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Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M3 selective receptor antagonist.

AIM: To evaluate the efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist, in the subgroup of older patients from a pooled analysis of three phase III, multicentre, randomized, double-blind clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS: 317 patients aged > or =65 years with OAB symptoms (urge incontinence, urgency and frequency) received up to 12 weeks' oral treatment with darifenacin 7.5 mg or 15 mg once daily or matching placebo. Efficacy was evaluated from daily electronic diary records. Safety endpoints included withdrawal rates and treatment-related adverse events. RESULTS: Darifenacin treatment of patients aged > or =65 years was associated with a dose-related, significant improvement of all the major symptoms of OAB. At week 12, the median reduction in incontinence episodes/week was greater with darifenacin 7.5 mg or 15 mg than in the corresponding placebo arms (66.7% vs. 34.8% and 75.9% vs. 44.8%, respectively, both p < 0.001). Both doses were also significantly superior to placebo in improving micturition frequency (both p < 0.001), bladder capacity (volume voided) (darifenacin 7.5 mg, p = 0.018, darifenacin 15 mg, p < 0.001), and the frequency of urgency episodes (both p < 0.001). Darifenacin was well tolerated. The most common treatment-related adverse events were dry mouth (7.5 mg, 20.6%; 15 mg, 30.9%; placebo, 4.5%) and constipation (7.5 mg, 18.6%; 15 mg, 23.6%; placebo, 6.4%), typically mild or moderate. Use of constipation remedies (laxatives, stool softeners or fibre supplements) was low and similar between groups (7.5 mg, 10.3%; 15 mg, 16.4%; placebo, 10.0%). There were few withdrawals due to treatment-related adverse events (7.5 mg, 1.0%; 15 mg, 9.1%; placebo, 2.7%), and no nervous system or cardiovascular safety concerns. CONCLUSIONS: The results demonstrate excellent efficacy, tolerability and safety with darifenacin 7.5 mg and 15 mg once-daily treatment for OAB in older patients.

Aged↗

The basis for drug treatment of the overactive bladder.

The normal bladder functions, storage and elimination of urine, are dependent on neural circuits in the brain and spinal cord that coordinate the activity of the detrusor and that of the smooth and striated muscles of the outflow region. Disturbances at different levels may cause the overactive bladder (OAB) syndrome, characterized by urge, frequency and urge incontinence. Knowledge about the mechanisms controlling both normal and abnormal micturition is mandatory for the detection of targets for pharmacological intervention. Such targets may be found in the central nervous system (CNS) or peripherally. Several CNS transmitters can modulate voiding, but few drugs with a defined CNS site of action have been demonstrated to be clinically useful. Traditionally, drugs for treatment o

Central Nervous System↗

Use of the short form of King's Health Questionnaire to measure quality of life in patients with an overactive bladder.

OBJECTIVE: To develop a short version of the King's Health Questionnaire (KHQ), as there is a practical need to have a shorter version to summarize the eight domain scores into fewer domains. PATIENTS AND METHODS: Data from 293 patients were obtained from a randomized, double-blind, placebo-controlled clinical trial in Japan of oxybutynin and tolterodine in patients with symptoms of an overactive bladder. The KHQ has two single-item and six multiple-item domains. To construct the short form of the KHQ one item was selected from the each of multiple-item domains, based on standardized structural coefficients estimated by confirmatory factor analysis (CFA) in a previous study. These six items include the domains: 'daily activities from role limitation', 'travel from physical limitation', 'social life from social limitation', 'family life from personal relationship', 'depressed from emotion' and 'tired from sleep and energy'. Based on the six selected items a series of psychometric analyses were conducted. RESULTS: Exploratory factor analysis (EFA) with promax rotation identified two factors 'limitation of daily life' (LDL) and mental health. LDL consisted of 'daily activities', 'travel' and 'social life', and mental health included 'family life', 'depressed' and 'tired'. Based on the results from the EFA, the second-order factor structure was tested by CFA. The model fitted the data well for both the male and female model. The KHQ short form showed excellent reliability with Cronbach's alpha coefficients for LDL and mental health for both genders. The domains in the short form were responsive to clinical efficacy variables, and had statistically significant sensitivity to change in the patients' perception of bladder condition in all domains. CONCLUSION: These analyses confirm the psychometric properties and clinical validity of the short-form KHQ, which appears to offer a practical, valid and reliable health-related quality-of-life instrument.

Aged↗

Reliability of a Thai version of King's Health Questionnaire in Thai females with overactive bladder symptoms.

