Mifepristone Treatment for Cocaine Dependence

米非司酮治疗可卡因依赖

基本信息

批准号：
8133491
负责人：
Wilfred Noel Raby
金额：
$ 18.62万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133491
关键词：
Abstinence Address Adrenalectomy Affect Animal Model Anterior Pituitary Gland Attenuated Behavior Binding Brain Catecholamines Characteristics Clinic Clinical Clinical Trials Clonidine Cocaine Cocaine Abuse Cocaine Dependence Cocaine Users Corticotropin Development Double-Blind Method Drug Addiction Drug Combinations Drug Exposure Drug usage Endocrine Environment Event Genetic Genetic Markers Genetic Polymorphism Genotype Glucocorticoid Receptor Glucocorticoids Goals Health Heterozygote Homozygote Human Hydrocortisone Individual Inpatients Intake Ketoconazole Laboratories Laboratory Procedures Laboratory Study Lead Link Long-Term Effects Measurable Measures Mediating Medical Mifepristone Modeling Monitor Moods Neuroendocrinology Opioid Receptor Outpatients Participant Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacological Treatment Phase Physiological Pilot Projects Pituitary-Adrenal System Placebo Control Placebos Procedures Process Protocols documentation RU-486 Randomized Receptor Gene Relapse Reporting Research Personnel Research Technics Risk Rodent Self Administration Steroids Stress Stress Tests Substance Addiction Substance abuse problem Surveys Sympathetic Nervous System System Temperament Testing Time Toxicology Training Trauma Universities Variant Voice addiction arm attenuation beta-Endorphin biological adaptation to stress career cocaine use craving design double-blind placebo controlled trial efficacy testing follow-up genetic analysis high risk inhibitor/antagonist nonhuman primate pre-clinical primary outcome programs receptor response secondary outcome stressor

项目摘要

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.

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的神经内分泌学培训合并，以开发新的物质成瘾治疗方法。哥伦比亚大学滥用药物滥用局已经并且将是一个令人兴奋的环境，以进行本k23中提出的试点研究。它的目标是测试米非酮（中央和外周糖皮质激素受体（GR）拮抗剂）是否可以降低可卡因使用和可卡因依赖性患者的应力敏感性的复发。压力与可卡因滥用有关，在临床调查和报告中，减少压力对可卡因使用的永久影响的措施可能代表了新的治疗途径。人类压力的实验室模型可靠地再现可卡因依赖性个体的可测量应力参数。此外，应力引起的可卡因渴望与更高的复发风险相关。我们假设通过用米非酮阻止GR，复发的风险将减少。我们将在三个阶段方案中检验该假设：第1阶段是5至7天的住院期，以诱导戒酒和执行基线应力敏感性测试。第2阶段是4周门诊，随机，双盲，安慰剂对照阶段，在此期间，患者参加诊所3倍/周的药物治疗（米非司酮600 mg vs.安慰剂），医疗监测，治疗和毒理学测试。第3阶段是类似于第2阶段的4周随访门诊期，但没有药物摄入量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测试。主要结果是时候复发到可卡因使用（从第1阶段的结束开始），其中次级结果是米非司酮前后的应力敏感性，以查看米非司酮是否通过对应激敏感性的效应来介导米非司酮的势能。所有参与者将在0PRM1受体处拟对Al 18G多态性进行基因分型，当结合β-内啡肽结合时，会介导前垂体上ACTH释放的强直抑制作用。由于Al 18G影响β内啡肽结合效力，因此它可能是应力敏感性的重要遗传标记。公共卫生相关性：没有对可卡因依赖的验证功效的药理治疗方法。由于经常将压力作为持续使用可卡因的原因，因此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。