治疗膀胱过度活动症的新药托特罗定

托特罗定是新型竞争性毒蕈碱受体拮抗剂，对膀胱的选择性远大于唾液腺的选择性，在临床上用于治疗由膀胱过度活动引起的尿频、尿急和急迫性尿失禁。疗效与奥昔布宁相当，耐受性却明显优于奥昔布宁。主要代谢物为5－羟甲基衍生物，也具有相似的药学活性。     

膀胱过度活动症治疗药Mirabegron

Mirabegron（Betanis@）是由Astellas公司开发的口服有效的新型选择性β3,肾上腺素能受体激动剂,已在日本首次获推荐批准,用于治疗膀胱过度活动症（OAB）,且也已在欧美递交上市申请。     

膀胱过度活动症的药物治疗

膀胱过度活动症近年来发病率明显增加并引起人们的广泛关注。相关药物开发及治疗效果的研究也逐渐增多。本文概述相关药物的作用机制和应用情况,为临床提供参考。     

膀胱过度活动症的新进展

<正>排尿功能障碍最常见的临床表现之一:膀胱过度活动症(Overactive bladder,OAB);主要症状为尿频、尿急、尿失禁,常伴有夜尿[1]。包括不稳定膀胱及逼尿肌反射亢进,在神经性膀胱称为逼尿肌反射亢进,在非神经性膀胱则称为逼尿肌不稳定[2],其发病原因则是多方面的。目前OAB的病因尚不完全清楚,目前的研究提示与     

膀胱过度活动症药物治疗的进展

膀胱过度活动症（OAB）是一种相当常见的慢性疾患,给患者的生活带来严重的困扰,相关药物开发及治疗效果的研究也逐渐增多。目前临床用于治疗OAB的主要药物有抗胆碱药物、钙拮抗剂及钾离子通道开放剂、肾上腺素受体激动剂以及神经感觉传人阻断剂等。本文对治疗膀胱过度活动症药物的进展做一综述。     

托特罗定缓释片治疗膀胱过度活动症的临床研究

目的评价酒石酸托特罗定缓释片治疗膀胱过度活动症的有效性与安全性。方法采用随机、双盲、双模拟平行对照的方法对膀胱过度活动症220例进行托特罗定缓释片剂型组（观察组,110例）和托特罗定原剂型组（对照组,110例）对比研究。托特罗定缓释片,每片4 mg,每日1次,口服;托特罗定片,每片2 mg,每日2次,口服。各连服6周。结果治疗后观察组24 h平均排尿次数由（12.21±3.10）次降至（8.50±2.31）次,24 h平均每次排尿量由（119.80±30.54）ml增至（215.50±68.52）ml、24 h平均尿失禁次数由（2.88±2.5）次减至（0.07±0.38）次。治疗前后比较,有极显著差异（P〈0.01）。两组治疗后相比较,无显著性差异。观察组对药物不良反应发生率为38.0%,中毒发生率为18.5%;对照组分别为40.8%和20.0%,总发生率两者无显著性差异（P〉0.05）。结论托特罗定缓释片与托特罗定片,其疗效与不良反应基本相同。但托特罗定缓释片,用药次数少,服用方便,为膀胱过度活动症治疗药物的最佳选择。     

膀胱过度活动症的诊断进展

目的:综述膀胱过度活动症的诊断进展。方法:分别对筛选性检查和选择性检查与问卷评估等用于膀胱过度活动症的诊断进行总结。结果:筛选性检查和选择性检查与问卷评估是三种不同的用于膀胱过度活动症诊断的方法。结论:临床泌尿外科医生应该加强对膀胱过度活动症的认识。     

膀胱过度活动治疗药Darifenacin

Darifenacin(Enablex)是由辉瑞公司开发、最近又被诺华公司购得的一种选择性毒蕈碱M3受体拮抗剂，用于治疗尿失禁。该药已于2002年12月在美国递交了新药申请，可望不久上市。     