OBJECTIVES: To develop and test the reliability of a Thai version of the King's Health Questionnaire (KHQ). MATERIAL AND METHOD: Three Thai Urologists forward translated the original English KHQ into a Thai version. Back translations were performed by an independent group of physicians. A consensus was reached on a final Thai version after comparing the original KHQ and various translations. Fifty Thai female patients with symptoms of overactive bladder were tested and retested every two weeks using the Thai version (twice) as well as the English version (once) of the KHQ. Test-retest reliability of the Thai questionnaire was measured using the kappa statistic. RESULTS AND CONCLUSION: The Thai version of the KHQ was found to be reasonably reliable for use in Thai female patients with over active bladder symptoms.

Adult↗

Advancements in pharmacologic management of the overactive bladder.

Continued developments in the understanding of lower urinary tract function have led to improvements in the pharmacologic manipulation of bladder dysfunction. Drug delivery changes have produced drugs that provide better efficacy and tolerability, thus improving patient compliance. Improvements in drug delivery systems have altered drug bioavailability and pharmacokinetics. Active current investigation in new agents and delivery systems for intravesical delivery has yielded intriguing early results that may substantially add to the armamentarium for the management of the overactive bladder (urgency, frequency, urge incontinence). New developments in the understanding of the neuropharmacology of the bladder, peripheral pelvic nerves, and sacral cord may provide agents with entirely new drug effects, either as primary agents or agents to be used in combination with currently available drugs. We herein review newer agents and drug delivery systems.

Adrenergic alpha-Antagonists↗

Overview of overactive bladder, prostatitis, and lower urinary tract symptoms for the primary care physician.

As an increasing number of treatment options for urologic disorders become available, patients with these conditions are more often able to be managed in the primary care setting. Primary care physicians, therefore, must become more knowledgeable of the proper urologic terminology and the screening tools that have traditionally been used by urologists. To that end, this article reviews the terminology associated with lower urinary tract symptoms and describes the evaluation and treatment of patients presenting with these symptoms. The diagnoses of overactive bladder and prostatitis are discussed, as well as the therapeutic options available for these patients.

Journal Article↗

Overactive bladder in the female patient: the role of estrogens.

The prevalence of urinary incontinence is known to increase with age, affecting 15% to 35% of community-dwelling women over 60 years of age. Other studies report a prevalence of 49% in women over 65 years of age. Epidemiologic studies have implicated estrogen deficiency in the etiology of lower urinary tract symptoms, although the role of estrogen replacement therapy remains controversial. This review presents recent evidence regarding the role of estrogen in lower urinary tract dysfunction, with a particular emphasis on the management of postmenopausal women with symptoms suggestive of overactive bladder.

Estrogens↗

Development and validation of patient-reported outcomes measures for overactive bladder: a review of concepts.

Patient-reported outcome (PRO) measures are a valuable means for determining how a disease and its treatment affect patients, including effects on health-related quality of life (HRQL). To ensure that the results obtained with PROs are clinically useful, data must be gathered using valid and reliable instruments. Developing such instruments requires a multistep, structured process that incorporates cognitive psychology, psychometric theory, and patient and clinician input. The process begins by determining the intent and purpose of the PRO and culminates in studies that demonstrate the measure's validity, reliability, and responsiveness. Several valid and reliable PROs are available for assessing the effects of treatment on symptom severity, symptom bother, and HRQL in patients with overactive bladder.

Cultural Characteristics↗

Transdermal oxybutynin: for overactive bladder.

Oxybutynin binds to the M(3) muscarinic receptors on the detrusor muscle of the bladder, preventing acetylcholinergic activation and relaxing the muscle. The transdermal system delivers oxybutynin over a 3- to 4-day period after application to intact skin. Peak plasma concentrations of oxybutynin and the major active metabolite, N-desethyloxybutynin, are reached 24 - 48 hours after a single application and therapeutic concentrations are maintained throughout the dosage interval. In a large, randomised, double-blind trial, transdermal oxybutynin 3.9 mg/day significantly decreased the median number of incontinence episodes per week compared with placebo (-19 vs -15, p = 0.0165) in patients with overactive bladder. In addition, the micturition frequency was reduced and average voided volume was increased by transdermal oxybutynin treatment. Significant reductions in incontinence episodes following transdermal oxybutynin treatment were also observed in two further studies and the clinical efficacy was similar to that of oral tolterodine or oral oxybutynin. Transdermal oxybutynin was well tolerated in clinical trials. Application site reactions were the most common adverse effect; however, the majority were mild to moderate in severity. Adverse events associated with anticholinergic drugs (e.g. dry mouth) were less frequently reported in patients treated with transdermal oxybutynin than in those receiving orally administered oxybutynin or tolterodine.

