Proof-of-Concept Investigations

概念验证调查

• 批准号: 8375648
• 负责人: Christine E. Marx
• 金额: $ 12.2万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8375648
• 关键词: Abstinence; Adrenal Glands; Advisory Committees; Affect; Aftercare; Air; Allopregnanolone; Anti-Anxiety Agents; Anxiety; Area; Auditory; Behavioral; Behavioral Symptoms; Biological; Biological Markers; Carbon Monoxide; Child; Cholesterol; Cigarette; Clinical; Clinical Trials; Clinical Trials Design; Cognitive; Control Groups; Cotinine; Data; Dehydroepiandrosterone Sulfate; Dependence; Development; Dimensions; Dropout; Evaluation; Exhibits; Failure; Gated Ion Channel; Goals; Health; Human; Intervention; Investigation; LDL Cholesterol Lipoproteins; Laboratories; Ligands; Link; Mass Spectrum Analysis; Measures; Mental Depression; Methodology; Modeling; N-Methylaspartate; Neurotransmitters; New Agents; Nicotine Dependence; Outcome; Participant; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Play; Post-Traumatic Stress Disorders; Pregnenolone; Process; Public Health; Randomized; Randomized Controlled Trials; Relapse; Replacement Therapy; Risk; Rodent Model; Role; Rosa; Schizophrenia; Selection for Treatments; Series; Serum; Severities; Signal Transduction; Smoker; Smoking; Smoking Behavior; Smoking Cessation Intervention; Stress; Symptoms; System; Technology; Testing; Therapeutic; Wit; Withholding Treatment; addiction; analog; arm; base; cardiovascular disorder risk; cigarette smoking; cohort; craving; dehydroepiandrosterone; depressive symptoms; design; disorder later incidence prevention; drug candidate; economic cost; evidence base; follow-up; ganaxolone; improved; indexing; innovation; male; neuronal excitability; neurosteroids; nicotine patch; novel; novel strategies; pre-clinical; prevent; receptor; resilience; response; smoking cessation; smoking relapse; treatment duration

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).

吸烟是一种具有严重健康后遗症的成瘾性，在世界范围内付出了巨大的人力和经济代价。虽然近年来取得了重大进展，但有效的药理学和行为戒烟干预仍然有限。初步数据表明，神经甾体可能是戒烟的新药物，并在压力诱导的复吸中发挥保护作用。因此，该项目将评估神经类固醇（双烯醇酮，脱氢表雄酮，加奈索酮）和其他有前途的候选人作为尼古丁替代疗法（NRT）在戒烟中的替代治疗。将采用平行组设计评价候选治疗。戒烟前尼古丁贴片治疗1周后，将80例对单独NRT治疗反应不足的受试者（使用呼出气体一氧化碳[CO]减少作为指标，与项目1：临床试验（PD：Rose）中使用的标准相同）随机分配至4种条件之一，包括3种候选药物和1种安慰剂对照条件。治疗将在戒烟前持续一周，戒烟后持续11周。使用我们提出的适应性治疗模型，NRT将在整个治疗期间持续进行，我们将尝试确定治疗干预措施，这些干预措施将被证明对单独使用NRT没有充分反应的吸烟者（约80%）有效增加NRT。将使用FagerstrQm尼古丁依赖性试验（FTND）跟踪尼古丁依赖严重程度，并通过在戒烟前每周测量呼气CO来评估随意吸烟的变化。将在基线时、NRT第一周后和NRT+选定药物第二周后进行实验室检查。在每次会议期间，还将使用起搏听觉序列添加测试（PASAT）评估压力诱导的渴望和吸烟行为。在两周内进行的三次实验室会议之后，参与者将尝试戒烟。将在戒烟日期后11周和6个月随访时评估吸烟和戒烟情况，并将其与戒烟前的生物和行为标志物（神经类固醇水平、压力诱导的渴望、呼气CO等）相关联。这些概念验证结果将用于指导治疗选择，以便在项目1：临床试验（PD：Rose）中进行更广泛的评价。