膀胱灌注辣椒辣素类似物治疗特发性膀胱过度活动症随机对照临床研究

目的探讨膀胱灌注辣椒辣素类似物（RTX）治疗特发性膀胱过度活动症（IOAB）的临床效果。方法IOAB患者26例随机分为试验A组和对照B组。A组14例，用100nmol／LRTX 100ml灌注膀胱保留30min后排空。B组12例，用1：5000呋喃西林（安慰剂）替代RTX，方法同A组。观察A，B两组用药前、用药后1个月、用药后3个月的临床症状（每日排尿次数、尿急程度）和尿动力学参数（FDV、MCBC、Qmax）。结果治疗前与治疗后1个月、3个月的临床症状和尿动力学参数比较，A组差异有显著意义（P〈0．01），B组差异无显著意义（P〉0．05）。14／26例（54％）有轻度尿道刺激症状或膀胱区不适，均可耐受。结论RTX单剂量膀胱灌注能安全有效地改善IOAB临床症状和尿动力学指标。     

新型抗胆碱药物索利那新治疗膀胱过度活动症的临床效果观察

目的探讨索利那新治疗膀胱过度活动症的临床疗效。方法 84例膀胱过度活动症患者,随机分为治疗组和对照组,各42例,治疗组患者采用新型抗胆碱药物索利那新治疗,对照组患者采用托特罗定治疗,比较两组患者治疗后临床症状的改善情况以及不良反应发生情况。结果治疗前两组患者24 h内排尿次数和急性尿失禁次数以及OABSS评分比较,差异均无统计学意义(P>0.05);治疗后,治疗组患者排尿次数和急性尿失禁次数显著少于对照组患者,OABSS评分显著低于对照组患者,差异有统计学意义(P<0.05);治疗组患者的不良反应发生率7.14%,显著低于对照组患者16.67%,差异有统计学意义(P<0.05)。结论新型抗胆碱药物索利那新治疗膀胱过度活动症临床效果佳,不良反应发生率低,安全性高。     

Fesoterodine: a novel muscarinic receptor antagonist for the treatment of overactive bladder syndrome

Background: Fesoterodine is a newly approved drug for the treatment of overactive bladder syndrome. Objective: The aim of this study was to review the preclinical and clinical data on fesoterodine. Methods: The study involved a search of the Medline database and the proceedings volumes of urological congresses. Results/conclusions: Fesoterodine functions as an orally active prodrug that is converted to the active metabolite 5-hydroxymethyltolterodine by non-specific esterases. 5-Hydroxymethyltolterodine is a muscarinic receptor antagonist. Fesoterodine is primarily eliminated as inactive metabolites along with significant renal excretion as the unchanged active metabolite 5-hydroxymethyltolterodine. Fesoterodine is indicated for use at doses of 4 and 8 mg once daily. In clinical studies both doses of fesoterodine were consistently superior to placebo in improving the symptoms of overactive bladder syndrome, with 8 mg/day having significantly greater effects than 4 mg/day.     

大剂量坦索罗辛与富马酸非索罗定联合治疗良性前列腺增生症的疗效及优质护理的作用

目的：探讨大剂量坦索罗辛联合富马酸非索罗定在良性前列腺增生症（ benign prostatic hyperplasia,BPH）中的应用及护理要点。方法：随机选取100例BPH患者,所有患者均口服坦索罗辛0．2 mg＋富马酸非索罗定4 mg,疗程12周。以随机数字表法将患者分为优质护理组和对照组各50例,优质护理组患者给予心理护理、用药指导、生活护理和饮食护理等优质护理,对照组患者仅给予常规护理。统计患者治疗前后国际前列腺症状评分、生活质量评分,测定最大尿流率,并进行护理效果评价。结果：治疗后,所有患者的国际前列腺症状评分、生活质量评分分别为（12．89±1．14）、（3．02±0．12）分,最大尿流率提高至（16．33±3．26） ml／s,与治疗前的差异均有统计学意义（P＜0．05）;优质护理组患者术后护理满意度和舒适度分别为98．00％（49／50）和96．00％（48／50）,均明显高于对照组的80．00％（40／50）和82．00％（41／50）,差异均有统计学意义（P＜0．05）。结论：大剂量坦索罗辛与富马酸非索罗定联合治疗BPH,可迅速缓解下尿路梗阻症状,联合给予优质护理后,可提高护理效果,改善患者生活质量。     