Administration, Cutaneous↗

Long-term safety of extended-release oxybutynin chloride in a community-dwelling population of participants with overactive bladder: a one-year study.

In this multicenter, open-label study of extended- and immediate-release oxybutynin chloride, community-dwelling participants were studied for up to 12 months to evaluate the long-term safety profile of extended-release oxybutynin. Quality-of-life assessments designed to measure the impact of incontinence and evaluate treatment outcome were used to study subjective improvement. A total of 904 women and 163 men (mean age 64 years, range 29-91 years) were enrolled. The majority of discontinuations were in the first 3 months (25.5%); of those who continued after 3 months, 62% remained on extended-release oxybutynin chloride for one year. The majority of discontinuations were for adverse events; dry mouth was the most frequently cited event leading to discontinuation (8.4%). Significant improvements were seen in QOL measures. Long-term therapy with extended-release oxybutynin chloride was generally well tolerated and effective, improving quality of life significantly in participants with overactive bladder over 3-12 months of therapy.

Adult↗

Prediction of Medicare drug formulary drugs for treatment of overactive bladder.

PURPOSE: With the establishment and signing into law the Medicare and Prescription Drug Improvement and Modernization Act of 2003, also known as Medicare Part D, medical costs are expected to soar. In fact, the program is expected to cost more than a trillion dollars through 2015. Establishment of the Medicare Part D drug formulary will allow cost containment but still absorb patient and physician preferences as well as a consideration of efficacy and safety data. MATERIALS AND METHODS: Potential Medicare formulary choices were examined in the anticholinergic class, as commonly used by urologists, and small in number of available drugs. Formulary selection parties and issues were individually analyzed, including the government in respect to cost containment, patients in relation to efficacy and cost, physicians in relation to preferences and influence and drug companies in relation to lobbying power, country of base of operations and market shares. Costs to Medicare and patients were calculated using discount Internet sites for pricing and simulated using Medicare Part D benefits. RESULTS: Generic oxybutynin is likely to be included because it is the least expensive to patients and Medicare, but it has the lowest efficacy. Detrol LA is likely to be the long acting choice due to efficacy, cost and manufacture by a United States based company. CONCLUSIONS: A simulation of cost analysis of anticholinergics for treatment of overactive bladder would help urologists better understand the Medicare formulary selection process.

Cholinergic Antagonists↗

Childhood urinary symptoms predict adult overactive bladder symptoms.

PURPOSE: A relationship between childhood urinary symptoms and adult lower urinary tract symptoms in women is often clinically suspected. In this analysis we investigated the relationship between childhood and adult urinary symptoms in middle-aged women. MATERIALS AND METHODS: A population based cohort of 2,109 women 40 to 69 years old who were members of a large health maintenance organization was randomly selected from age and race strata. Through self-reported questionnaires, women recalled a childhood history of and current urinary lower urinary tract symptoms, including frequent daytime urination, nocturia, urinary incontinence, nocturnal enuresis and UTIs. Current incontinence was also classified as urge or stress incontinence. Multivariate analysis was used to evaluate the association between childhood and current lower urinary tract symptoms controlling for age, race, hysterectomy status, parity, oral estrogen use, body mass index and diabetes. RESULTS: Women who reported childhood daytime frequency were more likely to report adult urgency (OR 1.9, 95% CI 1.3-2.6, p < 0.001). Frequent nocturia in childhood was strongly associated with adult nocturia (OR 2.3, 95% CI 1.5-3.5, p < 0.001). Childhood daytime incontinence was associated with adult urge incontinence (OR 2.6, 95% CI 1.1-5.9, p < 0.05), as was childhood nocturnal enuresis (OR 2.7, CI 1.3-5.5, p < 0.01). A history of more than 1 childhood UTI was associated with adult UTIs (OR 2.6, 95% CI 1.5-4.5, p < 0.001). CONCLUSIONS: Childhood urinary symptoms and UTIs were significantly associated with adult overactive bladder symptoms. There is a need to investigate the significance of childhood symptoms as predictors of eventual adult disorders to determine whether treatment of childhood symptoms will alter the prevalence of eventual adult disorders, and if such a history should alter clinical care of the older adult with OAB symptoms.

Adult↗

Responses of isolated normal human detrusor muscle to various spasmolytic drugs commonly used in the treatment of the overactive bladder.

