PHARMACOTHERAPIES OF COCAINE ADDICTION IN HUMANS

这项调查有三个目的。1 & 2评估可卡因滥用者多次递增剂量3苯基TROPANE（一种多巴胺转运体（DAT）阻滞剂）的急性和亚慢性安全性、耐受性和静脉药代动力学。3. 在大型动物（如狗或灵长类动物）中，以最大耐受（或毒性）剂量（mg/kg）的30%和60%为两种剂量，评估3苯基TROPANE引起的DAT占用变化。使用碘125、β CIT （RTI-55）和SPECT成像来估计数据占用率。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顺序住院/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TROPANE。受试者将接受四次依次递增的3苯基TROPANE静脉注射，每日一次剂量：动物毒性剂量的15%，30%,45%,60%。每次给药连续服用5天。在第1天和第5天获得完整的药代动力学资料，其间几天达到低谷水平。每次5天的给药期之后，在两次剂量增加之间至少有10个半衰期的洗脱期。这项研究的总持续时间约为每名受试者12周。6名自愿进行选择性SPECT扫描的受试者将在30%和60%的3苯基TROPANE毒性剂量下评估数据占用率。安全测量包括体格检查、生命体征（血压、心率、呼吸阻力、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（如抑郁和焦虑）的心理测量测定。安全性数据将通过对症状和不良事件的列表进行分析。本研究中发现的最佳剂量将决定后续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.