Twelve-month treatment of overactive bladder: efficacy and tolerability of tolterodine

CONTEXT: Tolterodine is a bladder-selective antimuscarinic agent designed for the treatment of overactive bladder. Traditional antimuscarinic therapies are poorly tolerated due to a high incidence of anticholinergic adverse events and consequently few patients remain on long term therapy. OBJECTIVE: To evaluate the long term efficacy and tolerability of tolterodine in patients with symptoms of overactive bladder. DESIGN: Twelve-month open-label extension of 4 randomised, placebo-controlled, double-blind, multinational, multicentre trials of 4 weeks' duration. PATIENTS: 714 patients (aged 18 to 92 years) with symptoms of overactive bladder who completed the double-blind portion of the studies. INTERVENTION: Tolterodine 2 mg twice daily for up to 12 months. MAIN OUTCOME MEASURES: Micturition diary variables: number of micturitions per 24 hours, number of urge incontinence episodes per 24 hours, mean urine volume voided per micturition. Safety variables: adverse events, study discontinuation rate. RESULTS: A total of 441 patients (62%) completed 12 months' open-label treatment with tolterodine, which significantly reduced the number of micturitions per 24 hours [mean change -2.4, 95% confidence interval (CI) -2.7 to -2.2, median change -20%, p < 0.0001] and number of urge incontinence episodes per 24 hours (mean change -1.3, 95% CI -1.6 to -1.0, median change -74%, p < 0.0001), while the mean volume voided per micturition was significantly increased (+33 ml, 95% CI +28 to +38, median change +18%; p < 0.0001). 41% of patients reported dry mouth (27% mild, 10% moderate, 3% severe). Dosage reduction to 1 mg twice daily was required in 23% of patients. 15% of patients withdrew from the study due to adverse events, with 5% having associated dry mouth. CONCLUSIONS: The high percentage of patients completing 12 months' treatment indicates that tolterodine is an effective and well tolerated agent for long term treatment of overactive bladder.     

Trospium chloride: an anticholinergic quaternary ammonium compound for the treatment of overactive bladder

The International Continence Society has defined overactive bladder (OAB) as urinary urgency, with or without urge urinary incontinence, usually with urinary frequency and nocturia. Approximately 17% of men and women in the US report OAB symptoms, which can affect quality of life. Trospium chloride, which has recently been introduced in the US as Sanctura, has been prescribed for > 10 years in Europe as, for example, Spasmo-lyt, Regurin and Spasmex. Trospium chloride has been shown to be effective in relieving OAB symptoms, and has a favourable safety profile, showing < 1% difference for all adverse events compared with placebo, except for dry mouth, constipation and headache. Metabolic drug-drug interactions are unlikely, given that trospium chloride is not metabolised by cytochrome P450 isozymes. The fast-acting efficacy of trospium chloride, coupled with its good safety profile and tolerability, make it an important new option for treatment of OAB.     

Trospium chloride: an anticholinergic quaternary ammonium compound for the treatment of overactive bladder

The International Continence Society has defined overactive bladder (OAB) as urinary urgency, with or without urge urinary incontinence, usually with urinary frequency and nocturia. Approximately 17% of men and women in the US report OAB symptoms, which can affect quality of life. Trospium chloride, which has recently been introduced in the US as Sanctura^®, has been prescribed for > 10 years in Europe as, for example, Spasmo-lyt, Regurin and Spasmex. Trospium chloride has been shown to be effective in relieving OAB symptoms, and has a favourable safety profile, showing < 1% difference for all adverse events compared with placebo, except for dry mouth, constipation and headache. Metabolic drug–drug interactions are unlikely, given that trospium chloride is not metabolised by cytochrome P450 isozymes. The fast-acting efficacy of trospium chloride, coupled with its good safety profile and tolerability, make it an important new option for treatment of OAB.     

Pharmacoeconomic evaluation of antimuscarinic agents for the treatment of overactive bladder

