Kappa Opioid Antagonist for Cocaine Addiction

可卡因滥用/依赖仍然是一个重大的社会和公共卫生问题，对相当数量的可卡因依赖者来说，目前的治疗干预措施无效。寻找一种治疗可卡因滥用的药物疗法是一个重要但难以实现的目标。该项目的主要目的是提供通过SPIRDAP机制开发的用于治疗可卡因依赖的口服活性、缓效、长效kappa拮抗剂JDTic的安全性数据。在这项研究项目启动之前，将在患有JDTic的正常人志愿者身上进行毒性和药代动力学研究(项目3 Kosten)。还必须确定JDTic在有大剂量可卡因滥用史的个人中的安全性(目标1)。此外，由于接受治疗可卡因依赖药物的个人很可能会继续服用可卡因，特别是在治疗的早期，因此必须确定这种药物组合是否会产生任何不良反应(目标2)。在这个项目中，将招募将在住院病房总共居住33天的可卡因依赖志愿者。将在每一次可卡因给药测试期间测量生理和主观影响，以评估联合使用的效果。为了评估JDTic在这一人群中的效果，每天将定期进行Kosten开发的不良事件症状问卷、Tiffany渴望问卷和抑郁症心理症状问卷的测试。研究前后将进行体格检查、心电图和实验室检查。此外 为了提供安全数据，这项研究还可能产生暗示潜在的信息 JDTic的疗效。动物数据表明，KOR拮抗剂，如JDTic，可减弱：应激诱导的可卡因反应恢复；增强可卡因产生地点偏爱的能力；以及强迫游泳测试大鼠的静止。因此，JDTic可以减轻导致试图戒除可卡因使用的个人复发的两个主要因素(压力和抑郁)(目标3)。如果在这些安全性研究中没有发现重大不良事件，则有必要研究JDTic对人类研究志愿者压力诱导的渴求的影响，并在可卡因依赖治疗寻求者的临床试验中作为预防复发的药物。

Cocaine abuse/dependence remains a major social and public health problem and for a significant number of cocaine dependent individuals, current treatment interventions are ineffective. Finding a pharmacological treatment for cocaine abuse is an important yet elusive goal. The primary purpose of this project is to provide safety data on an orally active, slow onset, long-acting kappa antagonist, JDTic, being developed through the SPIRDAP mechanism for the treatment of cocaine dependence. Prior to the initiation of this research project, toxicity and pharmacokinetic studies will have been carried out in normal human volunteers with JDTic (Project 3 Kosten). The safety of JDTic in individuals with a history of high dose cocaine abuse must also be determined (Aim 1). In addition, because it is likely that individuals receiving a medication for the treatment of cocaine dependence will continue to take cocaine, particularly early in treatment, it is essential to determine whether this drug combination produces any adverse reactions (Aim 2). In this project, cocaine dependent volunteers who will remain on an inpatient unit for a total of 33 days will be recruited. Physiological and subjective effects will be measured during each cocaine administration test session to assess the effects of the combination. To assess the effects of JDTic in this population, an adverse event symptom questionnaire developed by Kosten, the Tiffany craving questionnaire, and psychological symptom questionnaires of depression will be administered at regular intervals each day. Physicals, EKGs and laboratory tests will be done before and after the study. In addition to providing safety data, this research might also yield information suggestive of the potential efficacy of JDTic. Animal data have shown that KOR antagonists, such as JDTic, attenuate: stress-induced reinstatement of cocaine responding; the potentiation of cocaine's ability to produce place preference, and immobility of rats subjected to a forced swim test. Thus, JDTic may attenuate two of the major factors (stress and depression) that lead to relapse in individuals attempting to abstain from cocaine use (Aim 3). If no significant adverse events are found in these safety studies, studies of the effects of JDTic on stress-induced craving in human research volunteers and as a relapse prevention medication in clinical trials in cocaine dependent treatment seekers are warranted.