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

女性戒烟难度更大，复吸率也更高。有证据表明，女性 吸烟行为更容易受到情绪调节和压力的影响，而男性吸烟 行为更有可能受到尼古丁相关的积极强化的激励。药物治疗 针对吸烟的性依赖方面的发展是一个关键但不发达的领域 研究。瓜那法辛是一种肾上腺素能受体激动剂，它通过 刺激抑制性突触前α2a受体。胍法辛可减弱应激诱导的恢复 在临床前研究中滥用药物，并减弱伏隔核和前额叶皮质中的多巴胺释放。在……里面 我们的人体实验室研究表明，鸟嘌呤通过性别依赖的机制发挥作用。 胍法辛可减弱女性的应激反应，并减少男性吸烟相关的阳性强化。在一个 随机临床试验，我们发现愈创新显著增加戒烟(42%比19% 安慰剂；治疗结束时的患病率)，这种影响在女性中更明显(45%对15%) 男性(39%)和男性(23%)。我们还完成了三项元分析研究，总结了以下数据 29,005名吸烟者，发现varenicline对女性比男性更有效，这一点值得注意的是 尼古丁替代和安非他酮对女性的疗效较差。在机制方面，varenicline 减弱尼古丁强化和戒断对负面情绪和认知的影响，但 关于这些影响中的性别差异的研究很少。到目前为止，愈创木酚和 Varenicline是仅有的两种戒烟药物，它们的戒烟率相同或优惠 在女性中戒烟。瓜那法辛作用于去甲肾上腺素系统，而瓦伦尼克林作用于胆碱能系统。 这两种药物似乎都针对负面影响和尼古丁强化的方面。那里 重要的临床前数据表明去甲肾上腺素和乙酰胆碱系统在细胞内相互作用 在分子水平上，愈创新与瓦伦尼克林联合作用可产生相加效应。 戒烟，尤其是对女性。对于这项概念验证研究，我们计划进行一项机械性的 第2阶段双盲析因设计研究，以检验鸟嘌呤+的联合效应中的性别差异 1)瓦伦克林拮抗应激诱导的吸烟行为和吸烟相关的积极作用 实验室中的强化和2)在随后的治疗阶段改善戒烟结果。 重要的是，我们将检查联合使用瓜那法辛和伐伦克林的安全性，以及潜在的性别差异。 吸烟的潜在机制(例如，渴望、主观吸烟效应、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，这将是第一次研究 研究选择性α2a治疗潜力的性别差异及其相关机制 与nAChR部分激动剂varenicline联合使用，用于戒烟。

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.