Tolterodine for the treatment of urge urinary incontinence

Introduction: Overactive bladder (OAB) and its resultant urge urinary incontinence (UUI) are significant problems that medically, psychologically and financially affect people. The constellation of symptoms comprising OAB affects ～ 16% of the adult population and its prevalence increases with aging. The typical class of medications used to treat OAB is antimuscarinics.

Areas covered: OAB medications, with a focus on tolterodine for the treatment of UUI are reviewed. A thorough review of English language literature using EMBASE/Medline and PubMed has been performed.

Expert opinion: Tolterodine provides a reasonable starting point when treating patients with OAB and UUI. Efficacy and tolerability are generally comparable between tolterodine and other newer antimuscarinics. Tolterodine is a good option as part of the algorithm in the treatment of OAB and UUI.     

曲司氯铵——治疗伴有急迫性尿失禁症状的膀胱过度活动症的新药

曲司氯铵为新近上市的用于治疗伴有急迫性尿失禁症状的膀胱过度活动症的抗胆碱药物,具有抗胆碱能神经末梢M_1,M_2,M_3受体的作用,从而拮抗乙酰胆碱对人膀胱平滑肌的收缩效应。可有效降低膀胱平滑肌的紧张度、解除痉挛状态,显著增加最大膀胱容量、第1次逼尿肌收缩时膀胱容量,提高膀胱顺应性,降低最大逼尿肌压力,有效减轻尿频、尿急以及尿失禁症状。临床效能与奥昔布宁相当,而优于托特罗定。本品起效快、长期疗效优良,此外,本品仅具有抗胆碱药物的外周常见不良反应,如口干、便秘等,但不进入中枢神经系统,没有中枢神经系统毒性。本文对其药理学及临床研究进行综述。     

Oxybutynin chloride topical gel: a new formulation of an established antimuscarinic therapy for overactive bladder

Background: Oxybutynin, a cholinergic-muscarinic receptor antagonist, is established as a safe and effective pharmacological treatment for patients with overactive bladder syndrome (OAB). Oxybutynin is available in multiple immediate- and extended-release oral and two transdermal formulations. Oxybutynin chloride topical gel (OTG) (Gelnique^®, Watson Pharmaceuticals, Corona, CA, USA) was approved in January 2009 by the US FDA. OTG was designed to provide consistent plasma oxybutynin levels with daily application, favorably altering the circulating N-desethyloxybutynin metabolite:oxybutynin ratio, and to utilize a biocompatible delivery system, thus minimizing both the anticholinergic adverse effects of oral formulations and the application-site skin reactions associated with other available forms of transdermal delivery. Objective/methods: This review summarizes the pharmacological properties and the clinical efficacy and safety profile of OTG based on the published literature and unpublished data provided by the manufacturer upon request. Results/conclusion: OTG represents an efficacious, safe, and convenient alternative to other oxybutynin formulations and other oral anticholinergic medications for the treatment of OAB. Future studies and broad clinical experience should confirm the promising early experience observed with this formulation.     

Oxybutynin for treatment of urge urinary incontinence and overactive bladder: an updated review

Urge urinary incontinence (UUI) and overactive bladder are common conditions often associated with profound impairment of the health and quality of life of the patient. Antimuscarinic medications have been the mainstay of treatment for these disorders. Oxybutynin hydrochloride, one of the most widely used antimuscarinic agents, has attracted considerable interest from both clinicians and pharmacologists over the last three decades. Although efficacy of this drug has been proven to be high, its use is limited by antimuscarinic adverse effects, possibly related to its active metabolite N-desethyloxybutynin (N-DEO). The extended-release form of oxybutynin uses a push-pull osmotic release system which has significantly improved its tolerability and safety profile. A transdermal transport system has also been developed, bypassing the first-pass metabolism in the liver and gut. This system is associated with significant reduction in the production of the primary metabolite and additional improvement in the tolerability profile of the drug. Intravesical instillation of oxybutynin has been reported although the efficacy and safety of this delivery system has yet to be determined. This article comprehensively reviews the contemporary literature on the pharmacology, clinical efficacy and adverse reactions of oxybutynin in its various delivery forms, and compares them to other frequently used medications for UUI and overactive bladder.     

