Proof-of-Concept Investigations

吸烟是一种成瘾，具有严重的健康后遗症，在全球范围内造成巨大的人类和经济代价。尽管近年来取得了重大进展，但有效的药物和行为戒烟干预措施仍然有限。初步数据表明，神经类固醇可能代表了戒烟的新药物，并在应激诱导的复发中发挥保护作用。因此，该项目将评估神经类固醇(孕烯醇酮、脱氢表雄酮、加纳索龙)和其他有希望的候选药物作为尼古丁替代疗法(NRT)戒烟的辅助治疗。候选治疗将以平行臂设计进行评估。在戒烟前使用尼古丁贴片治疗一周后，80名单独对NRT(以呼出空气一氧化碳[CO]的减少为指标，与项目1：临床试验(PD：ROSE)使用的标准相同)的治疗反应不足的受试者将被随机分成四种情况之一，包括三种候选药物和一种安慰剂对照条件。停药前1周，停药后11周。使用我们建议的适应性治疗模式，NRT将在整个治疗期内持续进行，我们将尝试确定能够有效增加NRT的治疗干预措施，这些吸烟者对NRT没有足够的反应(约80%)。尼古丁依赖的严重程度将使用FagerstrQm尼古丁依赖测试(FTND)进行跟踪，临时吸烟的变化将通过在戒烟前每周测量呼出的空气CO来评估。停药前的实验室会议将在NRT的第一周和NRT加选定药物的第二周之后的基线上举行。在每一阶段，压力诱导的渴望和吸烟行为也将使用有节奏的听觉序列相加测试(PASAT)进行评估。在为期两周的三次实验室会议之后，参与者将尝试戒烟。戒烟和戒烟将在戒烟日期后11周和6个月的随访中进行评估，并与戒烟前的生物和行为指标(神经类固醇水平、应激性渴求、呼出的空气一氧化碳等)相关。这些概念验证结果将用于指导选择治疗方法，以便在项目1：临床试验(PD：ROSE)中进行更广泛的评估。

Cigarette smoking is an addicfion with major health sequelae, exacfing tremendous human and economic costs worldwide. Although significant progress has been achieved in recent years, effective pharmacologic and behavioral smoking cessation interventions remain limited. Preliminary data suggest that neurosteroids may represent novel agents for smoking cessation and play a protective role in stress-induced relapse. This project will hence evaluate neurosteroids (pregnenolone, DHEA, ganaxolone) and other promising candidates as adjunctive treatments to nicofine replacement therapy (NRT) in smoking cessation. Candidate treatments will be evaluated in a parallel-arm design. After one week of pre-cessation treatment with nicotine patch, 80 subjects who show an insufficient therapeutic response to NRT alone (using as an index the reduction in expired air carbon monoxide [CO], the same criterion as is used in Project 1: Clinical Trials (PD: Rose)) will be randomized to one of four conditions, comprising three candidate medicafions and a placebo control condition. Treatment will continue for one week pre-quit and 11 weeks post-quit. Using our proposed adaptive treatment model, NRT will be continued throughout the treatment period, and we will attempt to identify treatment intervenfions that will prove effective in augmenting NRT in smokers who do not respond adequately to NRT alone (approximately 80%). Nicotine dependence severity will be tracked using the FagerstrQm Test for Nicofine Dependence (FTND), and changes in ad lib smoking will be assessed by measuring expired air CO at weekly intervals pre-quit. Laboratory sessions pre-quit will be held at baseline, after the first week of NRT and after the second week of NRT plus selected agent. During each session, stress-induced craving and smoking behavior will also be assessed using the Paced Auditory Serial Addition Test (PASAT). After the three laboratory sessions conducted over the course of two weeks, participants will attempt to quit. Smoking and smoking abstinence will be assessed for 11 weeks after the quit date and at 6-month follow-up, and correlated with pre-cessation biological and behavioral markers (neurosteroid levels, stress-induced craving, expired air CO, others). These proof-of-concept findings will be used to guide the selection of treatments for more extensive evaluation in Project 1: Clinical Trials (PD: Rose).