Kappa Opioid Antagonist for Cocaine Addiction

用于治疗可卡因成瘾的 Kappa 阿片类药物拮抗剂

• 批准号: 7495038
• 负责人: THOMAS Richard KOSTEN
• 金额: $ 43.99万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495038
• 关键词: Absence of pain sensation; Acute; Adverse effects; Adverse event; Adverse reactions; Affective; Agonist; Analgesics; Animals; Anxiety; Attenuated; Chemistry; Clinical Trials; Cocaine; Cocaine Dependence; Cognitive; Cyclazocine; Data; Diuresis; Dose; Drug Kinetics; Dynorphins; Fingers; Goals; Hematology; Hour; Human; Investigation; Measurement; Measures; Mental Depression; Monitor; Naltrexone; Narcotic Antagonists; Opioid; Oral; Outpatients; Pain; Participant; Pentazocine; Personal Satisfaction; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physical Examination; Primates; Protocols documentation; Psychometrics; Purpose; Research; Running; Safety; Sedation procedure; Series; Serum; Substance Addiction; Symptoms; Temperature; Testing; Time; Treatment outcome; Urinalysis; Visual; Week; cognitive function; cohort; day; dosage; dysphoria; improved; kappa opioid receptors; oral tolerance; pressure

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.

这项研究将评估Kappa拮抗剂（JD-TIC）不断升级剂量的急性安全性，耐受性和口服药代动力学，该剂量的发作缓慢（例如4小时，峰值为24小时，峰值为24小时），拮抗作用持续时间很长（例如，21-28天）。为了评估Kappa拮抗作用，我们将在4天的住宅试点研究中从10名受试者开始，该研究将使用激动剂壳callazocine和Naltrexone（12.5 mg口服）优化Kappa挑战的参数。 Kappa效应包括利尿，吞咽困难，视觉或认知失真，镇静，镇痛以及对ARCI的PCAG和LSD量表的影响。镇痛将使用冷压力和手指压力测试评估以诱发疼痛。这个飞行员 在一个月的队列研究中，将有40名正常受试者，并进行开放，不断升级的JD-TIC剂量。我们期望JD-TIC在4天的住宅阶段对这种拮抗作用进行测试，随后为3周的门诊阶段对这种拮抗作用，以相关的方式减弱这些KAPPA效应。安全测量包括体格检查，生命体征（BP，HR，RR，温度）和12铅ECG，血液学/血清，化学/尿液学，认知功能和情感状态（例如抑郁和焦虑）的心理测定测定。安全数据将通过症状和不良事件的列表来分析。单剂量的口服JD-TIC给出了四个同类的10个正常人，为：15％，30％，45％，60％的最大耐受性动物（灵长类动物）剂量（MXTAD）。考虑到JD-TIC的缓慢发作和较长的拮抗持续时间，将获得药代动力学特征，安全性和功效评估。在每个剂量会话后将在住宅环境中进行4天，然后每周两次监测Kappa拮抗剂效应。在第一个队列完成后，第二个队列将从下一个最高剂量开始（例如30％Mxtad）。如果没有Kappa拮抗作用，并且在15％和30％的剂量下，则第三个队列可以以60％的MXTAD运行，如果没有Kappa的拮抗作用，并且最小或没有副作用发生。然后，最终剂量可能高达80％Mxtad。这两项研究共同涉及50个正常，并且每个队列受试者持续4周。本研究中发现的JD-TIC剂量优化将确定随后的可卡因给药研究的给药。