Kappa Opioid Antagonist for Cocaine Addiction

本研究将评估递增剂量的κ拮抗剂（JD-Tic）的急性安全性、耐受性和口服药代动力学，其起效缓慢（例如4小时，24小时达到峰值），拮抗作用持续时间很长（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，该研究将使用激动剂环佐辛0.8 mg口服沿着纳洛酮（12.5 mg口服）优化kappa激发的参数。Kappa效应包括利尿、烦躁不安、视觉或认知扭曲、镇静、镇痛和对ARCI的PCAG & LSD量表的影响。将使用冷加压和指压试验来评估镇痛，以诱导疼痛。这一试点 在为期一个月的COHORT研究中，将对40名正常受试者进行开放式递增JD-Tic给药。我们预计，在为期4天的住院期和随后的3周门诊期内，当检测这种拮抗作用时，JD-Tic将以剂量相关的方式减弱这些kappa效应。安全性测量包括体格检查、生命体征（BP、HR、RR、体温）和12导联ECG、血液学/血清、生化/尿液分析、认知功能和情感状态（例如抑郁和焦虑）的心理测量测定。将通过症状和不良事件列表分析安全性数据。将单剂量口服JD-Tic给予四个队列的10名正常人：最大耐受动物（灵长类动物）剂量（Mxalone）的15%、30%、45%、60%。考虑到JD-Tic起效缓慢且拮抗作用持续时间很长，将获得药代动力学特征、安全性和疗效评估。在每次给药后，受试者将在住宅环境中保持4天，然后每周两次监测持续的κ拮抗剂效应，持续3周。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% Mxaline）开始。如果在15%和30%剂量下没有κ拮抗作用和最小的副作用或没有副作用发生，则第三组可以在60% Mxaline下运行。最终剂量可高达80%Mxalone。这两项研究共涉及50名正常人，每名COHORT受试者持续4周。本研究中发现的JD-TIC剂量优化将确定后续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.