PHARMACOTHERAPIES OF COCAINE ADDICTION IN HUMANS

这项调查有三个目标。1和2评估可卡因滥用者多次递增剂量的3苯基托烷的急性和亚慢性安全性、耐受性和静脉药代动力学。3苯基托烷是一种多巴胺转运体(DAT)阻滞剂。3.评估3苯基托烷在两种剂量下对大型动物(如狗或灵长类动物)的DAT占有率的变化。DAT占有率将使用碘125、βCIT(RTI-55)和SPECT成像进行估计。这是一项单中心、非随机、多剂量、开放标签、固定顺序剂量递增的连续住院/日间医院设计，将在12名年龄在18至45岁的人类志愿者中研究静脉注射3苯基托烷。受试者将接受四次按顺序递增的静脉注射所选3苯基托烷的剂量，每日一次：动物毒性剂量的15%、30%、45%、60%。每一剂量将连续五天服用。在第一天和第五天将获得完整的药代动力学曲线，其间几天的水平为谷值。每次5天的剂量疗程之后，将在剂量递增之间至少有10个半衰期。这项研究的总持续时间约为每个受试者12周。6名自愿进行选择性SPECT扫描的受试者将被评估为30%的DAT占有率和60%的这种3苯基托烷的毒性剂量。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。这项研究中发现的剂量优化将决定随后的可卡因给药研究的剂量。

This investigation has three objectives. 1 & 2 To assess the acute and subchronic safety, tolerance, and intravenous pharmacokinetics of multiple escalating dosages of a 3 PHENYL TROPANE, which is a dopamine transporter (DAT) blocker, in cocaine abusers. 3. To assess the DAT occupancy changes induced by this 3 PHENYL TROPANE at two doses determined as 30% and 60% of the maximum tolerated (or toxic) dose in mg/kg in large animal species such as dog or primate. DAT occupancy will be estimated using iodine 125, beta CIT (RTI-55) and SPECT imaging. This a single-center, non-randomized, multiple dose, open label, fixed order dose escalating sequential residential/day hospital design that will study an intravenous 3 PHENYL TROPANE in 12 human volunteers ages 18 to 45 years old. Subjects will be treated with four sequentially escalating intravenous doses of the selected 3 PHENYL TROPANE at the following once daily dosages: 15%, 30% 45%, 60% of the animal toxic dose. Each given dose will be administered for five successive days. Complete pharmacokinetic profiles will be obtained on days one and five with trough levels on the intervening days. Each five- day dosage session will be followed by a minimum of 10 half-lives for washout between dose escalations. The total duration of this study is approximately 12 weeks per subject. Six subjects who volunteer for optional SPECT scanning will be assessed for DAT occupancy at 30%, and 60% of toxic doses of this 3 PHENYL TROPANE. 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. The dose optimization found in this study will determine dosing for the subsequent cocaine administration study.