Transdermal oxybutynin: a new treatment for overactive bladder

Overactive bladder has been successfully treated with oral anticholinergic drugs such as oxybutynin chloride. Although oral oxybutynin has been effective in controlling urinary urge incontinence and in decreasing incontinence episodes, adverse events, particularly dry mouth, often cause patients to discontinue oral therapy and to endure incontinence. Transdermal oxybutynin (Oxytrol^®, Watson Pharmaceuticals) is applied twice-weekly to maintain the efficacy of oral oxybutynin while significantly minimising side effects (e.g., dry mouth) that complicate therapy. By avoiding hepatic and gastrointestinal metabolism of oxybutynin, less N-desethyloxybutynin (N-DEO), the compound thought to be responsible for anticholinergic side effects, such as dry mouth, is produced. The new transdermal oxybutynin formulation offers patients with urinary incontinence an effective, safe and well-tolerated option for managing the symptoms of overactive bladder.     

Pharmacological agents for the treatment of urinary incontinence due to overactive bladder

Although the exact aetiology of overactive bladder is unknown to date, pharmacological therapy has been targeted to both the central and peripheral nervous systems. Potential CNS targets include GABA, opioid, serotonin (5-HT), dopamine and glutaminergic receptors as well as the α-adrenoceptors. Potential PNS targets include muscarinic receptors, calcium and potassium channels and α- and β-adrenergic receptors. Since acetylcholine is the primary excitatory neurotransmitter involved in bladder (detrusor) contraction and emptying, anticholinergic agents are the primary compounds used clinically to decrease involuntary detrusor contractions. Anticholinergic therapy has a stabilising effect on the bladder (detrusor muscle); increases bladder capacity; decreases frequency of involuntary detrusor contractions; and delays the initial urge to void, but does not affect warning time. However, the clinical utility of antimuscarinic therapy is limited by the lack of receptor selectivity, resulting in the classic anticholinergic side effects of dry mouth, blurred vision, constipation and potentially, CNS effects such as somnolence and impaired cognitive function. These unwanted side effects often result in premature discontinuation of therapy and poor compliance. Previous attempts to develop uroselective α-adrenergic receptor antagonists have not been successful and although research continues, the hope that this class of agents would be viable alternatives to the anticholinergics remains to be proven in the clinical setting. The recent demise of several potassium channel openers does not augur well for the future of this class of agent. The reasons for the discontinuation of trials with these agents have not been fully elucidated, but one must assume that they were not uroselective and the cardiovascular side effects rendered them less than useful clinically. The serotonin re-uptake inhibitors appear to be promising novel therapeutic agents aimed at controlling bladder over-activity through specific CNS pathways. The sensory side of the micturition reflex is a potential therapeutic target. Agents to desensitise afferent nerve endings involved in C-fibre afferent reflexes include capsaicin and resiniferatoxin. Their clinical applicability is currently being evaluated. Finally, the recent findings related to the role of the P2X3 receptor in the sensory aspects of bladder filling have created new interest in the future development of agents that will improve the management of this prevalent and debilitating condition.     

Oxybutynin gel for the treatment of overactive bladder

Benign prostatic hyperplasia is an increasingly prevalent condition affecting > 50% of men > 65 years of age. Although it is a condition that is unlikely to be life threatening, it can significantly affect quality of life with distressing lower urinary tract symptoms. Increasingly, medical therapy is being used as first-line treatment for men with moderate-to-severe lower urinary tract symptoms. Two main pharmacological classes of drugs are used: 5α-reductase inhibitors and α-1 selective blockers. Both these classes of drugs have shown good tolerability and clinical efficacy. This article examines the potential benefit of the use of combination therapy. In particular, what is the evidence for using doxazosin and finasteride therapy together?     

An appraisal of recently patented compounds for bladder overactivity and urinary incontinence

Bladder overactivity and urinary incontinence are lower urinary tract syndromes for which there is no adequate pharmacological treatment. The latter condition is associated with an involuntary loss of urine causing a hygienic and social concern to the patient. Recently, central and peripheral mechanisms that control bladder storage and voiding processes have been partly addressed and clarified. Novel antimuscarinic agents, as well as newer formulations of available drugs and selective antagonists at α_1D-receptors, have been patented, in addition to selective agonists at the β₃-adrenoceptor and selective antagonists at 5-hydroxytryptamine, subtype 1A and 7 (5-HT_1A and 5-HT₇) receptors. Other potential therapeutic options include neurokinin type 1 and 2 (NK1/NK2) tachykinin receptor antagonists and potassium channel openers. The aforementioned agents may contribute to the pharmacological armamentarium in urology treatment, although their therapeutic effectiveness and safety profile remain to be validated in the clinical setting.     