STUDY OBJECTIVE: To compare the cost-effectiveness of various antimuscarinic agents for the treatment of overactive bladder (OAB). METHODS: A decision-analysis model was developed and included clinical outcomes (i.e., therapy continued or discontinued, treatment success or failure, OAB-induced comorbidities) and costs for drugs and treatment of OAB-induced comorbidities (i.e., urinary tract infections, fractures, depression, and skin infections). Treatment success was defined as complete continence. A systematic MEDLINE literature search from January 1990-January 2006 identified English-language articles concerning the eight antimuscarinic drugs: darifenacin, solifenacin, trospium, immediate-release oxybutynin, extended-release oxybutynin, transdermal oxybutynin, immediate-release tolterodine, and extended-release tolterodine. Probabilities and cost data for these drugs were retrieved from the literature, and drug costs were based on 2005 average wholesale prices. The analysis was constructed from a payer's perspective. The time frame for the model was 3 months. RESULTS: Expected costs for each patient with OAB ranged from $3373 when treated with solifenacin to $3769 when treated with immediate-release oxybutynin. The average cost/patient with continued and successful treatment was lowest for solifenacin ($6863). Solifenacin dominated all other antimuscarinic agents because they were associated with high costs and low effectiveness. Success rates were the key parameters driving the sensitivity analysis. CONCLUSION: Among various antimuscarinic agents, solifenacin 5 mg had the lowest costs and highest effectiveness in the treatment of OAB.     

Effect of anticholinergic use for the treatment of overactive bladder on cognitive function in postmenopausal women

Background: Overactive bladder (OAB) is a common condition affecting the elderly. The mainstay of treatment for OAB is medical therapy with anticholinergics. However, adverse events have been reported with this class of drugs, including cognitive changes. Objective: The objective of this study was to investigate the effect of an anticholinergic medication, trospium chloride, on cognitive function in postmenopausal women being treated for OAB. Methods: This was a prospective cohort study conducted at a urogynaecology clinic at one academic medical centre from January to December 2010, with 12-week follow-up after medication initiation. Women aged 55 years or older seeking treatment for OAB and opting for anticholinergic therapy were recruited. Baseline cognitive function was assessed via the Hopkins Verbal Learning Test-Revised Form (HVLT-R) [and its five subscales], the Orientation, Memory & Concentration (OMC) short form, and the Mini-Cog evaluation. After initiation of trospium chloride extended release, cognitive function was reassessed at Day 1, Week 1, Week 4 and Week 12. Bladder function was assessed via three condition-specific quality-of-life questionnaires. Secondary outcomes included change in bladder symptoms, correlation between cognitive and bladder symptoms, and overall medication compliance. The main outcome measure was change in HVLT-R score at Week 4 after medication initiation, compared with baseline (pre-medication) score. Results: Of 50 women enrolled, 35 completed the assessment. The average age was 70.4 years and 77.1% had previously taken anticholinergic medication for OAB. At enrollment 65.7% had severe overactive bladder and 71.4% had severe urge incontinence. Cognitive function showed an initial decline on Day 1 in HVLT-R total score (p?=?0.037), HVLT-R Delayed Recognition subscale (p?=?0.011) and HVLT-R Recognition Bias subscale (p?=?0.01). At Week 1 the HVLT-R Learning subscale declined from baseline (p?=?0.029). All HVLT-R scores normalized by Week 4. OMC remained stable throughout. The Mini-Cog nadired at a 90.9% pass rate at Week 4. OAB symptoms did not improve until Week 4, based on questionnaire scores (p?相似文献   

In vivo characterization of muscarinic receptors in peripheral tissues: evaluation of bladder selectivity of anticholinergic agents to treat overactive bladder

The present study was undertaken to characterize in vivo muscarinic receptors in peripheral tissues (urinary bladder, submaxillary gland, colon, stomach, heart) of mice, and further to evaluate bladder-selectivity of anticholinergic agents to treat overactive bladder. Following i.v. injection of [(3)H]QNB in mice, the radioactivity in peripheral tissues was exclusively detected as the unchanged form. The in vivo specific [(3)H]QNB binding in particulate fraction of tissue homogenates of mice showed a pharmacological specificity which characterized muscarinic receptors. Binding parameters (K (d) and B (max)) for in vivo specific [(3)H]QNB binding differed between mouse tissues. Oral administration of oxybutynin attenuated significantly in vivo specific [(3)H]QNB binding in all tissues of mice. From ratios of AUC(urinary bladder)/AUC(other tissues) of time-dependent muscarinic receptor occupancy, oral oxybutynin has been shown to exert little urinary bladder selectivity. Following oral administration of propiverine, there was a significant reduction of in vivo specific [(3)H]QNB binding in the urinary bladder, colon and submaxillary gland, but not in the stomach and heart. From the ratios of AUC(urinary bladder) to AUC(submaxillary gland) or AUC (heart), it has been shown that oral propiverine exerts higher selectivity to muscarinic receptors in the urinary bladder than in the submaxillary gland and heart. Similarly, tolterodine displayed high selectivity to muscarinic receptors in the urinary bladder than in the submaxillary gland. Thus, the present study has demonstrated that [(3)H]QNB may be a useful ligand for in vivo characterization of muscarinic receptor binding of anticholinergic agents to treat overactive bladder. Propiverine and tolterodine have exhibited in vivo selectivity of muscarinic receptor in the mouse urinary bladder rather than in the submaxillary gland, and such receptor binding specificity may be the reason of lower incidence of dry mouth.     

