Kappa Opioid Antagonist for Cocaine Addiction

这项研究将评估Kappa拮抗剂(JD-Tic)剂量递增的急性安全性、耐受性和口服药代动力学，该药起效缓慢(例如，4小时，高峰在24小时)，拮抗持续时间很长(例如，21-28天)。为了评估kappa拮抗作用，我们将从10名受试者开始，进行为期4天的住宅试点研究，该研究将优化kappa挑战的参数，使用激动剂环氮唑新0.8毫克和纳曲酮(12.5毫克口服)。Kappa效应包括利尿、烦躁不安、视觉或认知扭曲、镇静、止痛以及ARCI对PCAG和LSD量表的影响。将通过冷加压和指压试验来评估止痛效果。这位飞行员 在为期一个月的队列研究中，40名正常受试者将接受为期一个月的开放的JD-Tic剂量递增研究。我们希望JD-Tic在为期4天的住院阶段和随后3周的门诊阶段进行这种拮抗测试时，以一种与剂量相关的方式减弱这些kappa效应。安全测量包括体检、生命体征(BP、HR、RR、体温)和12导联心电图、血液学/血清、化学/尿液分析、认知功能和情感状态(例如抑郁和焦虑)的心理测量。安全数据将通过症状和不良事件的表格进行分析。10名正常人的4个队列分别口服单剂JD-Tic：最大耐受量(MxTAD)的15%、30%、45%、60%。考虑到JD-Tic的缓慢起效和非常长的拮抗持续时间，将获得药代动力学、安全性和有效性评估。每次给药后，受试者将在住宅环境中保持4天，然后进行为期3周的每周两次监测，以观察持续的kappa拮抗剂效果。在第一个队列完成后，第二个队列将以下一个最高剂量(例如30%MxTAD)开始。如果在15%和30%的剂量下没有卡帕拮抗和最小或没有副作用，第三个队列可以运行在60%的MxTAD。最终剂量可能高达80%的MxTAD。这两项研究总共涉及50名正常人，每个队列受试者持续时间长达4周。这项研究中发现的JD-TIC剂量优化将决定随后的可卡因给药研究的剂量。

This investigation will assess the acute safety, tolerance, and oral pharmacokinetics of escalating dosages of a kappa antagonist (JD-Tic), which has a slow onset (e.g. 4 hours with a peak at 24 hours) and very long duration of antagonism (e.g. 21-28 days). To assess kappa antagonism we will start with 10 subjects in a 4- day residential PILOT STUDY that will optimize the parameters of a kappa challenge using the agonist cyclazocine 0.8 mg orally along with naltrexone (12.5 mg oral). The kappa effects include diuresis, dysphoria, visual or cognitive distortion, sedation, analgesia and effects on the PCAG & LSD scales from the ARCI. Analgesia will be assessed using cold pressor and finger pressure tests to induce pain. This PILOT will be followed by 40 normal subjects in a month long COHORT STUDY with open, escalating JD-Tic dosing. We expect JD-Tic to attenuate these kappa effects in a dose related way when tested for this antagonism during a 4-day residential phase followed by a 3-week outpatient phase. Safety measurements include physical examinations, vital signs (BP, HR, RR, temperature) and 12-lead ECGs, hematology/serum, chemistry/urinalyses, psychometric determinations of cognitive function and affective state (e.g. depression and anxiety). Safety data will be analyzed by tabulation of symptoms and adverse events. A single dose of oral JD-Tic is given to four cohorts of 10 normals as: 15%, 30%, 45%, 60% of the maximally tolerated animal (primate) dose (MxTAD). Pharmacokinetic profiles, safety and efficacy assessments will be obtained taking into consideration JD-Tic's slow onset and very long duration of antagonism. After each dosage session subjects will be kept in a residential setting for 4 days followed by 3 weeks of twice weekly monitoring for continued kappa antagonist effects. After completion of the first cohort, the second will be started at the next highest dose (e.g. 30% MxTAD). The third cohort may be run at 60% MxTAD, if no kappa antagonism and minimal or no side effects occur at the 15% and 30% dosages. The final dosage may then be as high as 80% MxTAD. The two studies together involve 50 normals and lasts upto 4 weeks per COHORT subject. The JD-TIC dose optimization found in this study will determine dosing for the subsequent cocaine administration study.