Effects of GTS-21 on smoking behavior and neurocognitive function

GTS-21对吸烟行为和神经认知功能的影响

• 批准号: 8893551
• 负责人: SARA JO NIXON
• 金额: $ 26.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893551
• 关键词: Abstinence; Address; Adult; Adverse effects; Affect; Agonist; Anger; Animals; Anxiety; Area; Attention; Attentional deficit; Behavior; Behavioral; Brain; Cardiovascular Physiology; Cardiovascular system; Chronic; Cigarette; Cigarette Smoker; Clinical; Cognition; Cognitive; Communities; Comorbidity; Cotinine; Data; Development; Disease; Dopamine; Dose; Double-Blind Method; Drug Combinations; Electrophysiology (science); Environmental Tobacco Smoke; Future; GTS-21; Health; Human; Intervention; Laboratories; Literature; Maintenance; Measurement; Measures; Mediation; Mediator of activation protein; Medical; Memory; Mental Depression; Mental disorders; Modeling; Moods; Neurocognition; Neurocognitive; Neurosciences; Nicotine; Nicotinic Receptors; Participant; Pattern; Performance; Persons; Pharmaceutical Preparations; Physiological; Placebo Control; Placebos; Population; Prevalence; Property; Publishing; Randomized; Readiness; Recruitment Activity; Relapse; Relative (related person); Reporting; Rewards; Risk; Role; Running; Safety; Sampling; Self Administration; Series; Sex Characteristics; Short-Term Memory; Smoker; Smoking; Smoking Behavior; Statistical Study; Stimulus; Symptoms; Testing; Time; United States; Update; Withdrawal; Withdrawal Symptom; Woman; Work; base; cigarette smoking; design; dysphoria; improved; interest; liver function; men; negative mood; neurobehavioral; neurobehavioral test; non-smoking; novel; phase 2 study; primary outcome; public health relevance; receptor; response; screening; sex; smoking cessation; smoking relapse

 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.

 描述（由申请人提供）：尼古丁认知和成瘾作用的主要调节剂是烟碱乙酰胆碱受体（nAChR）。α4β2 受体亚型的刺激通常被认为是尼古丁许多与奖赏相关的特性的原因。此外，数据表明 α7 可以控制尼古丁相关的多巴胺流出和自我给药行为。总而言之，这些发现表明 α7 操作可能对与有效戒烟相关的许多神经行为终点产生积极影响，此前对新型 α7 部分激动剂 GTS-21 的研究已证明它具有神经认知功能。据我们所知，其神经认知作用及其对吸烟行为的影响尚未在慢性病中得到系统研究。因此，这项 2 期研究将提供必要的第一步，以测量 GTS-21 对目前健康的长期吸烟者的吸烟、情绪、神经认知功能和大脑电生理学的影响。女性对吸烟和戒烟的了解尤其不足，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，使用双盲、安慰剂对照的平行小组设计，对 54 名（27 名女性）社区吸烟者进行研究。已通过筛查排除那些患有严重精神疾病和/或重大医疗疾病并且已证明准备戒烟的人，将参加为期 7 周的主动试验（加上筛查和 1 周安慰剂磨合期），但同等条件除外。每个性别的人数必须分配到每个组，受试者将被随机分配到 75 毫克/每天两次（BID）、150 毫克/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、实验室测试。评估尽管心血管和肝功能，并提供有关吸烟行为和情绪状态的每周更新，但现有的研究反映了这些剂量的药物的安全性，因此，将在整个试验过程中收集安全性数据，这是主要关注点。然而，正在提供与吸烟相关的神经行为领域（即吸烟、情绪/情感、认知）的初步功效数据。作为一项初步研究，统计能力必然是有限的。这些数据将指导未来的研究，以替代剂量、暴露。时间、药物替代品和/或药物组合将被考虑。