The spasmolytic activity of flavoxate (CAS 15301-69-6) and the anticholinergic agents oxybutynin (CAS 5633-20-5), tolterodine (CAS 124937-51-5) and trospium chloride (CAS 10405-02-4), all of which are commonly utilized in the treatment of urinary incontinence, on muscarinic tension and electrically evoked contractions of isolated human detrusor smooth muscle strips was studied using the organ bath technique. Within the concentration ranges tested (trospium chloride 10(-11)-10(-6) mol/l, flavoxate and oxybutynin 10(-9)-10(-5) mol/l, tolterodine 10(-10)-10(-5) mol/l), each drug caused a concentration-dependent relaxation of the tension elicited by muscarinic stimulation and dose-dependently attenuated the contractions induced by electrical field stimulation (EFS). The effects of trospium chloride and tolterodine on carbachol-induced muscarinic tension were more pronounced than those of oxybutynin, while trospium chloride and oxybutynin were most effective in inhibiting the contractions induced by EFS. Flavoxate was significantly less effective than all other drugs tested. Regardless the individual drug concentrations needed for maximal efficacy, the potency of oxybutynin and flavoxate to reverse muscarinic tension and attenuate EFS-evoked contractions was almost comparable while tolterodine and trospium chloride were more effective in relaxing the muscarinic tension of the detrusor strip preparations than causing inhibition of EFS-induced contractions. Our results again underline the ratio for the use of nortropane analogues (trospium chloride) and phenylpropylamine cresols (tolterodine) in the treatment of frequency, urgency and urge incontinence secondary to an overactive bladder.

Carbachol↗

Tolterodine for overactive bladder: time to onset of action, preferred dosage, and 9-month follow-up.

This is a prospective study of 28 patients who had urinary frequency (>8 times/day) and either urgency or urge incontinence (>1 time/day). After a 2-week run-in period (visit 1), the patients were started on tolterodine 1 mg twice a day (bid) (visit 2). They were followed at 4 and 8 weeks (visits 3 and 4). The patients were contacted by telephone 1 week after visit 2. Tolterodine was increased to 2 mg bid if the patient had incomplete improvement at either the initial phone call or during visit 3. Evaluation criteria were daily micturition charts including urinary frequency, nocturia, leakage episodes, average urine volume per day, and average voided volume. Tolterodine was well tolerated without side effects in 20 (80%) of 28 patients. Eight patients (20%) dropped out after enrollment because of side effects in 3, no improvement in 2, and missing visits (>1) in 3. Drug dosage in the 20 patients who tolerated tolterodine was 1 mg bid in 3 and 2 mg bid in 17 (85%). According to micturition charts, urinary frequency, nocturia, and leakage episodes decreased significantly after tolterodine treatment, whereas average urine volume per day and average voided volume did not change significantly. There were no electrocardiographic or biochemical abnormalities due to tolterodine treatment. Mean follow-up was 9.4 months. All 20 patients who tolerated tolterodine continue to take the medication without significant side effects. We conclude that tolterodine is well tolerated and effective for overactive bladders. Two milligrams bid is the dosage preferred by the majority of patients and the onset of action is seen within 1 week of treatment. Long-term compliance and efficacy are excellent, with no dropout in >9 months of follow-up.

Adult↗

Transdermal oxybutynin in the treatment of adults with overactive bladder: combined results of two randomized clinical trials.

The safety and efficacy of oxybutynin transdermal delivery system (oxybutynin-TDS) versus placebo in adults with urge and mixed urinary incontinence was investigated using combined results from double-blind stages of 2 phase 3 clinical trials. Study 1: placebo-controlled, parallel-group comparison of 3 oxybutynin-TDS doses in 12-week double-blind and open-label periods, followed by a 28-week open-label extension. Study 2 was a 12-week randomized, double-blind, placebo-controlled comparison of oxybutynin-TDS versus long-acting tolterodine and placebo, followed by a 52-week open-label extension. Efficacy analysis included 241 patients receiving oxybutynin-TDS, 244 receiving placebo. Most participants were Caucasian women (92%). Approximately 60% received prior anticholinergic therapy. Primary outcome was determined by changes from baseline to end of treatment in frequency of incontinence episodes, frequency of urination, and void volume. Oxybutynin-TDS was significantly more effective than placebo in reducing median daily incontinence episodes (-3.0 vs placebo -2.0; P=.00004) and daily urinary frequency (-2.0 vs -1.0; P=.0023), and in increasing void volume (25 mL vs 5.5 mL; P<.00001). Overall rates of anticholinergic adverse events (AEs) were 12.8% for oxybutynin-TDS and 11.0% for placebo (P=0.5421). The most common systemic anticholinergic AEs were dry mouth (7.0% for oxybutynin-TDS vs 5.3% for placebo) and constipation (2.1% vs 2.0%). Application site erythema occurred in 7.0% of participants who received oxybutynin-TDS (3.7% discontinuation rate); pruritus occurred in 16.1% (3.3% discontinuation rate). Transdermal oxybutynin was shown to be efficacious, with a proven safety profile. It may be utilized for patients with overactive bladder as a treatment option that could enhance compliance.

