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A transparent film-forming hydrogel formulation for tolterodine was developed using ternary phase diagram and Box-Behnken design (BBD). Carbopol 980 (neutralized by triethanolamine), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC) and Tween 80 were used as matrices. Solvent was the mixture of water and ethyl alcohol. The measured 24 h cumulative drug release rate (86.02%) was consistent with the predicted value (85.42%) in mice. Steady-state flux (J) of tolterodine in optimized formulation across rat full skin, epidermal, dermis and subcutaneous tissue were 15.83, 18.55, 37.15 and 81.82 μg cm(-2) h(-1), respectively. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) results suggested that the hydrogels could impact lipid status in SC, which was consistent with Ea (8.638 kcal/mol) of tolterodine from optimized formulation in rats. In the pharmacokinetic studies, sustained-release over 24 h and absolute bioavailability of the hydrogels (24.53%) was higher than tolterodine tablets (15.16%) in rats. The hydrogels were suitable for systemic administration of tolterodine for the treatment of overactive bladder., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: To investigate patient satisfaction with antimuscarinic treatment of overactive bladder syndrome, and to identify factors having a significant influence on satisfaction., Methods: A cross-sectional questionnaire survey was carried out to assess treatment satisfaction among male and female patients with overactive bladder (age ≥20 years) in the Hokuriku district of Japan. The overactive bladder symptom scores, treatment efficacies, adverse events (dry mouth and constipation), and patient satisfaction scores were investigated and compared among patients using different antimuscarinic therapeutics., Results: In total, 977 survey respondents (52.6% men; mean age 73.6 years) received antimuscarinic treatment. The mean overactive bladder symptom score of these patients was 6.17; in addition, 32.3% patients were satisfied with their treatment, but 33.1% were dissatisfied. Factors having a significant influence on treatment satisfaction were sex (men were less satisfied), efficacy, adverse events and the overactive bladder symptom score. Constipation negatively influenced patient satisfaction to a greater extent than did dry mouth. Patient satisfaction varied according to the drug used. Constipation was less severe with the immediate-release-type agents (imidafenacin and oxybutynin) than with the extended-release-type (propiverine, solifenacin or tolterodine)., Conclusions: Just one-third of Japanese Hokuriku patients with overactive bladder seem to be satisfied with their antimuscarinic treatment. Patient satisfaction is impaired by poor efficacy and the presence of adverse events; furthermore, constipation should be recognized as an adverse event that negatively influences patient satisfaction to a greater extent than dry mouth. Patient satisfaction differs according to the antimuscarinic agent used, with higher patient satisfaction being associated with less severe constipation., (© 2013 The Japanese Urological Association.)

The aim of the current investigation is to optimize ethosomes statistically for enhancing transdermal potential of Tolterodine Tartrate (TT). Ethosomes bearing TT were prepared by cold method and characterized for various parameters like vesicle size, vesicle shape, surface morphology and % drug entrapment. Microscopic examinations suggest ethosomes as spherical unilamellar vesicles with a smooth surface. Optimized ethosomal vesicles were of 890±2.67nm size and showed 79.83±3.18% drug entrapment. Ex-vivo permeation studies across rat skin resulted in increased flux of 4.69±0.24μg/cm(2)/hr and decreased lag time of 0.13±0.05 hr when compared with drug solution (0.546±0.05μg/cm(2)/hr, 3±0.2 hr).This shows enhancement of transdermal delivery by 8.82 times. Anatomical changes in skin samples due to vesicle-skin interaction were observed on histological examination. Optimized formulation on storage at 4°C for 120 days showed insignificant growth in vesicular size revealing low aggregation of vesicles. The results collectively suggest ethosomes as carriers for accentuated transdermal delivery of TT.

