Does doxazosin attenuate stress-induced smoking and improve clinical outcomes?

多沙唑嗪是否可以减轻压力诱发的吸烟并改善临床结果？

• 批准号: 8292606
• 负责人: SHERRY ANN MCKEE
• 金额: $ 24.91万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292606
• 关键词: Abstinence; Adrenergic Agonists; Adrenergic Antagonists; Adrenergic Receptor; Adverse effects; Agonist; Alcohols; Area; Attention; Attenuated; Behavior; Benign Prostatic Hypertrophy; Brain; Cardiovascular system; Catecholamines; Cigarette; Clinical; Clinical Trials; Clonidine; Cocaine; Corticotropin; Corticotropin-Releasing Hormone; Data; Development; Double-Blind Method; Doxazosin; Effectiveness; Extinction (Psychology); FDA approved; Guanfacine; Half-Life; Human; Hydrocortisone; Hypertension; Imagery; Investigation; Laboratories; Laboratory Animals; Maintenance; Marketing; Mediating; Mediator of activation protein; Modeling; Moods; Nicotine; Norepinephrine; Outcome; Pathway interactions; Patient Self-Report; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilot Projects; Placebo Control; Placebos; Prazosin; Psychological reinforcement; Randomized; Receptors, Adrenergic, alpha-2; Relapse; Research; Role; Safety; Sedation procedure; Smoker; Smoking; Smoking Behavior; Stress; System; Testing; Therapeutic; Time; Titrations; Tobacco; Tobacco Dependence; Withdrawal Symptom; alpha 2 agonist; alpha-1 adrenergic receptors; base; brief intervention; craving; deprivation; design; improved; medication compliance; negative mood; noradrenergic; open label; phase 2 study; pre-clinical; pre-clinical research; presynaptic; receptor; smoking cessation; smoking relapse; treatment duration

DESCRIPTION (provided by applicant): Stress is a primary contributor to the maintenance of, and relapse to smoking, and targeting stress-related relapse as a medication development strategy is a critical yet relatively unexplored area of research. Preclinical findings suggest tha noradrenergic pathways are involved in stress-induced relapse and that their manipulation may be of therapeutic benefit. Using our validated human laboratory model to examine stress- precipitated smoking lapse behavior, we have demonstrated that guanfacine, which reduces the noradrenergic tone by stimulating the alpha-2 adrenergic receptors, increased the ability to resist smoking compared to placebo, and decreased tobacco craving and ad-lib smoking following stress. This suggests a role for the noradrenergic system in stress-induced tobacco relapse. Guanfacine also reduced smoking during a subsequent brief treatment period. Based on the circuit level effects of norepinephrine on its receptors, we hypothesize that an alpha-1 adrenergic receptor antagonist should have similar effects to the alpha-2 receptor agonist. To elucidate the type of adrenergic receptors mediating the effects of norepinephrine, we collected preliminary data on stress reactivity in the laboratory with a selective alpha-1 adrenergic receptor antagonist, prazosin, supporting a role for alpha-1 adrenergic receptors in stress-induced tobacco relapse. However, prazosin is short-acting and must be administered three times daily, reducing the likelihood of medication compliance and limiting its potential effectiveness. Doxazosin (Cardura(R), Pfizer, marketed for hypertension and benign prostatic hyperplasia) is an alpha-1 agent similar to prazosin, but has a longer half-life (22hrs) improving the likely compliance with and effectiveness of this medication. Thus, the primary aim of this Explorarory/Developmental R21 application is to conduct an initial Phase II double-blind, between-subject, placebo-controlled pilot study to evaluate whether an alpha-1 adrenergic antagonist, doxasozin (0mg/day, 4mg/day, 8mg/day) counteracts stress-induced effects on smoking behavior in the laboratory (i.e., increases the ability to resist smoking, reduces ad-lib smoking) and improves clinical outcomes during a subsequent brief treatment phase (i.e., reductions in smoking behavior). We will also examine potential mechanisms underlying stress-precipitated smoking lapse (e.g., craving, mood, cardiovascular reactivity, HPA axis reactivity, catecholamines) and explore additional mechanisms hypothesized to underlie noradrenergic effects on smoking behavior (e.g., reductions in withdrawal symptoms and smoking-related reinforcement). To our knowledge, this will be the first investigation examining the therapeutic potential and associated mechanisms of a selective alpha-1 adrenergic antagonist, doxazosin for the treatment of tobacco dependence. Positive findings will validate our hypothesis on the role of norephinephrine receptor subtypes in stress reactivity, and will provide key information necessary to expand this investigation to a clinical trial. PUBLIC HEALTH RELEVANCE: Stress is a primary contributor to the maintenance of, and relapse to smoking, and targeting stress-related relapse as a medication development strategy is a critical yet relatively unexplored area of research. Preclinical findings suggest that noradrenergic pathways are involved in stress-induced relapse and that their manipulation may be of therapeutic benefit. The primary aim of this Exploratory/Developmental R21 application is to conduct an initial Phase II double-blind, between-subject, placebo-controlled pilot study to evaluate whether an alpha-1 adrenergic antagonist, doxasozin (0mg/day, 4mg/day, 8mg/day) counteracts stress- induced effects on smoking behavior in the laboratory (i.e., increases the ability to resist smoking, reduces ad- lib smoking) and improves clinical outcomes during a subsequent brief treatment phase (i.e., reductions in smoking behavior).

