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

女性戒烟更困难，复吸率更高。有证据表明，女性 吸烟行为更可能是由情绪调节和压力引起的，而男性吸烟行为更可能是由情绪调节和压力引起的。 行为更有可能是由尼古丁相关的正强化。药物治疗 针对吸烟的性别依赖方面的发展是一个关键的，但不发达的领域， research.胍法辛是一种肾上腺素能受体激动剂，通过 抑制性突触前α 2a受体的刺激。胍法辛减弱应激诱导的恢复， 药物滥用的临床前研究和衰减多巴胺释放的大脑皮层和前额叶皮层。在 人类实验室研究表明，胍法辛通过性别依赖机制发挥作用。 胍法辛减弱女性的应激反应和男性吸烟相关的正强化。中 在一项随机临床试验中，我们发现胍法辛显著增加了戒烟率（42%对19%）， 安慰剂;治疗结束时的患病率），并且在女性中效果更明显（45% vs. 15%） 与男性相比（39% vs. 23%）。我们还完成了三项荟萃分析研究， 29，005名吸烟者，发现伐尼克兰对女性比男性更有效，值得注意的是， 尼古丁替代品和安非他酮对妇女的效果较差。关于机制，伐伦克林 减弱尼古丁为基础的强化，以及对消极情绪和认知的戒断相关影响， 关于这些影响的性别差异几乎没有调查。迄今为止，胍法辛和 伐尼克兰是仅有的两种产生相同或优惠率的戒烟药物， 在女人身上放弃。胍法辛靶向去甲肾上腺素能系统，伐尼克兰靶向胆碱能系统， 根据系统，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 是重要的临床前数据，确定去甲肾上腺素能和乙酰胆碱系统在细胞内相互作用， 和分子水平，与胍法辛和伐尼克兰联合治疗可能会产生累加效应， 戒烟，尤其是女性。对于这个概念验证研究，我们计划进行一个机械的 II期双盲、析因设计研究，以检查胍法辛+ 伐尼克兰对1）抵消压力诱导的吸烟行为和吸烟相关的积极影响 在实验室中的强化和2）在随后的治疗阶段期间改善禁欲结果。 重要的是，我们将检查胍法辛与伐尼克兰联合使用的安全性，以及潜在的性别差异 在吸烟的潜在机制中（例如，渴望，主观香烟效应，消极情绪，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α 2a治疗潜力和相关机制的性别差异 激动剂胍法辛联合nAChR部分激动剂伐尼克兰用于戒烟。

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.