The article presents the results of the examination and treatment of 30 patients with overactive bladder receiving M-anticholinergic drug tolterodine at a dose of 2 mg twice a day for 1 month. Evaluating the effectiveness of the drug was performed on the basis of the data on voiding diary, urodynamic changes, and results of ultrasound examination. The analysis showed that treatment with tolterodine within 15 days has a positive trend: normalization of urination was observed in 96.6% of patients, 76.6% of patients have reported decrease of the frequency of urgency urination, and episodes of imperative urinary incontinence decreased in 83.3% of patients. The therapy promoted the increase the duration and volume of urination, reduction of maximum uroflow rate, indicating that the effectiveness of treatment. On the 30th day of treatment, the vast majority (80%) of the patients reported improvement of their wellbeing.

Objective: The purpose of this study was to develop hydroxypropylmethylcellulose (HPMC)-based sustained release (SR) tablets for tolterodine tartrate with a low drug release variation., Methods: The SR tablets were prepared by formulating a combination of different grades of HPMC as the gelling agents. The comparative dissolution study for the HPMC-based SR tablet as a test and Detrusitol SR capsule as a reference was carried out, and the bioequivalence study of the two products was also conducted in human volunteers., Results: The amount of HPMC, the grade of HPMC and the combination ratio of different grades of HPMC had remarkable effects on drug release from the SR tablets. Both the test and reference products had no significant difference in terms of comparative dissolution patterns in four different media (f₂ > 50). Furthermore, the dissolution method and rotation speed showed no effects on the drug release from the two products. The 90% confidence intervals of the AUC(0-36) and C(max) ratios for the test and reference products were within the acceptable bioequivalence intervals of log0.8-log1.25., Conclusions: A HPMC-based SR tablet for tolterodine tartrate with a low release variation was successfully developed, which was bioequivalent to Detrusitol® SR capsule.

To examine the efficacy, safety and tolerability of tolterodine in children with overactive bladder in comparison with standard treatment i.e. oxybutynin as demonstrated in randomized clinical trials and other studies. A systematic search was done to screen the studies evaluating the effect of tolterodine in children with non-neurogenic overactive bladder. Results of studies were pooled and compared. Efficacy was determined from micturition diaries and dysfunctional voiding symptoms score. Safety and tolerability were assessed from the reported treatment emergent adverse events. A total of six randomized clinical trials and 11 other studies of tolterodine in children with urinary incontinence were included in the present systematic review. The dose of tolterodine used in different settings ranged from '0.5 to 8 mg/day' instead of '0.5 to 8 mg/kg per day' and the duration of studies ranged from 2 weeks to 12 months. Both extended and immediate release preparations of tolterodine were shown to have comparable efficacy and tolterodine proved to have comparable efficacy with better tolerability than oxybutynin in these studies. It can be concluded that tolterodine is efficacious in treatment of urinary incontinence in children. Moreover, its efficacy is comparable to oxybutynin, the most commonly prescribed anticholinergic in this condition, while having better tolerability. Hence, it can be considered as first line therapy for the treatmentof urinary incontinence in children.