The emergence of new drugs for overactive bladder

Overactive bladder is a common and distressing problem. Standard therapy is directed towards modifying the detrusor motor sensitivity and response via anticholinergic medication. Currently available medications are reviewed and alternative targets for treatment are presented.     

Discovery history and clinical development of mirabegron for the treatment of overactive bladder and urinary incontinence

Introduction: Overactive bladder (OAB) and urinary incontinence, although not life-threatening, are very bothersome chronic health conditions. The limitations of current pharmacological treatment urge the need for novel drugs with alternative mechanisms of action. Huge efforts in this area of research led to the synthesis of several selective and potent β3-adrenoceptor agonists that gained relevance through research during the late 80s and 90s. Mirabegron was the first compound of this new class of drugs that showed preclinical efficacy in several models of storage bladder dysfunction, together with a favorable human pharmacological profile. Having passed the proof-of-concept stage, an extensive clinical development and pharmacology program was performed during the last 10 years, involving > 10,000 individuals, before mirabegron was granted marketing approval.

Areas covered: In this case history, the authors review the milestones in mirabegron's discovery based on a systematic literature review.

Expert opinion: Thanks to its tolerability and safety/efficacy balance, mirabegron has potential to fill a need for new treatment options for OAB, and paves the way for further development of a completely new class of drugs aimed to treat this condition. However, the exact role of mirabegron in clinical practice has yet to be defined. Further studies are needed in order to clarify, together with post-launch information, critical safety issues and cost-effectiveness in head-to-head comparison with current standard treatments.     

Managing urinary incontinence in women - a review of new and emerging pharmacotherapy

ABSTRACT

Introduction

The pharmacological treatment of urinary incontinence and overactive bladder (OAB) has been, for a longer time, based on antimuscarinic agents. In recent years, two other pharmacological principles have been introduced for the treatment of OAB and urgency urinary incontinence: the β3-adrenergic agent mirabegron and botulinum neurotoxin. Meanwhile, there is lack of effective drugs for the treatment of stress incontinence.     

奥昔布宁对下尿路刺激症及急迫性尿失禁病人的疗效

目的：比较国产与进口奥昔布宁对下尿路刺激症及急迫性尿失禁病人的疗效。方法：２０３例下尿路刺激症及急迫性尿失禁病人（男性１３５例，女性６８例，年龄５２±ｓ１７ａ），随机分试验组１２３例与对照组８０例，试验组与对照组分别给国产与进口奥昔布宁片５ｍｇ，ｐｏ，ｔｉｄ，７～１４ｄ。儿童减半。结果：以总点数、尿流率及尿量评估２组皆有显著疗效（Ｐ＜０．０１），２组间疗效差别不显著（Ｐ＞０．０５）。不良反应轻微。结论：国产与进口奥昔布宁对治疗下尿路刺激症及急迫性尿失禁疗效相仿。     

Pharmacotherapy of overactive bladder syndrome

Urinary incontinence is a common and distressing condition that is known to adversely affect quality of life. Overactive bladder (OAB) is the term used to describe the symptom complex of urgency with or without urge incontinence, usually with frequency and nocturia. Drug therapy, in addition to behavioral modification, remains integral in the management of women with OAB, and the development of new drugs, treatment regimens and methods of delivery should improve patient compliance and acceptability. Developments over the last 10 years have led to the launch of several new drugs for the treatment of OAB that may offer greater efficacy while minimizing adverse effects. This article critically reviews the current pharmacological treatment of OAB in addition to providing a rationale for treatment.     

The emerging role of solifenacin in the treatment of overactive bladder

Although antimuscarinic drug therapy has been proven to be effective in the management of patients with symptoms of the overactive bladder syndrome, compliance with medication is often affected by the antimuscarinic adverse effects of dry mouth, constipation, somnolence and blurred vision. The development of bladder-selective M₃-specific antagonists offers the possibility of increasing efficacy whilst minimising adverse effects. At present there are no M₃-specific antagonists currently available although solifenacin and darifenacin are both under development and are due to be launched in 2004. The purpose of this article is to review the pharmacology and clinical trial data available for solifenacin, in addition to examining its role in the treatment of the overactive bladder syndrome.     

