Effects of GTS-21 on smoking behavior and neurocognitive function

 描述(申请人提供)：尼古丁的认知和成瘾作用的主要媒介是烟碱型乙酰胆碱受体(NAChRs)。α4？2受体亚型的刺激通常被认为与尼古丁的许多奖赏相关特性有关。然而，α7型nAChRs似乎分享了对尼古丁相关的多巴胺外流和自我给药行为的控制。此外，数据表明，α7亚基可能是尼古丁提高认知能力的基础。综上所述，这些发现表明，α7操作可能会对一些与有效戒烟相关的神经行为终点产生积极影响。之前对新型α7部分激动剂GTS-21的研究表明，它在其他临床但不吸烟的人群中具有神经认知益处。就我们所知，无论是它的神经认知效应，还是它对吸烟行为的影响，都没有在没有精神合并症的慢性吸烟者身上进行过系统的研究。因此，这项第二阶段研究将提供必要的第一步，以衡量GTS-21对目前健康的长期吸烟者的小样本吸烟、情绪、神经认知表现和脑电生理学的影响。由于女性对吸烟的维持和戒烟尤其缺乏了解，因此将尽一切努力招募足够数量的女性进行初步性别比较。采用双盲、安慰剂对照的平行分组设计，54名(27名女性)社区吸烟者接受了筛查，排除了那些患有严重精神障碍和/或重大医学障碍的人，并已证明准备戒烟，他们将参加一项为期7周的积极试验(加上筛查和为期1周的安慰剂磨合)。除了必须将相同数量的性别分配给每一组外，受试者将被随机分配到75毫克/天两次(BID)、150 mg/BID或安慰剂/BID。在整个研究期间，参与者将接受重复的神经行为测试，心血管和肝功能的实验室评估，并每周提供有关吸烟行为和情绪状态的最新信息。现有的对严重精神障碍患者的研究反映了这种剂量药物的安全性。因此，尽管安全性数据将在整个试验过程中收集，但主要关注的是提供与吸烟相关的神经行为领域(即吸烟、情绪/影响、认知)的初步疗效数据。作为初步研究，统计能力必然会受到限制。然而，这些数据将指导未来的研究，其中将考虑替代剂量、暴露时间、药物替代品和/或药物组合。

 DESCRIPTION (provided by applicant): The major mediators of nicotine's cognitive and addictive effects are nicotinic acetylcholine receptors (nAChRs). Stimulation of the α4ß2 receptor subtype is generally considered responsible for many reward- associated properties of nicotine. However, α7 type nAChRs appear to share control over nicotine-associated dopamine efflux and self-administration behaviors. Furthermore, data indicate that α7 subunits may underlie the cognitively enhancing effects of nicotine. Taken together, these findings suggest α7 manipulation may positively affect a number of neurobehavioral endpoints relevant to effective nicotine cessation. Previous work with a novel α7 partial agonist, GTS-21, has demonstrated it has neurocognitive benefits in other clinical, but non-smoking, populations. To the best of our knowledge, neither its neurocognitive effects, nor its effects on smoking behaviors have been systematically examined in chronic smokers without psychiatric comorbidities. Thus, this Phase 2 study will provide a necessary first step to measure the effects of GTS-21 on smoking, mood, neurocognitive performance, and brain electrophysiology in a small sample of currently healthy, chronic smokers. Because smoking maintenance and cessation are particularly poorly understood among women, every effort will be made to recruit sufficient numbers of women for preliminary sex comparisons. Using a double-blind, placebo controlled parallel group design, 54 (27 women) community smokers who have been screened to exclude those with major psychiatric disorders and/or significant medical disorders and who have a demonstrated readiness to quit, will participate an 7 week active trial (plus screening and 1-week placebo run-in). With the exception that equal numbers of each sex must be assigned to each group, subjects will be randomly assigned to 75 mg/twice a day (BID), 150 mg/BID, or placebo/ BID. Across the study period, participants will undergo repeated neurobehavioral testing, laboratory assessments of cardiovascular and liver function, and provide weekly updates regarding smoking behavior and mood state. Existing studies of persons with major psychiatric disorders reflect the safety of the drug at these doses. Therefore, although safety data will be collected throughout the trial, the primary focus is on providing preliminary efficacy data across smoking-related neurobehavioral domains (i.e., cigarette use, mood/affect, cognition). As a preliminary study, statistical power will be necessarily limited. However, these data will guide future research wherein alternative doses, exposure time, drug alternatives and/or drug combinations would be considered.