New Medication Treatments for Stimulant Dependence

治疗兴奋剂依赖的新药物治疗

• 批准号: 7313772
• 负责人: NASSIMA AIT-DAOUD
• 金额: $ 60.57万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313772
• 关键词: Abstinence; Acute; Address; Amphetamines; Anterior; Behavioral; Brain Stem; Brain region; Cerebrovascular Circulation; Chronic; Clinical; Clinical Data; Cocaine; Cocaine Dependence; Cognitive Therapy; Daily; Data; Dopamine; Dopamine Receptor; Double-Blind Method; Female; Funding; Human; Individual; Intake; Laboratories; Laboratory Study; Measurable; Mediating; Mediator of activation protein; Medicine; Mission; Neurons; Numbers; Ondansetron; Outcome; Patient Self-Report; Personal Satisfaction; Pharmaceutical Preparations; Pilot Projects; Placebos; Psychological reinforcement; Psychostimulant dependence; Quality of life; Randomized; Randomized Controlled Trials; Relapse; Research Personnel; Self Administration; Serotonin; Serotonin Receptors 5-HT-3; Signal Transduction; Social Functioning; Specimen; Testing; Therapeutic; Translating; Urine; Week; Withdrawal; Withdrawal Symptom; Work; behavioral sensitization; benzoylecgonine; concept; craving; day; improved; male; neurochemistry; pre-clinical; preclinical study; preference; programs; psychosocial; psychostimulant; restoration

DESCRIPTION (provided by applicant): Cortico-mesolimbic dopamine (CM-DA) function is the primary neurochemical mediator of cocaine reinforcement. Serotonin-3 (5-HT3) receptors modulate CM-DA function. Preclinical studies show that 5-HT3 antagonists decrease CM-DA receptor-mediated effects, including hyperlocomotion. 5-HT3 antagonists decrease cocaine-induced behavioral sensitization and tolerance and decrease self-administration, particularly in acute withdrawal states. In humans, ondansetron-pretreated individuals compared with controls show increased neuronal activation and right cerebral blood flow (rCBF). Taken together, it is, therefore, reasonable to hypothesize that ondansetron can be used to aid the restoration of normative dopamine (DA) function during the period of recent withdrawal from cocaine use, thereby decreasing the potential for relapse to drug taking once abstinence has been achieved. Human laboratory studies also show that ondansetron reduces preference for psychostimulants, including cocaine and amphetamine. Further, in a NIDA-funded randomized, double-blind, pilot study (N = 16 subjects/group) to detect a therapeutic signal for ondansetron (0.25, 1.0, and 4.0 mg b.i.d.) vs. placebo, we showed that ondansetron 4 mg b.i.d. was significantly more efficacious at increasing the weekly proportion of cocaine-free urine specimens. Hence, human laboratory and initial clinical data provide compelling evidence for the proposition that ondansetron is an efficacious treatment for cocaine dependence. As a proof-of-concept of our hypothesis, we propose to establish whether ondansetron can aid in reducing or ceasing cocaine use among currently using cocaine dependent individuals. We will do a randomized controlled trial in which subjects receive either ondansetron (4 mg b.i.d.) or placebo (N = 100 subjects/group * 2 groups = 200) as an adjunct to standardized weekly cognitive behavioral therapy (CBT) and Brief Behavioral Compliance Enhancement Treatment (BBCET) for 8 weeks. Our primary aims are to test two predictions of our hypothesis: 1) ondansetron will be superior to placebo at increasing the weekly proportion of cocaine-free (abstinent) days (assessed by a combination of self-reported use and urine analysis for benzoylecgonine, the major metabolite of cocaine), and 2) ondansetron will be superior to placebo at increasing the weekly mean proportion of subjects with cocainefree urines. Our secondary aim is to test whether: 1) ondansetron will be superior to placebo at decreasing cocaine craving, and these reductions in cocaine craving will be associated with decreased cocaine intake, and 2) ondansetron is superior to placebo at improving psychosocial functioning and quality of life, and specific reductions in cocaine use translate to general and measurable improvements in clinical functioning. This study supports the work of a new investigator to address NIDA's mission to develop safe and efficacious medicines for the treatment of cocaine dependence.

描述（由申请人提供）：皮质中脑边缘多巴胺（CM-DA）功能是可卡因强化的主要神经化学介质。 5-羟色胺-3 (5-HT3) 受体调节 CM-DA 功能。临床前研究表明，5-HT3 拮抗剂可降低 CM-DA 受体介导的作用，包括过度运动。 5-HT3 拮抗剂可降低可卡因诱导的行为敏感性和耐受性，并减少自我给药，特别是在急性戒断状态下。在人类中，与对照组相比，接受昂丹司琼预处理的个体显示出神经元激活和右脑血流量（rCBF）增加。因此，综上所述，可以合理地假设昂丹司琼可用于在最近戒除可卡因使用期间帮助恢复正常的多巴胺（DA）功能，从而降低戒断后复发吸毒的可能性。人体实验室研究还表明，昂丹司琼降低了对精神兴奋剂的偏好，包括可卡因和安非他明。此外，在一项由 NIDA 资助的随机、双盲、初步研究（N = 16 名受试者/组）中，检测昂丹司琼（0.25、1.0 和 4.0 mg b.i.d.）与安慰剂相比的治疗信号，我们发现昂丹司琼 4 mg b.i.d.在增加每周不含可卡因的尿液样本的比例方面显着更有效。因此，人类实验室和初始临床数据为昂丹司琼是治疗可卡因依赖的有效方法这一主张提供了令人信服的证据。作为我们假设的概念验证，我们建议确定昂丹司琼是否有助于减少或停止目前使用可卡因依赖者的可卡因使用。我们将进行一项随机对照试验，其中受试者接受昂丹司琼（4 mg b.i.d.）或安慰剂（N = 100 名受试者/组 * 2 组 = 200）作为标准化每周认知行为治疗 (CBT) 和简短行为依从性增强治疗 (BBCET) 的辅助疗法，为期 8 周。我们的主要目的是检验我们假设的两个预测：1) 昂丹司琼在增加每周无可卡因（戒断）天数的比例方面优于安慰剂（通过结合自我报告的使用情况和苯甲酰爱康宁（可卡因的主要代谢物）尿液分析进行评估），2) 昂丹司琼在增加每周无可卡因（戒断）天数的受试者的平均比例方面优于安慰剂。 不含可卡因的尿液。我们的次要目的是测试：1）昂丹司琼在降低可卡因渴望方面是否优于安慰剂，并且可卡因渴望的减少与可卡因摄入量的减少有关；2）昂丹司琼在改善心理社会功能和生活质量方面优于安慰剂，可卡因使用的具体减少转化为临床功能的一般和可测量的改善。这项研究支持一位新研究者的工作，以实现 NIDA 的使命：开发安全有效的药物来治疗可卡因依赖。