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

基本信息

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
项目类别：
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

项目摘要

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.

有证据表明，女性戒烟更困难，复吸率也更高。吸烟行为更可能是受到情绪调节和压力的推动，而男性吸烟行为更有可能是由尼古丁相关的积极强化所激发。针对吸烟的性别依赖性方面的发展是一个关键但尚未开发的领域研究表明，胍法辛是一种肾上腺素能受体激动剂，可通过降低去甲肾上腺素能活性。刺激抑制性突触前 α2a 受体可减弱应激诱导的恢复。临床前研究中滥用药物并减弱伏隔核和前额皮质的多巴胺释放。人类实验室研究表明，胍法辛通过性别依赖性机制发挥作用。胍法辛减弱了女性的应激反应性和男性与吸烟相关的正强化。随机临床试验中，我们发现胍法辛显着提高戒烟率（42% vs. 19%）安慰剂；治疗结束点患病率），并且这种影响在女性中更为明显（45% vs. 15%）我们还完成了三项荟萃分析研究，总结了来自男性的数据。 29,005 名吸烟者发现伐尼克兰对女性比男性更有效，这一点值得注意就机制而言，尼古丁替代品和安非他酮对女性效果较差。减弱基于尼古丁的强化以及戒断相关的对负面情绪和认知的影响，但迄今为止，很少有关于这些影响的性别差异的调查。伐尼克兰是仅有的两种可产生相同或优惠比例的戒烟药物胍法辛针对的是去甲肾上腺素能系统，伐尼克兰针对的是胆碱能系统。系统中，这两种药物似乎都针对负面情绪和基于尼古丁的强化。重要的临床前数据表明去甲肾上腺素能系统和乙酰胆碱系统在细胞中相互作用和分子水平上，与胍法辛和伐尼克兰联合治疗可能会产生累加效应戒烟，特别是女性戒烟对于这项概念验证研究，我们计划进行一项机制研究。 2 期双盲析因设计研究，旨在检验胍法辛 + 联合效应的性别差异伐尼克兰 1) 抵消压力引起的吸烟行为和吸烟相关积极影响实验室强化以及 2) 在后续治疗阶段改善戒断结果。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吸烟的潜在机制（例如渴望、主观香烟效应、消极情绪、戒断、据我们所知，这将是第一项研究。研究选择性 α2a 的治疗潜力和相关机制的性别差异激动剂胍法辛与 nAChR 部分激动剂伐尼克兰联合用于戒烟。