Treatment of Overactive Bladder with Once-daily Extended-release Tolterodine or Oxybutynin: The Antimuscarinic Clinical Effectiveness Trial (ACET)

Summary

Treatment with the antimuscarinic agents tolterodine and oxybutynin is the mainstay of therapy for overactive bladder, a chronic and debilitating condition characterized by urinary urgency with or without urge incontinence, usually in combination with urinary frequency and nocturia. This study consisted of two trials; in one, patients with overactive bladder were randomized to 8 weeks of open-label treatment with either 2?mg or 4?mg of once-daily extended-release tolterodine (TER), and in the other to 5?mg or 10?mg of extended-release oxybutynin (OER). The study protocol and design were identical for the two trials and site selection ensured that there was no bias in either trial for the tendency of investigators to prescribe one drug rather than the other, or for geographical location. A total of 1289 patients were enrolled, 669 in the tolterodine trial (TER 2?mg, n?=?333; TER 4?mg, n?=?336) and 620 in the oxybutynin trial (OER 5?mg, n?=?313; OER 10?mg, n?=?307). Fewer patients prematurely withdrew from the trial in the TER 4?mg group (12%) than either the OER 5?mg (19%; p?=?0.01) or OER 10?mg groups (21%; p?=?0.002). More patients in the OER 10?mg group than the TER 4?mg group withdrew because of poor tolerability (13% vs 6%; p?=?0.001). After 8 weeks, 70% of patients in the TER 4?mg group perceived an improved bladder condition, compared with 60% in the TER 2?mg group, 59% in the OER 5?mg group and 60% in the OER 10?mg group (all p?<?0.01 vs TER 4?mg). Response to therapy was greater in a subgroup of patients whose perception of bladder condition was moderate to severe at baseline (TER 4?mg 77% vs OER 10?mg 65%; p?<?0.01). Dry mouth was dose-dependent with both agents, although differences between doses only reached statistical significance in the oxybutynin trial (OER 5?mg vs OER 10?mg; p?=?0.05). Patients treated with TER 4?mg reported a significantly lower severity of dry mouth compared with OER 10?mg. In conclusion, the greater efficacy and tolerability of tolterodine ER 4?mg suggests improved clinical effectiveness compared with oxybutynin ER 10?mg.     

Incidence of Common Cancers in Users of Antimuscarinic Medications for Overactive Bladder: A Danish Nationwide Cohort Study

The purpose of this study was to estimate the incidence rate (IR) of 10 common cancers in new users of antimuscarinic overactive bladder (OAB) medications. We conducted a cohort study using data recorded in Danish registers for patients newly exposed to the OAB drugs, darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine or trospium in years 2004–2012, aged ≥18 years and without cancer before treatment initiation. We estimated IRs for each study cancer (bladder, breast, colorectal, lung, melanoma, non‐Hodgkin lymphoma, pancreas, prostate, renal and uterine), standardised by age and sex and explored IR trends over time since treatment initiation. For all cancer analyses, only the first incident targeted cancer was considered. Of 72,917 patients (60% women; mean age at treatment start: 66 years), 3475 developed a study cancer during 259,072 person‐years of follow‐up. The most common study cancers were prostate (48.1% of study cancers in men), breast (40.0% of study cancers in women) and lung (15.4% of all study cancers). The overall standardised study cancer IR was 5.4 per 1000 person‐years (95% confidence interval, 5.3–5.6); IRs were similar across individual OAB drugs. The standardised IRs for bladder and prostate cancers, which have symptoms in common with OAB, were highest in the first 6 months of treatment initiation and lower thereafter. In contrast, IRs for other study cancers were nearly constant during follow‐up. Cancer IRs did not vary substantially by individual OAB drug. Protopathic bias is a plausible explanation for the higher rates of bladder and prostate cancers observed soon after starting OAB drug treatment.     