AE9C90CB: a novel, bladder-selective muscarinic receptor antagonist for the treatment of overactive bladder

Background and purpose:

AE9C90CB (N- [(1R, 5S, 6R)-3-azabicyclo [3.1.0] hex-6-ylmethyl]-2-hydroxy-N-methyl-2, 2-diphenylacetamide), a novel muscarinic receptor antagonist, was synthesized for the treatment of overactive bladder. Here we describe the in vitro and in vivo profiles of AE9C90CB for action in bladder over salivary gland and compare it with four agents already in clinical use (tolterodine, oxybutynin, solifenacin and darifenacin).

Experimental approach:

Radioligand binding assay and isolated tissue-based functional assay were used to evaluate affinity, potency, and receptor subtype selectivity of compounds. Inhibition of carbachol-induced increase in intravesicular pressure and salivary secretion were measured in anaesthetized rabbits to assess the functional selectivity.

Key results:

In vitro radioligand binding study using human recombinant muscarinic receptors showed that AE9C90CB had greater affinity for M₃ muscarinic receptors with pKi of 9.90 ± 0.11 and was 20-fold more selective for M₃ than for M₂ muscarinic receptors. AE9C90CB exhibited an unsurmountable antagonism on rat bladder strips (pK_B, 9.13 ± 0.12). In anaesthetized rabbits after intravenous administration, AE9C90CB dose dependently inhibited carbachol-induced increase in intravesicular pressure and salivary secretion, and exhibited functional selectivity for urinary bladder over salivary gland which was ninefold better than that of oxybutynin.

Conclusions and implications:

We have identified AE9C90CB, a compound exhibiting moderate selectivity for M₃ over M₂ receptors but greater selectivity for urinary bladder over salivary gland than oxybutynin, tolterodine, solifenacin and darifenacin. Therefore, AE9C90CB may be a promising compound for the treatment of overactive bladder with reduced potential to cause dry mouth than currently available antimuscarinic drugs.     

Effects of tolterodine ER on patient-reported outcomes in sexually active women with overactive bladder and urgency urinary incontinence

ABSTRACT

Objective: To assess the effects of tolterodine extended release (ER) on patient-reported outcomes (PROs) in sexually active women with overactive bladder (OAB) and urgency urinary incontinence (UUI).

Research design and methods: This multicenter, double-blind, placebo controlled trial included 411 women aged?≥18 years reporting OAB symptoms for ≥3 months; ≥8 micturitions per 24 hours (including ≥0.6 UUI episodes and ≥3 OAB micturitions) in 5-day bladder diaries at baseline, and being in a sexually active relationship for ≥6 months. Subjects randomized to placebo or tolterodine ER completed validated OAB- or incontinence-specific questionnaires, including the Patient Perception of Bladder Condition (PPBC), Overactive Bladder Questionnaire (OAB-q), Urgency Perception Scale (UPS), and the Incontinence Impact Questionnaire (IIQ) at baseline and week 12, as well as the Perception of Treatment Benefit and Treatment Satisfaction questions at week 12. This study is registered with ClinicalTrials.gov (identifier: NCT00143481)

Results: The mean age of enrolled women was approximately 48 years. Compared with placebo, the tolterodine ER group reported significant baseline to week 12 improvements in PPBC responses (p?=?0.0048); OAB-q Symptom Bother, total Health-Related Quality of Life (HRQL), and HRQL domain scores (all p?<?0.05); IIQ Emotional Health domain scores (p?<?0.05); proportions of subjects reporting treatment benefit (79 vs. 54%; p?<?0.0001) and satisfaction (78 vs. 59%; p?<?0.0001). Improvements on the UPS were not significantly different.

Conclusions: Tolterodine ER treatment was associated with improvements in multiple OAB- and incontinence-specific PROs in a sexually active, relatively young, and racially diverse population of women. The findings provide clinicians with new insights into the impact of OAB and its treatment on HRQL in this population, which has been underrepresented in previous OAB studies. Study limitations include a potential underestimation of the impact of OAB symptoms resulting from the exclusion of women who may not be sexually active because of their urinary symptoms.

Trial registration: ClinicalTrials.gov identifier: NCT00143481.     

