PHARMACOTHERAPIES OF COCAINE ADDICTION IN HUMANS

这项调查有三个目标。1和2评估可卡因滥用者中多次递增剂量的3苯基托品烷（其为多巴胺转运蛋白（DAT）阻断剂）的急性和亚慢性安全性、耐受性和静脉内药代动力学。3.在大型动物种属（如犬或灵长类动物）中，评估该3-苯基托品烷在两种剂量（确定为最大耐受（或毒性）剂量（mg/kg）的30%和60%）下诱导的DAT占用率变化。将使用碘125、β CIT（RTI-55）和SPECT成像估计DAT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连续住院/日间医院设计，将在12名年龄为18至45岁的人类志愿者中研究静脉注射3-苯基托品。受试者将接受四次依次递增的静脉内剂量的所选3-苯基托品治疗，每日一次剂量如下：动物毒性剂量的15%、30%、45%、60%。每次给药将连续给药5天。将在第1天和第5天获得完整的药代动力学曲线，并在间隔日获得谷水平。每个5天给药期后，剂量递增之间至少有10个半衰期用于洗脱。本研究的总持续时间约为每例受试者12周。将评估自愿进行可选SPECT扫描的6名受试者在30%和60%毒性剂量下的DAT占用率。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。本研究中发现的剂量优化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.