药物成瘾的新疗法。哥伦比亚大学药物滥用司一直是并将是开展本K23中提议的试点研究的一个激励环境。其目的是测试米非司酮，一种中枢和外周糖皮质激素受体（GR）拮抗剂，是否可以减少可卡因依赖患者对可卡因使用的复发和应激敏感性。临床调查和报告显示，精神压力与可卡因滥用有关，采取措施减少精神压力对可卡因使用的长期影响，可能是一种新的治疗途径。人类压力的实验室模型可靠地再现了可卡因依赖个体的可测量压力参数;此外，压力诱导的可卡因渴望与更高的复发风险相关。我们推测，通过米非司酮阻断GR，复发的风险将降低。我们将在三个阶段的方案中测试这一假设：第一阶段是5至7天的住院期，以诱导禁欲并进行基线压力敏感性测试。第2阶段是一个为期4周的门诊、随机、双盲、安慰剂对照阶段，在此期间，患者每周3次前往诊所接受药物治疗（米非司酮600 mg vs.安慰剂）、医学监测、治疗和毒理学测试。第3阶段是一个为期4周的随访门诊阶段，类似于第2阶段，但没有药物摄入，以测试米非司酮的长期影响。在第3阶段结束时重复应力敏感性试验。主要结果将是可卡因使用复发的时间（第1阶段结束后的天数），次要结果是米非司酮前后的压力敏感性，以观察米非司酮的潜在作用是否通过对压力敏感性的影响来介导。将对所有参与者在OPRM 1受体处的A118 G多态性进行基因分型，OPRM 1受体在结合β内啡肽时介导垂体前叶处ACTH释放的紧张性抑制。由于A118 G影响β内啡肽结合效力，因此它可能是应激敏感性的重要遗传标记。公共卫生相关性：目前尚无有效的药物治疗来治疗可卡因依赖。由于压力经常被认为是持续使用可卡因的原因，直接影响大脑和身体压力机制的药物可以为可卡因和其他药物成瘾提供新的治疗方法。

DESCRIPTION (provided by applicant): My career goal with this application is to study how laboratory and clinical trial research techniques be merged with my training in neuroendocrinology to develop new treatments for substance addictions. The Division on Substance Abuse at Columbia University has been and would be a stimulating environment to carry out the pilot study proposed in this K23. Its goal is to test if mifepristone, a central and peripheral glucocorticoid receptor (GR) antagonist, can decrease relapse to cocaine use and stress sensitivity in cocaine dependent patients. Stress is implicated in cocaine abuse in clinical surveys and reports, and measures to reduce the perpetuating effect of stress on cocaine use could represent a new treatment avenue. Laboratory models of stress in humans have reliably reproduced measurable stress parameters in cocaine dependent individuals; moreover, stress induced cocaine cravings have been correlated with a higher risk of relapse. We hypothesize that by blocking the GR with mifepristone, the risk of relapse will diminish. We will test this hypothesis during a three phase protocol: phase 1 is a 5 to 7 day inpatient phase to induce abstinence and perform baseline stress-sensitivity testing. Phase 2 is a 4 week outpatient, randomized, double-blind, placebo-controlled phase during which patients attend the clinic 3x/week for medication (mifepristone 600 mg vs. placebo), medical monitoring, therapy, and toxicology testing. Phase 3 is a 4 week follow-up outpatient phase similar to phase 2, but without medication intake to test the long term effects of mifepristone. Stress sensitivity testing is repeated at the end of phase 3. The primary outcome will be time to relapse to cocaine use (days from end of phase 1), with secondary outcomes being stress sensitivity before and after mifepristone to see if mifepristone's potential effect is mediated through an effect on stress sensitivity. All participants will be genotyped for the Al 18G polymorphism at the 0PRM1 receptor, which, when binding beta endorphin, mediates tonic inhibition of ACTH release at the anterior pituitary. As Al 18G affects beta endorphin binding potency, it may be an important genetic marker of stress sensitivity. PUBLIC HEALTH RELEVANCE: No pharmacological treatments of proven efficacy exist to treat cocaine dependence. As stress is frequently cited as a cause of continued cocaine use, medications that directly affect the brain and body's stress mechanisms could provide new treatments for cocaine and other drug addictions.