Ocular surface changes following oral anticholinergic use for overactive bladder

Objective: To investigate the effect of oral solifenacin succinate on Schirmer I test results, tear break-up time (TBUT) and Ocular Surface Disease Index (OSDI) scores in overactive bladder (OAB) patients and to compare these results with those of healthy control subjects.

Materials and methods: The female OAB patients who were prescribed oral solifenacin succinate 5?mg/day (Group I, N?=?80) and age-matched healthy female subjects (Group II, N?=?40) were recruited for the study and underwent ophthalmological examination prior to oral treatment and after 4 weeks. They completed the OSDI questionnaire and underwent ocular surface tests including Schirmer I test and TBUT.

Results: The statistical analysis of the Schirmer I test and TBUT revealed no significant difference between the baseline and 4th week values in both groups (Group I, p?=?0.506 and p?=?0.070 consecutively) (Group II, p?=?0.810 and p?=?0.823 consecutively). OSDI scores were found to be significantly increased in group I (21.8?±?4.2 vs 23.1?±?4.6, p?=?0.020) and remained unchanged in group II (20.5?±?7.0 vs 20.7?±?7.0, p?=?0.805).

Conclusions: Short-term solifenacin succinate treatment has no effect on the Schirmer I test results and TBUT, but ocular surface symptoms appeared to be exacerbated in respect with increased OSDI scores. However, the clinical significance needs to be further evaluated with larger studies.     

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.     

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 alpha-adrenoceptors. Potential PNS targets include muscarinic receptors, calcium and potassium channels and alpha- and beta-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 alpha-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.     

Darifenacin in the treatment of overactive bladder

Darifenacin is a novel muscarinic M(3) selective receptor antagonist developed for the once-daily treatment of overactive bladder, a chronic, debilitating and highly prevalent condition affecting adults of all ages. Preclinical research has confirmed the pharmacological profile of darifenacin as a potent antimuscarinic agent with up to 59-fold higher affinity for M(3) receptors than other muscarinic receptor subtypes and selectivity for the bladder over other tissues expressing these receptors. Extensive research in large, randomized, placebo-controlled trials have demonstrated that darifenacin, at doses of 7.5 and 15 mg once daily (q.d.), is efficacious in the treatment of overactive bladder, improving the core symptoms of urinary urgency, urge incontinence, increased micturition frequency and bladder capacity. In addition, post-hoc analyses have shown that many patients can achieve clinically meaningful continence levels, e.g., > or =90% reduction in incontinence episodes or > or =7 consecutive dry days. These results are supported by significant improvements in quality of life, which have paralleled the overactive bladder symptom reductions. Both fixed and flexible darifenacin dosing regimens produce these beneficial effects, which extend to the more vulnerable population of older patients. Hence, in conjunction with data showing that this agent has a good safety and tolerability profile, these findings indicate that darifenacin may provide an effective alternative pharmacotherapy for the treatment of patients with overactive bladder.     

Darifenacin: in the treatment of overactive bladder

Darifenacin is a selective muscarinic M3-receptor antagonist that has been evaluated in clinical trials in patients with overactive bladder syndrome (OAB) using a controlled-release formulation. In multicentre, randomised, double-blind trials in patients with OAB, darifenacin 7.5 or 15 mg once daily for 12 weeks significantly reduced the frequency of urinary incontinence, frequency of micturition and frequency and severity of urgency versus placebo. A significant difference from placebo was apparent 2 weeks after starting treatment. At a dosage of 30 mg once daily, darifenacin significantly prolonged warning time compared with placebo. Darifenacin 15 mg once daily for 2 weeks was as effective as oxybutynin 5 mg three times daily at reducing the frequency of urinary incontinence and frequency and severity of urgency in patients with OAB. Darifenacin was generally well tolerated in clinical trials. The most common adverse events were dry mouth and constipation. CNS tolerability appeared to be similar to that of placebo. Darifenacin had no adverse effect on cognitive function in healthy elderly volunteers.     

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.     