Pharmacotherapy of overactive bladder: epidemiology and pathophysiology of overactive bladder

Introduction: Overactive bladder (OAB) describes complex symptoms, comprising of urinary urgency, with or without urinary incontinence, often with increased daytime frequency and nocturia in the absence of infection or other obvious etiology. OAB is highly prevalent and affects physical and mental health, activities of daily life and the quality of life of millions of adults. The pathophysiology of OAB and detrusor overactivity is still not completely known, but is most probably multifactorial.

Areas covered: The epidemiology and pathophysiology of OAB is reviewed. A literature search using PubMed from 2000 to 2010 was undertaken for this review with pertinent older papers referenced as needed to gain a clearer understanding of the epidemiology of OAB and related bladder pathophysiology, which it is hoped will lead to more effective and better-tolerated treatments for OAB.

Expert opinion: With recent advances in our understanding of the basic science of OAB, it is becoming clear that the control of bladder function is far more complex than previously believed. Recent research has highlighted several potential targets for the treatment of OAB, particularly within the mechanosensory pathways.     

Tolterodine for the treatment of overactive bladder

Background: The overactive bladder syndrome is a common condition affecting ～ 12% of men and women. It is extremely disturbing with a great impact on quality of life. Its treatment involves a combination of behavioural and pharmacological therapy. The latter includes antimuscarinic drugs such as tolterodine. Objective: To review the safety and efficacy of tolterodine in the treatment of overactive bladder in comparison with other available antimuscarinic agents. Methods: A Pubmed search was carried out differentiating randomised, clinical trials; longitudinal, retrospective studies; and metanalysis on the use of tolterodine for overactive bladder treatment. In the comparison with other antimuscarinic agents, only randomised, clinical trials were considered. Results/conclusion: Tolterodine is available as immediate- or extended-release formulations. It has been extensively evaluated with long-term, randomised trials for safety and efficacy showing a significant improvement in overactive bladder symptoms with an excellent tolerability profile.     

Emerging drugs for overactive bladder

Introduction: Overactive bladder (OAB) is a common problem which can have disastrous effects on the quality of life of the sufferer. There are established treatments for the problem but they have significant adverse effects. Better drugs and new treatment modalities are necessary to deal with OAB.

Area covered: Antimuscarinics, mirabegron and intravesical injection of botulinum toxin A are established treatments for OAB. Sacral neuromodulation is more invasive but has been successful in treating OAB. Phase II and III trials are in progress for newer β3-agonists and various combinations of antimuscarinics, β3-agonists and antidiuretics. Targeted secretion inhibitors (TSI) can increase efficacy and reduce adverse effects. Liposome integrated botulinum toxin A has an advantage of effective administration by intravesical instillation. Both medicines are in Phase II trials. Many other drugs which have promising results are discussed.

Expert opinion: Newer antimuscarinics have better tolerability. Long-term data for mirabegron has shown that it is more effective in severe OAB. Combination drugs may prove to be more effective with less adverse effects. Emerging treatments with TSI, lipotoxin and gene therapy appear promising.     

New insights into molecular targets for urinary incontinence

Urinary incontinence (UI) is a disease affecting quality of life of 200 million patients worldwide. It is characterized by involuntary loss of urine. The factors involved are cystitis, detrusor hyperreflexia, spinal injury, benign prostatic hyperplasia, etc. The surge in the number of reviews on this subject indicates the amount of research devoted to this field. The prevalence is increasing at an alarming rate but unfortunately, only a few medications are currently available for this condition. There are peripheral as well as central targets including cholinergic, vanilloid, prostaglandin, kinin, calcium channel, cannabinoid, serotonin, and GABA-receptors, which act by different mechanisms to treat different types of incontinence. Drugs acting on the central nervous system (CNS) increase urinary bladder capacity, volume, or pressure threshold for micturition reflex activation while peripherally acting drugs decrease the amplitude of micturition contraction and residual volume. Anticholinergic drugs specifically M3 receptor antagonists are the first choice but have frequent side effects such as dry mouth, CNS disturbances, etc. Therefore, there is a need to understand the biochemical pathways that control urinary dysfunction to determine the potential to which they can be exploited in the treatment of this condition. This article reviews the central and peripheral molecular targets and the potential therapeutic approaches to the treatment of UI.