In this study, transdermal gel formulations for tolterodine were developed to investigate the effects of gel matrix and chemical enhancers on drug skin permeation from tolterodine hydrogels. In vitro permeation studies of tolterodine through excised mouse skin were carried out using Franz-type diffusion cells. In the optimum gel formulation, Carbopol 940 was selected as the gel matrix. Compared to gels without enhancer, tolterodine hydrogels with N-methyl pyrrolidone (NMP) showed significant enhancing effect on transdermal permeation of tolterodine (p<0.05). The results of in vitro percutaneous delivery experiment showed that the relationship of the steady accumulative percutaneous amount (Q, μg cm(-2)) of tolterodine hydrogels and time was Q4-12h=770.19t(1/2)-966.99. Tolterodine permeated at the steady-state speed of 770.19 μg cm(-2)h(-1) and its release coincided with Higuchi Equation. The pharmacokinetic properties of the optimized tolterodine formulation were studied in rabbits. The absolute bioavailability of tolterodine was 11.47%. Since the absence of hepatic first-pass metabolism, only a single active compound-tolterodine was detected in the plasma. A skin irritation study was also carried out on rabbits, and the results showed tolterodine hydrogels had no skin irritation. In the pharmacodynamic study, the significant effects of tolterodine hydrogels on the inhibition of pilocarpine-induced rat urinary bladder contraction were last to 12h, indicating that tolterodine hydrogels could produce prolonged pharmacological responses. In conclusion, tolterodine hydrogels were formulated successfully using Carbopol 940 and NMP and these results helped in finding the optimum formulation for percutaneous drug release. It is quite evident that tolterodine hydrogels may offer a possibility to avoid the first-pass effect, resulting in a single active compound of tolterodine in plasma, which may profit on the patient under the dose control and the reduction of potential adverse effect from two active compounds in the body., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results., Methods: This prespecified pooled analysis of three randomised, double-blind, placebo-controlled, 12-week studies, evaluated efficacy and safety of once-daily mirabegron 25 mg (safety analysis), 50 or 100 mg (efficacy and safety analyses) and tolterodine ER 4 mg (safety analysis) for the treatment of symptoms of overactive bladder (OAB). Co-primary efficacy measures were change from baseline to Final Visit in the mean number of incontinence episodes/24 h and mean number of micturitions/24 h. Key secondary efficacy end-points included mean number of urgency episodes/24 h and mean volume voided/micturitions, while other end-points included patient-reported outcomes according to the Treatment Satisfaction-Visual Analogue Scale (TS-VAS) and responder analyses [dry rate (posttreatment), ≥ 50% reduction in incontinence episodes/24 h, ≤ 8 micturitions/24 h (post hoc analysis)]. The safety analysis included adverse event (AE) reporting, laboratory assessments, ECG, postvoid residual volume and vital signs (blood pressure, pulse rate)., Results: Mirabegron (50 and 100 mg once daily) demonstrated statistically significant improvements compared with placebo for the co-primary end-points, key secondary efficacy variables, TS-VAS and responder analyses (all comparisons p < 0.05). Mirabegron is well tolerated and demonstrates a good safety profile. The most common AEs (≥ 3%) included hypertension, nasopharyngitis and urinary tract infection (UTI); the incidence of hypertensive events and UTIs decreased with increasing dose. For mirabegron, the incidence of the bothersome antimuscarinic AE, dry mouth, was at placebo level and of a lesser magnitude than tolterodine., Conclusion: The efficacy and safety of mirabegron are demonstrated in this large pooled clinical trial dataset in patients with OAB., (© 2013 Astellas Pharma Europe Ltd. International Journal of Clinical Practice published by John Wiley & Sons Ltd.)

Unlabelled: It has previously been shown that elocalcitol might protect bladder contractile function in experimental models and that elocalcitol has beneficial effects in patients with LUTS. In humans, elocalcitol was demonstrated with a very good safety profile but only exhibited limited efficacy on LUTS in patients with BPH and overactive bladder (OAB). Recent reports show that therapies with antimuscarinics, when combined with other drugs in clinical use, might perform better than a monotherapy in managing LUTS. It is not known how a combination of elocalcitol and an antimuscarinic performs on bladder dysfunction. The present study suggests that concomitant use of secosteroids and antimuscarinics has additive beneficial effects on obstruction-related functional changes in an experimental model. If confirmed also in a clinical setting, this could allow for individual dose adjustments to improve efficacy in obstruction-related LUTS, and possibly reduce unwanted adverse activities by antimuscarinic therapy., Objective: To evaluate the effects of tolterodine on urodynamics in elocalcitol- or vehicle-treated rats with partial urethral obstruction (PUO)., Materials and Methods: After ethical approval, 20 female Sprague-Dawley rats were subjected to PUO and treated (gavage) for 14 days (once daily) with elocalcitol (75 µg/kg) or vehicle. Cystometries were performed on day 15 in awake rats before and after i.v. administration of tolterodine (1, 10 and 100 µg/kg)., Results: No differences in bladder weights or body/bladder weight ratios were noted between groups. Tolterodine dose-dependently increased micturition intervals and volumes and bladder capacity in both elocalcitol- (n = 11) and vehicle-treated rats (n = 9). In elocalcitol-treated rats, flow pressure (FP) was dose-dependently reduced (12-20%) by tolterodine, whereas no effect on FP was noted in vehicle-treated animals (P < 0.05). Flow compliance (FC) was increased by tolterodine by 21-54% in vehicle-treated rats, and by 47-131% (P < 0.05 vs vehicle) in elocalcitol-treated animals. Maximal tension vs bladder weight was improved in elocalcitol-treated rats in comparison to vehicle (P < 0.05). The area under the curve (AUC) was reduced by tolterodine with 11-16% in vehicle-treated rats and 26-30% in elocalcitol -treated rats (P < 0.05)., Conclusions: Elocalcitol-treatment improved the effects of tolterodine on bladder compliance at the start of flow. The effects of tolterodine on AUC suggest that elocalcitol exerts additional beneficial actions on PUO-induced functional changes during the filling phase of micturition. The reduction of FP and increase in FC by elocalcitol and tolterodine could have translational value and, if valid in humans, support combined therapy in benign prostatic obstruction (BPO)-related lower urinary tract symptoms (LUTS)., (© 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.)

