Triple Re-uptake Inhibitor, SKL 10406, as a New Treatment for Alcohol Dependence

 描述（由申请人提供）：FDA批准三种药物作为酒精依赖的治疗药物：双硫仑，阿坎酸和纳洛酮，但由于疗效差或副作用，这些药物很少被处方。另一种是托吡酯，它能有效地减少酒精的使用，但它会引起一系列的副作用，限制了它的耐受性。另一类潜在有效的治疗包括三重摄取抑制剂。三重摄取抑制剂增强由5-羟色胺（5-HT）、去甲肾上腺素（NE）和多巴胺（DA）介导的神经信号传导。两种三重摄取抑制剂（DOV 102，677和阿米替丁/DOV 21，947）已被证明可减少啮齿动物的酒精自我给药。在一项初步研究中，我们发现一种新开发的三重再摄取抑制剂SKL 10406也能减少啮齿动物的酒精摄入量。我们现在建议评估SKL 10406作为酒精依赖的新治疗方法。第一阶段具体目标：在饮酒的健康志愿者中进行SKL 10406（25、50和75 mg PO BID）单药治疗和与酒精联合治疗的人体实验室安全性评价（n=20）。已制定剂量递增和停止规则。本研究将描述SKL 10406与中毒剂量的酒精联合使用时的副作用、安全性和最大耐受剂量。里程碑：我们将确定当与酒精组合时不会引起不可接受的毒性的SKL 10406剂量，所述不可接受的毒性定义为在SKL 10406的最低剂量下超过一个SAE。第二阶段具体目标：进行SKL 10406治疗酒精依赖的双盲、随机、安慰剂对照门诊临床试验（n=72）。主要结局指标将是研究过程中自我报告的重度饮酒天数（男性e5饮酒/天，女性e4饮酒/天）的比例（插补脱落作为基线率），这是酒精依赖临床试验的标准结局。

 DESCRIPTION (provided by applicant): Three medications are approved by the FDA as treatments for alcohol dependence: disulfiram, acamprosate and naltrexone, but these are seldom prescribed due to poor efficacy or side effects. Another, topiramate, is effective for reducing alcohol use but it causes a range of side effects that limit its tolerability. Another clas of potentially effective treatments includes triple uptake inhibitors. Triple uptake inhibitors enhance neural signaling that is mediated by serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Two triple uptake inhibitors (DOV 102,677 & amitifadine/DOV 21,947) have been shown to reduce alcohol self-administration in rodents. In a pilot study we showed that a newly developed triple reuptake inhibitor, SKL 10406, reduced alcohol intake in rodents as well. We now propose to evaluate SKL 10406 as a new treatment for alcohol dependence. Phase I Specific Aim: To conduct a human laboratory safety evaluation (n=20) of SKL 10406 (25, 50, and 75 mg PO BID) alone and combined with alcohol in alcohol-experienced healthy volunteers. Dose escalation and stopping rules are in place. This study will characterize the side effects, safety profile, and maximum tolerated dose of SKL 10406 when combined with an intoxicating dose of alcohol. Milestone: we will identify a dose of SKL 10406 that when combined with alcohol does not cause unacceptable toxicity, defined as more than one SAE at the lowest dose of SKL 10406. Phase II Specific Aim: To conduct a double-blind, randomized placebo-controlled outpatient clinical trial of SKL 10406 as a treatment for alcohol dependence (n=72). The primary outcome measure will be proportion of self-reported heavy drinking days (e5 drinks/day for males and e4 drinks/day for females) over the course of the study (imputing dropouts as baseline rate), a standard outcome in clinical trials for alcohol dependence.