Antimuscarinic Potency and Bladder Selectivity of PNU-200577, a Major Metabolite of Tolterodine

Abstract: PNU-200577 (labcode DD 01 [(R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine) is a major pharmacologically active metabolite of tolterodine, a new muscarinic receptor antagonist intended for the treatment of an overactive bladder. In virro, PNU-200577 produced a competitive and concentration-dependent inhibition of carbachol-induced contraction of guinea-pig isolated urinary bladder strips (K_B=0.84 nM; pA₂=9. 14). In vivo, PNU-200577 was significantly more potent at inhibiting acetylcholine-induced urinary bladder contraction than electrically induced salivation in the anaesthetised cat (ID₅₀ 15 and 40 nmol. kg^?l, respectively; P<0.0l). In radioligand binding studies carried out in homogenates of guinea-pig tissues and Chinese hamster ovary cell lines expressing human muscarinic ml-m5 receptors, PNU-200577 was not selective for any muscarinic receptor subtype. Thus, PNU-200577 is similar to tolterodine in terms of antimuscarinic potency, functional selectivity for the urinary bladder in vivo and absence of selectivity for muscarinic receptor subtypes in vitro. The results of this study clearly indicate that PNU-200577 contributes to the therapeutic action of tolterodine, in view of its high antimuscarinlc potency, similar serum concentration and lower degree of protein binding.     

Botulinum toxin A for the Treatment of Overactive Bladder

The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder.     

Variation in Cardiovascular Risk Related to Individual Antimuscarinic Drugs Used to Treat Overactive Bladder: A UK Cohort Study

Background

Blocking muscarinic receptors could have an effect on cardiac function, especially among elderly patients with overactive bladder (OAB).

Study Objective

To investigate the risk of cardiovascular (CV) events in users of antimuscarinic drugs to treat OAB.

Design, Setting, and Participants

Cohort study of new users of darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium, 18 years or older, in the United Kingdom's Clinical Practice Research Datalink (CPRD), 2004–2012.

Outcome Measurements and Main Results

Using tolterodine as the reference, we estimated propensity‐score–stratified incidence rate ratios (IRRs) for acute myocardial infarction, stroke, CV mortality, major adverse cardiac events (MACE, a combined end point of the previous three), and all‐cause death for individual antimuscarinic drugs. The study cohort included 119,912 new users of OAB drugs. The mean age at cohort entry was 62 years, 70% were female, and the mean follow‐up was 3.3 years. The adjusted IRR for MACE and current use of oxybutynin compared with current use of tolterodine was 1.14 (95% confidence interval [CI] 1.01–1.30). In contrast, the IRR was 0.65 (CI 0.56–0.76) for current use of solifenacin compared with tolterodine. In this study, performed with health care data, the distribution of risk factors was relatively similar across users of different OAB drugs and, although our analyses controlled for a range of measured potential confounders, residual confounding cannot be ruled out.

Conclusions

In an observational comparative study of users of medications to treat OAB conducted in routine clinical practice, the risk for CV side effects was increased in users of oxybutynin and decreased in users of solifenacin compared with users of tolterodine.     

新型口服抗癫痫药吡仑帕奈

吡仑帕奈是α-氨基-3-羟基-5甲基-4-异唑丙酸受体拮抗剂,为一种具有全新作用机制的抗癫痫药,临床上用于伴有或不伴有继发性强直的12岁以上患者癫痫部分发作的辅助治疗。本文对吡仑帕奈的作用机制、药效学、药代动力学、药物相互作用、临床评价和安全性等进行综述,以期为临床合理用药提供参考。     

Differences between Binding Affinities of some Antimuscarinic Drugs in the Parotid Gland and those in the Urinary Bladder and Ileum

Abstract: Possible differences between the muscarinic receptors in the guinea pig urinary bladder and those in the ileum and the parotid gland were investigated, using a receptor binding technique. The affinities of 18 antimuscarinic drugs were indirectly derived from the ability to inhibit the receptor-specific binding of the radioligand (–)³H-QNB. The Hill coefficients were close to unity which indicated that the drugs were bound to apparently uniform populations of receptors within each tissue. In contrast to traditional muscarinic antagonists, four drugs – namely, oxybutynine, dicyclomine, benzhexol and pirenzepine – bound with a significantly higher affinity in the parotid gland than in the urinary bladder and ileum. A tendency towards reversed selectivity was found for secoverine. Thus, the present results further support the hypothesis that differences in muscarinic receptors between tissues exist, e.g. smooth muscle compared with parotid gland, which can be detected only by certain antimuscarinic drugs.