Phase 2 study examining efficacy and mechanisms of combining varenicline and guanfacine for smoking cessation in women and men

第 2 期研究检验伐尼克兰和胍法辛联合治疗女性和男性戒烟的功效和机制

• 批准号: 10192689
• 负责人: SHERRY ANN MCKEE
• 金额: $ 79.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192689
• 关键词: Abstinence; Acetylcholine; Adrenergic Agonists; Affect; Agonist; Area; Attenuated; Blood Pressure; Bupropion; Cardiovascular system; Cessation of life; Cigarette; Clinical Research; Clinical Trials Design; Cognition; Combined Modality Therapy; Corticotropin; Data; Development; Dopamine; Double-Blind Method; Female; Guanfacine; Heart Rate; Human; Hybrids; Hydrocortisone; Imagery; Intervention; Investigation; Laboratories; Laboratory Study; Meta-Analysis; Molecular; Morbidity - disease rate; Nicotine; Outcome; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Placebos; Positive Reinforcements; Prefrontal Cortex; Prevalence; Psychological reinforcement; Public Health; Randomized; Randomized Clinical Trials; Regulation; Relapse; Research; Research Design; Safety; Sex Differences; Smoker; Smoking; Smoking Behavior; Stress; System; Therapeutic; Titrations; Tobacco use; United States; Withdrawal; Woman; base; cholinergic; cognitive function; craving; deprivation; design; drug of abuse; efficacy evaluation; head-to-head comparison; hypothalamic-pituitary-adrenal axis; improved; male; men; mortality; negative affect; negative mood; neuroimaging; nicotine patch; nicotine replacement; noradrenergic; phase 2 study; pre-clinical; preclinical study; presynaptic; programs; receptor; sex; smoking cessation; stress reactivity; treatment duration; varenicline

Women have more difficulty quitting smoking and have higher rates of relapse. Evidence indicates that female smoking behavior is more likely to be motivated by affect regulation and stress, whereas male smoking behavior is more likely to be motivated by nicotine-related positive reinforcement. Pharmacotherapy development targeted toward sex-dependent aspects of smoking is a critical, yet underdeveloped area of research. Guanfacine is an adrenergic receptor agonist which reduces noradrenergic activity through stimulation of inhibitory presynaptic α2a receptors. Guanfacine attenuates stress-induced reinstatement to drugs of abuse in preclinical studies and attenuate dopamine release in accumbens and pre-frontal cortex. In human laboratory studies, we have shown that guanfacine operates through sex-dependent mechanisms. Guanfacine attenuated stress reactivity in women and smoking-related positive reinforcement in men. In a randomized clinical trial, we found that guanfacine significantly increased smoking cessation (42% vs. 19% placebo; end-of-treatment point prevalence), and that effects were more pronounced in women (45% vs. 15%) versus men (39% vs. 23%). We have also completed three meta-analytic studies summarizing data from 29,005 smokers, finding that varenicline is more efficacious for women, compared to men, which is notable as nicotine replacement and bupropion are less efficacious for women. With regards to mechanisms, varenicline attenuates nicotine-based reinforcement, and withdrawal related effects on negative mood and cognition but there has been little investigation regarding sex differences in these effects. To date, guanfacine and varenicline are the only two smoking cessation medications which either produce equal or preferential rates of quitting in women. While guanfacine targets the noradrenergic system and varenicline targets the cholinergic system, both medications appear to target aspects of negative affect and nicotine-based reinforcement. There is significant preclinical data identifying that the noradrenergic and acetylcholine systems interact at the cellular and molecular level, and combined treatment with guanfacine and varenicline may produce additive effects on smoking cessation, particularly for women. For this proof of concept study, we plan to conduct a mechanistic Phase 2 double-blind, factorial design study to examine sex differences in the combined effect of guanfacine + varenicline on 1) counteracting the effects of stress-induced smoking behavior and smoking-related positive reinforcement in the laboratory and 2) improving abstinence outcomes during a subsequent treatment phase. Importantly, we will examine the safety of combining guanfacine with varenicline, and potential sex differences in mechanisms underlying smoking (e.g., craving, subjective cigarette effects, negative mood, withdrawal, cognitive function, cardiovascular reactivity, and HPA-axis levels). To our knowledge, this will be the first study investigating sex differences in the therapeutic potential and associated mechanisms of a selective α2a agonist, guanfacine, combined with a nAChR partial agonist, varenicline for smoking cessation.

妇女吸烟更困难，退休率更高。证据表明女性 吸烟行为更有可能受到影响调节和压力的动机，而男性吸烟 行为更有可能是由尼古丁相关的阳性加强动机。药物治疗 针对性吸烟方面的发展是一个关键但欠发达的领域 研究。瓜宁是一种肾上腺素能受体激动剂，可通过 刺激抑制性突触前α2a受体。鸟汀会减轻压力引起的恢复原状 临床前研究中的滥用药物，并减轻伏伏胺和额外皮层的多巴胺释放。 人类实验室研究，我们已经表明鸟汀通过性别依赖性机制运行。 鸟汀减弱了女性的压力反应性，男性与吸烟相关的阳性增强。在 随机临床试验，我们发现鸟明显着增加了戒烟（42％比19％ 安慰剂；治疗点的患病率），这种影响在女性中更为明显（45％比15％） 与男性（39％比23％）。我们还完成了三项荟萃分析研究，总结了来自 与男性相比，有29,005名吸烟者发现Varenicline对女性更有效，这是显着的 尼古丁替代和安非他酮对女性的效率较低。关于机制，varenicline 减弱基于尼古丁的增强，以及对负面情绪和认知的戒断相关影响，但 关于这些影响的性别差异的调查很少。迄今为止，瓜芬和 Varenicline是仅有的两种戒烟药物，其产生相等或优先的速率 退出女性。而鸟汀靶向去甲肾上腺素系统和葡萄烯素的靶向胆碱能 系统，两种药物似乎都针对负面影响和基于尼古丁的增强的方面。那里 是明显的临床前数据，确定去甲肾上腺素能和乙酰胆碱系统在细胞上相互作用 和分子水平，以及与鸟宁和varenicline结合治疗可能会对 戒烟，尤其是女性。对于此概念研究证明，我们计划进行机械 第2阶段双盲阶乘设计研究，以检查鸟法丝 +的综合作用的性别差异 1）应对压力引起的吸烟行为和与吸烟相关的阳性的影响 在实验室中的加强和2）在随后的治疗阶段改善禁欲。 重要的是，我们将研究将鸟汀与varenicline结合以及潜在的性别差异的安全性 在吸烟的机制中（例如，渴望，主观香烟效应，负面情绪，戒断， 认知功能，心血管反应性和HPA轴水平）。据我们所知，这将是第一个研究 研究选择性α2a的治疗潜力和相关机制的性别差异 激动剂，鸟汀，结合了nachr局部激动剂，戒烟。