Administration, Cutaneous↗

Food does not influence the pharmacokinetics of a new extended release formulation of tolterodine for once daily treatment of patients with overactive bladder.

OBJECTIVE: To determine whether food intake influences the pharmacokinetics of a new, once daily, extended release (ER) capsule formulation of tolterodine in healthy volunteers, and to compare its bioavailability with that of the existing immediate release (IR) tablet. DESIGN: Open, randomised, 3-way crossover trial. PARTICIPANTS: 17 healthy volunteers (3 females, 14 males) aged between 19 and 50 years. With the exception of 1 male volunteer, all participants were classified as extensive metabolisers by cytochrome P450 2D6 genotyping. METHODS: Volunteers received single oral doses of tolterodine L-tartrate ER 8 mg (2 x 4 mg capsules) on an empty stomach or with a standardised high-fat breakfast. Reference therapy comprised tolterodine L-tartrate IR 4 mg (2 x 2 mg tablets), administered in the fasting state. Serum concentrations of tolterodine, its active 5-hydroxymethyl metabolite (5-HM) and the active moiety (sum of unbound tolterodine + 5-HM) were measured for up to 72 hours post-dose. Safety endpoints were also determined. RESULTS: No effect of food on the bioavailability of tolterodine ER capsules was apparent and there was no sign of dose-dumping with meals. The geometric mean fed:fasting ratio of area under the serum concentration-time curve to infinity (AUCinfinity) of the active moiety, for all volunteers combined, was 0.95 (90% confidence interval 0.88 to 1.03). Equivalence with respect to AUCinfinity (dose-corrected) was also found for the ER capsule compared with the IR tablet, although uncorrected maximum serum concentrations were around 50% lower despite the fact that the capsule dose was twice as high. Seven volunteers reported adverse events, predominantly headache. No volunteer reported dry mouth. Overall, there were no safety concerns. CONCLUSIONS: The new ER formulation of tolterodine shows no pharmacokinetic interaction with food. On the basis of these results, patients with overactive bladder may, therefore, be advised to take the drug without regard to the timing of meals, maximising convenience during therapy.

Adult↗

[Clinical effects of oxybutynin hydrochloride in the treatment of unstable bladder and overactive neurogenic bladder: a long-term clinical trial].

Clinical effects and therapeutic usefulness of oxybutynin hydrochloride were evaluated in a long-term clinical trial on patients with unstable bladders and neurogenic bladders. Of the 46 patients entered into the trial, 37 were those diagnosed with an unstable bladder and 9 with a neurogenic bladder with overactive detrusor. In 37 of the cases (80%), the period of drug administration reached up to 12 weeks and in 16 cases (34%) the drugs were administered for more than 24 weeks. The average administration period was 165.9 days. The average total given dose was 1776.9 mg and average dose per day was 10.7 mg. Excellent and good responses were obtained in 76.3, 88.9 and 69.6% at 12 and 24 weeks after start of administration and at the time of discontinuing the drug, respectively. The cystometric changes at pre- and post-administration were evaluated on 23 cases and revealed a significant increase in volume at first sensation and maximum desire to void. Maximum resting intravesical pressure was significantly declined and uninhibited detrusor contractions were significantly suppressed. Side effects were noted in 11 of the 46 cases (23.9%), most of which were well tolerated by the patients. In 4 cases the drug had to be discontinued because of the side effects. Dry mouth was the most common side effect, occupying almost half of the incidents. No significant abnormality was noted on blood laboratory data, blood pressure or heart rate, following the drug administration. In one case slight increase in serum glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase was encountered, but its relationship with the drug was obscure. The clinical usefulness of this drug (excellent and good) was 78.9, 88.9 and 69.6% at 12 and 24 weeks after start of administration, and at the time of drug discontinuation, respectively. The present long-term trial proved that oxybutynin hydrochloride is an exceedingly effective and safe agent for clinical management of unstable bladder and overactive neurogenic bladder.

Adolescent↗