Unlabelled: Experimental urethral obstruction in rats alters micturition patterns with non-voiding activity (NVA) during filling cystometry, showing similarity to that observed in human detrusor overactivity. Several drug classes with therapeutic potential in overactive bladder in humans have been tested in this model in rats, rabbits or guinea pigs, but no detailed analysis of drug effects on cystometric patterns has been published. The present study uses a rat model of overactivity with partial bladder outflow obstruction (BOO) in combination with the procedures to analyse NVA to study the effects of the anticholinergic drug tolterodine and the novel β(3)-adrenoceptor agonist mirabegron. The current data for the first time show that NVA in rats with BOO is sensitive to both the muscarinergic antagonist tolterodine and the β(3)-adrenoceptor agonist mirabegron, but with clear differences between the two drugs: during progression of bladder filling, tolterodine affected both the amplitude and frequency of NVA whereas mirabegron affected primarily the frequency. In addition, tolterodine dose-dependently reduced voiding contractions, while mirabegron did not. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism which is sensitive to cholinergic excitatory and beta-adrenergic inhibitory inputs. Such concepts could provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs., Objective: To investigate the hypothesis that tolterodine and the β(3)-adrenoceptor agonist mirabegron exert their actions on the motor component of the motor/sensory system in the bladder wall: non-voiding activity (NVA)., Materials and Methods: The present study used standard cystometric techniques and a conscious rat model of partial bladder outflow obstruction (BOO). A single dose of either tolterodine (0.01, 0.1 0.3 or 1.0 mg/kg) or mirabegron (0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg) was given i.v. to each animal., Results: In the dose ranges used, tolterodine reduced the voiding contraction amplitude, whereas mirabegron did not. Non-voiding activity consisted of small (<0.6 mmHg) and large (>0.6 mmHg) transients. As a fill progressed, both tolterodine and mirabegron reduced the cumulative activity of the large non-voiding contractions, but had little effect on the small transients. Tolterodine affected both the amplitude and frequency of NVA, whereas mirabegron affected primarily the frequency., Conclusions: Non-voiding activity is sensitive to muscarinergic antagonists and β(3)-adrenoceptor agonists, but there are clear differences between the two drugs. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism with cholinergic excitatory and adrenergic inhibitory inputs. Such concepts may provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs., (© 2012 ASTELLAS PHARMA EUROPE B.V. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.)

