Dmochowski Roger R, Miklos John R, Norton Peggy A, Zinner Norman R, Yalcin Ilker, Bump Richard C
Department of Urologic Surgery, Vanderbilt University, Nashville, Tennessee, USA.
J Urol. 2003 Oct;170(4 Pt 1):1259-63. doi: 10.1097/01.ju.0000080708.87092.cc.
Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, increases rhabdosphincter contractility via the stimulation of pudendal motor neuron alpha-1 adrenergic and 5-hydroxytryptamine-2 receptors. In this first phase 3 study we assessed the efficacy and safety of duloxetine in women with stress urinary incontinence (SUI).
A total of 683 North American women 22 to 84 years old were enrolled in this double-blind, placebo controlled study. The case definition included a predominant symptom of SUI with a weekly incontinence episode frequency (IEF) of 7 or greater, the absence of predominant symptoms of urge incontinence, normal diurnal and nocturnal frequency, a bladder capacity of 400 ml or greater, and a positive cough stress test and stress pad test. After a 2-week placebo lead-in period subjects were randomly assigned to receive placebo (339) or 80 mg duloxetine daily (344) as 40 mg twice daily for 12 weeks. Primary outcome variables included IEF and an incontinence quality of life questionnaire. Van Elteren's test was used to analyze percent changes in IEF with a stratification variable of weekly baseline IEF (less than 14 and 14 or greater). ANCOVA was used to analyze incontinence quality of life scores.
Mean baseline IEF was 18 weekly and 436 subjects (64%) had a baseline IEF of 14 or greater. There was a significant decrease in IEF with duloxetine compared with placebo (50% vs 27%, p <0.001) with comparably significant improvements in quality of life (11.0 vs 6.8, p <0.001). Of subjects on duloxetine 51% had a 50% to 100% decrease in IEF compared with 34% of those on placebo (p <0.001). These improvements with duloxetine were associated with a significant increases in the voiding interval compared with placebo (20 vs 2 minutes, p <0.001) and they were observed across the spectrum of incontinence severity. The discontinuation rate for adverse events was 4% for placebo and 24% for duloxetine (p <0.001) with nausea the most common reason for discontinuation (6.4%). Nausea, which was also the most common side effect, tended to be mild to moderate and transient, usually resolving after 1 week to 1 month. Of the 78 women who experienced treatment emergent nausea while taking duloxetine 58 (74%) completed the trial.
These phase 3 data are consistent with phase 2 data and they provide further evidence for the safety and efficacy of duloxetine as a pharmacological agent for the treatment of women with SUI.
度洛西汀是一种选择性5-羟色胺和去甲肾上腺素再摄取抑制剂，通过刺激阴部运动神经元α-1肾上腺素能受体和5-羟色胺-2受体增加尿道外括约肌收缩力。在这项首个3期研究中，我们评估了度洛西汀治疗压力性尿失禁（SUI）女性的疗效和安全性。
本双盲、安慰剂对照研究共纳入683名22至84岁的北美女性。病例定义包括以SUI为主要症状，每周尿失禁发作频率（IEF）为7次或更多，无急迫性尿失禁主要症状，昼夜排尿频率正常，膀胱容量为400毫升或更大，以及咳嗽压力试验和压力垫试验阳性。经过2周的安慰剂导入期后，受试者被随机分配接受安慰剂（339例）或每日80毫克度洛西汀（344例），分两次服用，每次40毫克，共12周。主要结局变量包括IEF和尿失禁生活质量问卷。采用范埃尔teren检验分析IEF的百分比变化，分层变量为每周基线IEF（小于14次和14次或更多）。采用协方差分析分析尿失禁生活质量评分。
平均基线IEF为每周18次，436名受试者（64%）的基线IEF为14次或更多。与安慰剂相比，度洛西汀治疗后IEF显著降低（50%对27%，p<0.001），生活质量也有相当显著的改善（11.0对6.8，p<0.001）。接受度洛西汀治疗的受试者中，51%的人IEF降低了50%至100%，而接受安慰剂治疗的受试者中这一比例为34%（p<0.001）。与安慰剂相比，度洛西汀带来的这些改善与排尿间隔时间显著延长相关（20分钟对2分钟，p<0.001），且在整个尿失禁严重程度范围内均有观察到。安慰剂组不良事件停药率为4%，度洛西汀组为24%（p<0.001），恶心是最常见的停药原因（6.4%）。恶心也是最常见的副作用，往往为轻至中度且短暂，通常在1周至1个月后缓解。在服用度洛西汀期间出现治疗中恶心的78名女性中，58名（74%）完成了试验。
这些3期数据与2期数据一致，为度洛西汀作为治疗SUI女性的药物的安全性和有效性提供了进一步证据。