描述（由申请人提供）：压力是维持和复发吸烟和靶向与压力相关的复发作为药物开发策略的主要贡献者，这是一个关键但相对尚未开发的研究领域。临床前的发现表明，甲肾上腺素能途径参与压力诱导的复发，其操纵可能具有治疗益处。使用我们经过验证的人类实验室模型来检查压力沉淀的吸烟衰减行为，我们证明了鸟汀通过刺激α-2肾上腺素能受体来降低去甲肾上腺素能的张力，增加了与安慰剂相比抵抗吸烟的能力，并降低了压力下的毒品渴望和吸烟。这表明去甲肾上腺素能系统在应激诱导的烟草复发中起作用。在随后的短暂治疗期间，鸟明还减少了吸烟。基于去甲肾上腺素对其受体的电路水平影响，我们假设α-1肾上腺素能受体拮抗剂应具有与α-2受体激动剂相似的作用。为了阐明介导去甲肾上腺素作用的肾上腺素能受体的类型，我们通过选择性α-1肾上腺素能受体拮抗剂Prazosin，支持alpha-1肾上腺素能受体在压力诱导的tobacaCco诱导的tobacco co Replesape中的作用。但是，普唑嗪是短暂的，必须每天三次给药，从而降低了药物合规性的可能性并限制了其潜在有效性。多沙唑嗪（Cardura（R），辉瑞（Pfizer）销售高血压和良性前列腺增生性）是一种类似于普拉唑嗪类似的α-1剂，但具有更长的半衰期（22小时），可提高对这种药物的可能符合性和有效性。 因此，这种探索性/发育R21应用的主要目的是进行初始II期双盲，受试者间，安慰剂对照的试点研究，以评估alpha-1肾上腺素能拮抗剂，多克萨斯素（0mg/day，0mg/day，4mg/day，4mg/day，8mg/day，8mg/day）对吸烟的影响（I.在随后的短暂治疗阶段（即吸烟行为减少），并改善了吸烟）并改善了临床结果。我们还将研究胁迫促进的吸烟失误的潜在机制（例如，渴望，情绪，心血管反应性，HPA轴反应性，Catecholamines），并探索避免对Noradren型基础的其他机制探索其他机制，对Noradrenren疗法对吸烟行为的影响（例如，减轻戒断症状和吸烟式促进式促进）。据我们所知，这将是首次研究选择性α-1肾上腺素能拮抗剂的治疗潜力和相关机制，用于治疗烟草依赖性的毒素。积极的发现将验证我们关于去甲肾上腺素受体亚型在压力反应性中的作用的假设，并将提供必要的关键信息，以将该研究扩展到临床试验。 公共卫生相关性：压力是维持吸烟和复发的主要贡献者，并将与压力相关的复发作为药物开发策略是关键但相对尚未开发的研究领域。临床前的发现表明，去甲肾上腺素能途径参与压力诱导的复发，并且它们的操纵可能具有治疗益处。此探索性/发育R21应用的主要目的是进行初始II期双盲，受试者间，安慰剂对照的试点研究，以评估α-1肾上腺素能拮抗剂，多克萨斯素（0mg/day，4mg/day，4mg/day，8mg/day，8mg/day）是否对吸烟的影响（I. LIB吸烟）并在随后的短暂治疗阶段（即吸烟行为减少）改善临床结果。