Effects of GTS-21 on smoking behavior and neurocognitive function

 描述（由申请方提供）：尼古丁认知和成瘾作用的主要介质是烟碱乙酰胆碱受体（nAChR）。α 4 β 2受体亚型的刺激通常被认为是尼古丁的许多奖赏相关性质的原因。然而，α7型nAChR似乎共同控制尼古丁相关的多巴胺外排和自我给药行为。此外，数据表明α7亚基可能是尼古丁增强认知作用的基础。综上所述，这些发现表明α7操纵可能会对与有效戒烟相关的许多神经行为终点产生积极影响。先前对一种新型α7部分激动剂GTS-21的研究表明，它在其他临床但非吸烟人群中具有神经认知益处。据我们所知，无论是它的神经认知效应，也没有它对吸烟行为的影响已被系统地检查在慢性吸烟者没有精神病合并症。因此，这项2期研究将提供必要的第一步，以测量GTS-21对目前健康的慢性吸烟者的小样本中吸烟，情绪，神经认知性能和脑电生理学的影响。由于妇女对保持吸烟和戒烟的了解特别少，将尽一切努力招募足够数量的妇女进行初步的性别比较。采用双盲、安慰剂对照平行组设计，54名（27名女性）社区吸烟者将参加一项为期7周的活性药物试验（加上筛选和1周安慰剂导入期），这些吸烟者已接受筛选，排除了患有严重精神疾病和/或重大医学疾病的吸烟者，并已证明准备戒烟。除每组必须分配相同数量的性别外，受试者将被随机分配至75 mg/每日两次（BID）、150 mg/BID或安慰剂/ BID组。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，并提供有关吸烟行为和情绪状态的每周更新。对患有严重精神疾病的人的现有研究反映了这些剂量的药物的安全性。因此，尽管将在整个试验过程中收集安全性数据，但主要重点是提供吸烟相关神经行为领域的初步疗效数据（即，吸烟、情绪/情感、认知）。作为一项初步研究，统计效力必然有限。然而，这些数据将指导未来的研究，其中替代剂量，暴露时间，药物替代品和/或药物组合将被考虑。

 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.