Selegiline for Smoking Cessation

描述(由申请人提供)： 尽管尼古丁替代疗法和缓释安非他酮用于治疗尼古丁依赖，但仍有相当大比例的吸烟者无法戒烟，因此需要新的有效的戒烟药物疗法。多巴胺在尼古丁强化中起关键作用，单胺氧化酶B(MAO-B)抑制剂优先抑制多巴胺代谢，可能有助于戒烟。为了支持这一假设，在初步研究中，我们已经表明，与安慰剂相比，选择性MAO-B抑制剂盐酸司来吉兰(10毫克/天)显著增加了戒烟率。这份R01报告建议对200名尼古丁依赖型香烟吸烟者进行随机、双盲、安慰剂对照试验，以确定司来吉兰的戒烟效果。受试者将在试验第15天的目标戒烟日期之前的两周内每天服用10毫克司来吉兰(每日2次5毫克)或安慰剂(每天两次)。所有吸烟者都将接受每周简短的个人戒烟咨询。主要的戒烟结果测量将是6个月随访时的7天点戒烟情况，次要戒烟结果测量将包括在试验的最后四周(第29-56天)持续戒烟以及在8周试验结束时(49-56天)的7天点戒烟情况。其他次级治疗结果指标将包括试验中的滞留、尼古丁戒断和渴求、体重、抑郁症状、使用MEMS技术的司来吉兰研究用药依从性以及尿司来吉兰代谢物的检测。数据分析将集中在意向治疗样本上，并将利用优势比和逻辑回归分析来确定司来吉兰对戒断结果的影响，并利用分层线性模型(HLM)来确定持续结果(例如，渴望和戒断、体重、抑郁症状)。我们预测司来吉兰将优于安慰剂，并将导致更大的烟草渴望和戒断的抑制。这项试验的积极结果将进一步支持司来吉兰治疗尼古丁依赖的安全性和有效性。

DESCRIPTION (provided by applicant): Despite the utility of nicotine replacement therapies and sustained-release bupropion for the treatment of nicotine dependence, there is still a significant proportion of cigarette smokers who are unable to quit smoking, and thus new and effective pharmacotherapies for smoking cessation are needed. Dopamine plays a critical role in nicotine reinforcement, and monoamine oxidase B (MAO-B) inhibitors, which preferentially inhibit dopamine metabolism, may have utility for smoking cessation. In support of this hypothesis, in preliminary studies, we have shown that the selective MAO-B inhibitor selegiline hydrochloride (10 mg/day) significantly increases smoking abstinence rates compared to placebo. This R01 re-submission proposes to study n=200 nicotine dependent cigarette smokers in a randomized, double-blind, placebo-controlled trial to determine the efficacy of selegiline for smoking cessation. Subjects would be inducted onto 10 mg/day of selegiline (5 mg po bid) or placebo (twice daily) over a two-week period prior to the target quit date on trial Day 15. All smokers would receive manualized brief weekly individual smoking cessation counseling. The primary smoking cessation outcome measure will be 7-day point prevalence smoking abstinence at the 6-month follow-up, and secondary cessation outcome measures will include continuous smoking abstinence during the last four weeks of the trial (Days 29-56) and 7-day point prevalence abstinence at the end of the 8-week trial (Days 49-56). Other secondary treatment outcome measures will include retention in the trial, nicotine withdrawal and craving, body weight, depressive symptoms, and selegiline study medication adherence using MEMS technology and detection of urinary selegiline metabolites. Data analysis will focus on an intention-to-treat sample and will utilize Odds Ratios and logistic regression analyses to determine the effects of selegiline on cessation outcomes, and hierarchical linear models (HLM) for continuous outcomes (e.g., craving and withdrawal, weight, depressive symptoms). We predict that selegiline will be superior to placebo, and will lead to greater suppression of tobacco craving and withdrawal. Positive results from this trial would add further support for the safety and efficacy of selegiline for the treatment of nicotine dependence.