The article presents the results of evaluation of effect of M-cholinoblocer tolterodine on the symptoms of lower urinary tract diseases (LUTD) and quality of life of patients with recurrent chronic cystitis. The study included 47 patients with chronic recurrent cystitis at acute stage with non-obstructive type of urination and LUTS. Group 1 included 23 women aged 45 to 56 years, who received tolterodine on the background of antibacterial therapy, taking into account the sensitivity of the isolated strain. Control group included 24 patients who received standard antibacterial therapy, also taking into account the sensitivity of the pathogen, and spasmolytics. The groups were almost homogeneous and did not differ on the basic characteristics. Analysis of the results of the study showed that tolterodine as a symptomatic therapy can reduce the time of rehabilitation. Therapy with tolterodine has shown clinical efficacy for 85.7% of women, has improved the quality of life by 24.8% compared with the control group, and provided relief of urgent and irritative symptoms in the short time.

Some patients after prostatic surgery demonstrate hyperactivity symptoms. These symptoms can be relieved by M-cholinoblockers. We analysed prospectively the results of treatment of 23 patients (mean age 69.8 years) with clinically localized prostatic cancer after radical retropubic prostatectomy. The patients were examined before and after 3 months of treatment. All the patients received tolterodin (urotol) per os in a dose 2 mg twice a day. The results of the therapy showed that M-cholinoblocker tolterodin (urotol) is effective and well tolerated in patients with hyperactive symptoms after radical prostatectomy.

What Is Already Known About This Subject: Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. The formation of 5-HMT from tolterodine occurs via CYP2D6, and some subjects are poor metabolizers CYP2D6. On the other hand, the formation of 5-HMT from fesoterodine occurs via ubiquitous esterases. Cross-study comparisons of data from phase 1 studies suggest that active moiety exposures are considerably more variable following tolterodine extended release vs. fesoterodine., What This Study Adds: This head-to-head study confirmed the findings of reduced pharmacokinetic variability of fesoterodine and further delineates that tolterodine, and not 5-HMT, was the principal source of variability after administration of tolterodine extended release. The data suggest that fesoterodine delivers 5-HMT consistently, regardless of CYP2D6 status, with up to 40% higher bioavailability compared with tolterodine., Aims: Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. Formation of 5-HMT from fesoterodine and tolterodine occurs via esterases and CYP2D6 respectively. This randomized, crossover, open-label, multiple-dose study in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) compared the pharmacokinetics of fesoterodine vs. tolterodine extended release (ER)., Methods: Subjects received fesoterodine and tolterodine ER with a ≥3-day washout period. Treatment comprised 4-mg once daily doses for 5 days escalated to 8-mg once daily for 5 days. Pharmacokinetics of active moieties were compared by drug, dose and genotype., Results: Active moiety exposures following fesoterodine and tolterodine ER increased proportional to dose in EMs and PMs. In EMs only, coefficients of variation for AUC and C(max) following fesoterodine (up to 46% and 48% respectively) were lower than those following tolterodine ER (up to 87% and 87% respectively). Following fesoterodine and tolterodine ER administration, active moiety exposures ranged up to sevenfold and 40-fold respectively. Mean urinary excretion of 5-HMT following fesoterodine 4 and 8 mg, respectively, was 0.44 and 0.89 mg in EMs and 0.60 and 1.32 mg in PMs. Following tolterodine ER 4 and 8 mg, it was 0.38 and 0.71 mg respectively (EMs only). Renal clearance was similar regardless of administered drug, dose or genotype., Conclusions: Tolterodine, not 5-HMT, was the principal source of variability after tolterodine ER administration. Fesoterodine delivers 5-HMT with less variability than tolterodine, regardless of CYP2D6 status, with up to 40% higher bioavailability. The pharmacokinetics of fesoterodine were considerably less variable than TER., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Aim: To investigate changes in urodynamic parameters after tolterodine treatment for female overactive bladder syndrome, especially in patients with voiding dysfunction., Methods: Between January and December 2006, 44 patients were enrolled for six months of treatment with tolterodine. Pre-treatment and post-treatment urodynamic studies were scheduled for the enrolled patients., Results: Among the remaining 33 patients (11 dropped out), bladder capacity (P < 0.001) and post-void residual urine (P = 0.009) increased, and functional urethral length (P = 0.049) and pad weight test (P = 0.03) decreased after treatment. Besides this, detrusor pressure at maximal urine flow, functional urethral length, maximal urethral pressure and maximal urethral closure pressure were less affected by tolterodine in patients with voiding dysfunction, compared to those without voiding dysfunction., Conclusions: Tolterodine treatment increased bladder capacity and decreased urine leakage; however, some urodynamic parameters in patients with voiding dysfunction were less affected by tolterodine treatment., (© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.)