Imidafenacin for the treatment of overactive bladder

Introduction: Imidafenacin (KRP-197/ONO-8025) is the latest antimuscarinic (AM) developed for the treatment of overactive bladder syndrome (OAB) and, at the moment, it is marketed only in Japan. This compound has been developed to improve the tolerability of AM therapy by binding specifically the M₃ receptor subtype, thus limiting undesirable adverse events (AEs).

Areas covered: This systematic review offers a brief explanation of the mechanism of action and of the pharmacokinetics of imidafenacin and helps readers to understand the clinical efficacy, tolerability, and safety of the compound in the setting of OAB therapy.

Expert opinion: Imidafenacin is an AM drug with excellent efficacy, tolerability, and safety. It is indicated for patients with nocturia, nocturnal polyuria, and benign prostatic hyperplasia. This compound, due to its pharmacokinetic properties, gives the opportunity to be easily adjusted in its dosages. Further studies should assess the pharmacokinetics, clinical efficacy, safety, and tolerability of imidafenacin in Caucasian and African populations because this AM agent, at the moment, has been evaluated just in Asian populations. More studies should evaluate and compare efficacy, safety, and tolerability of imidafenacin also with other largely utilized AMs, such as oxybutynin, tolterodine, and fesoterodine, or with the other M3 selective compound, darifenacin.     

Mirabegron for the treatment of overactive bladder

Overactive bladder (OAB) syndrome is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urge urinary incontinence, in the absence of urinary tract infection or other obvious pathology. Mirabegron (YM-178, Betanis?) is a novel, once-daily, orally active, first-in-class selective β(3)-adrenoceptor agonist that improves symptoms associated with OAB by enhancing storage function and relaxing the urinary bladder. Mirabegron has been approved in Japan for the indication of urgency, urinary frequency and urge urinary incontinence associated with OAB, and was recently submitted for approval to U.S. and European authorities for the same indication. In phase III clinical trials performed in Europe, the U.S. and Australia, mirabegron at doses of 50 or 100 mg for 12 weeks significantly decreased the mean number of incontinence episodes and micturition episodes per 24 hours, and was safe and well tolerated. Mirabegron may be an alternative in patients with OAB who are poor responders to antimuscarinic agents or intolerant of their adverse effects.     

Solifenacin: treatment of overactive bladder

An investigational muscarinic antagonist, solifenacin is indicated in the treatment of overactive bladder. Solifenacin works to decrease bladder activity by inhibiting contraction of the smooth muscle wall surrounding the bladder. Micturition normally occurs following stimulation of acetylcholine muscarinic M3 receptors within the detrusor muscle wall. As a potent and selective muscarinic receptor antagonist, solifenacin acts specifically at the M3 receptor site. Initial data have shown solifenacin to be more bladder-selective than its predecessors. It is this selective mode of action that gives solifenacin the potential to limit commonly experienced anticholinergic side effects. These developments could translate into higher patient compliance with the potential for better long-term results. Solifenacin has been shown to have a favorable risk/benefit ratio. At a once-daily oral dose of 5 mg/day, clinical data have shown solifenacin to be effective in reducing the symptoms of overactive bladder, with an incidence of dry mouth comparable to that associated with placebo. Results from phase I, II and III clinical trials have shown solifenacin to have a promising efficacy and safety profile for the treatment of overactive bladder. Comparative clinical trials are now needed to determine whether these initial results can prove solifenacin to be more beneficial than other commonly administered antimuscarinics.     

Long-term safety,tolerability, and efficacy of fesoterodine treatment in men and women with overactive bladder symptoms

Abstract

Objective:

To evaluate long-term safety, tolerability, and efficacy of fesoterodine for men and women with overactive bladder (OAB) symptoms.     

The overactive bladder: review of current pharmacotherapy in adults. Part 1: pathophysiology and anticholinergic therapy

Overactive bladder is a syndrome characterised by urinary urgency, with or without urge incontinence, and usually with frequency and nocturia. It affects millions of people of all ages worldwide and causes significant morbidity, especially in terms of health-related quality of life. It poses a huge economic burden on health resources. Managing such patients involves a thorough history, physical examination and the use of pertinent investigations before the initiation of treatment. Therapy consists of lifestyle changes, bladder training, anticholinergics, second-line agents such as resiniferatoxin instillation or botulinum toxin injections into the bladder in refractory cases and, finally, in intractable cases, surgery. In the first part of this review of pharmacotherapy for the treatment of this condition, the focus is on the pathophysiological factors potentially involved in overactive bladder and covers the wide range of currently available first-line anticholinergic agents. Treatment algorithms are suggested on the basis of current literature.