NEW STRATEGIES FOR ANTICOCAINE MEDICATIONS

申请人摘要： 本申请是根据NIDA RFA DA-96-002，Strategic 可卡因成瘾药物治疗创新研究计划 (SPIRCAP)。我们提出了一系列整合的临床前和临床 旨在识别新的抗可卡因药物并评估 可卡因治疗的激动剂和拮抗剂途径 上瘾。四个相互关联的研究项目(在五个月进行 独立网站)将专注于药物化学、临床前行为 药理学、临床前心血管生理学和住院临床 评估。研究计划将通过行政管理部门进行管理 核心，一个SPIRCAP指导委员会将指导整个计划 指导和确保组件项目和 MDD/NIDA合作研究协议(U19)。 我们建议对两类小说的安全性和有效性进行评估 抗可卡因药物：(1)全部和部分多巴胺D1激动剂，以及 (2)kappa类阿片激动剂。完全的多巴胺D1激动剂模仿一些行为 可卡因的影响，并将允许检查 “替代-激动剂”的治疗理念。部分多巴胺D1激动剂和 Kappa阿片激动剂阻断可卡因和Will的一些行为效应 允许对“拮抗者”治疗概念进行评估。这两种类型的 药物将在相同的条件下进行平行研究进行评估 条件。首先，每种药物的慢性治疗对 静脉注射。将在恒河猴身上检查可卡因和食物自我管理 猴子。不同剂量的治疗药物对慢性阻塞性肺疾病的影响 将研究可卡因的剂量-效应曲线。随后，每一次治疗 将在可卡因自我给药的累进比率测试中进行检查 目的：确定药物对可卡因增强效果的影响。自.以来 可卡因具有潜在的致命性心脑血管毒性， 行为有效的治疗药物的安全性，单独和在 与可卡因的结合，也将在临床前研究中进行 心血管生理学。这些临床前评估的结果 安全性和有效性将决定新药的顺序 在临床实验室研究中进行检查。 新疗法的临床评估将需要申请IND 提交给FDA进行安全性和有效性研究。我们建议检查单次剂量 在住院研究中每一种有希望的新治疗药物 临床研究病房条件受控。生理的、主观的 每种治疗的神经内分泌效应将单独和 在单盲条件下，与两剂可卡因联合使用。 这些为期5天的住院研究的结果将确定可行性 进行为期30天的研究，以评估慢性疾病的影响 每一种新型治疗方法的管理。这是一个全面的、集成的 研究计划将确定最安全和有效的药物治疗 可卡因的治疗及其抗可卡因的基本机制 行为。

APPLICANT'S ABSTRACT: This application was submitted in response to NIDA RFA DA-96-002, Strategic Program for Innovative Research on Cocaine Addiction Pharmacotherapy (SPIRCAP). We propose a series of integrated preclinical and clinical studies designed to identify novel anti-cocaine medications and to evaluate both agonist and antagonist approaches to the treatment of cocaine addiction. Four inter-related research projects (conducted at five independent sites) will focus on medicinal chemistry, preclinical behavioral pharmacology, preclinical cardiovascular physiology and inpatient clinical evaluations. The research program will be managed through an Administrative Core, and a SPIRCAP Steering Committee will guide the overall program direction and ensure communication between the component projects and MDD/NIDA in a cooperative study agreement (U19). We propose to evaluate the safety and efficacy of two classes of novel anti-cocaine medications: (1) full and partial dopamine D1 agonists, and (2) kappa opioid agonists. Full dopamine D1 agonists mimic some behavioral effects of cocaine and will allow an examination of the "substitution-agonist" concept of therapy. Partial dopamine D1 agonists and kappa opioid agonists block some behavioral effects of cocaine and will allow an evaluation of the "antagonist" concept of therapy. Both types of medications will be evaluated in parallel studies conducted under identical conditions. First, the effects of chronic treatment with each medication on i.v. cocaine and food self-administration will be examined in rhesus monkeys. The effect of a range of doses of the treatment medications on cocaine dose-effect curves will be studied. Subsequently, each treatment will be examined in progressive ratio tests of cocaine self-administration to determine medication effects on cocaine's reinforcing efficacy. Since cocaine has potentially lethal cardiovascular and cerebrovascular toxicity, the safety of behaviorally effective treatment medications, alone, and in combination with cocaine, also will be examined in preclinical studies of cardiovascular physiology. The results of these preclinical evaluations of safety and efficacy will determine the sequence of novel medications examined in clinical laboratory studies. Clinical evaluation of novel treatments will require application for an IND to FDA for safety and efficacy studies. We propose to examine single doses of each promising novel treatment medication in inpatient studies under controlled clinical research ward conditions. The physiological, subjective and neuroendocrine effects of each treatment will be evaluated, alone, and in combination with two doses of cocaine, under single-blind conditions. The results of these 5-day inpatient studies will determine the feasibility of conducting 30-day studies to evaluate the effects of chronic administration of each novel treatment. This comprehensive, integrated research program will identify the most safe and effective medication for cocaine treatment and suggest the basic mechanisms of its anti-cocaine actions.