Objective: • To show the superior efficacy of fesoterodine over tolterodine extended release (ER) in a placebo-controlled overactive bladder (OAB) trial with predefined treatment comparisons for both diary measures and patient-reported outcomes., Materials and Methods: • In this 12-week, double-blind, double-dummy trial, subjects reporting >1 urgency urinary incontinence (UUI) episode and ≥8 micturitions per 24 h at baseline were randomized to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks), tolterodine ER 4 mg, or placebo. • Subjects completed 3-day bladder diaries, the Patient Perception of Bladder Condition (PPBC) and the Urgency Perception Scale (UPS) at baseline and weeks 1, 4 and 12 and the OAB Questionnaire at baseline and week 12., Results: • A total of 2417 subjects were randomized. At week 12, fesoterodine 8 mg showed superiority over tolterodine ER 4 mg and placebo on UUI episodes (primary endpoint), micturitions, urgency and most other diary endpoints, and on the PPBC, UPS and all OAB Questionnaire scales and domains (all P < 0.05). • Superiority of fesoterodine 8 mg over tolterodine ER 4 mg was seen as early as week 4 (3 weeks after escalation to fesoterodine 8 mg). At week 1, fesoterodine 4 mg was superior to placebo on most diary variables, the PPBC and the UPS (all P < 0.05). Dry mouth and constipation rates were 28% and 4% with fesoterodine, 13% and 3% with tolterodine ER, and 5% and 2% with placebo. • Discontinuation rates as a result of adverse events were 5%, 3% and 2% for fesoterodine, tolterodine ER and placebo, respectively., Conclusions: • In this randomized study, which is the largest to compare antimuscarinic efficacy performed to date, fesoterodine 8 mg was superior to tolterodine ER 4 mg for UUI episodes, micturitions and urgency episodes, as well as for self-reported patient assessments of bladder-related problems, urgency, symptom bother and health-related quality of life. • The superiority of fesoterodine 8 mg over tolterodine ER 4 mg was observed as early as 3 weeks after escalation from fesoterodine 4 mg for most outcomes. These data may have important implications for the clinical management of OAB patients previously treated with tolterodine ER., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

This paper describes the successful design and development of dual pharmacology β-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Aim: To determine the efficacy of toterodine extended release (ER) treatment for 1 year in older men with benign prostatic hyperplasia (BPH) and storage symptoms treated with alpha-blockers and/or 5-alpha-reductase inhibitors (5ARI)., Methods: Men aged over 70 years with BPH/bladder outlet obstruction (BOO) and clinical storage symptoms were randomly treated with or without tolterodine ER in combination with alpha-blockers and/or 5ARI for 12 months. Among them, 50 patients (group 1) received additive tolterodine extended release (ER) 4 mg q.d., another 87 patients (group 2) did not. All patients had a baseline and 12th month post-treatment evaluation, which comprised of uroflowmetry, post-void residual (PVR) volume, International Prostate Symptom Score (IPSS), and quality of life index (QoL-I), transrectal ultrasound of the prostate and serum prostate specific antigen., Results: One hundred thirty-seven of 153 enrolled patients with a mean age of 74.9 years completed the study. Treatment benefit demonstrated in both groups included deceased total, voiding and storage IPSS scores, increased peak urinary flow rate and deceased QoL-I. Inter-group difference was only observed on the storage domain of IPSS score (P = 0.012). The mean PVR after treatment did not significantly differ between two groups. Two patients of group 1 and three of group 2 developed acute urinary retention. Among group 1, six patients discontinued tolterodine ER for intolerable dry mouth; among group 2, three patients reported dizziness., Conclusions: This longer comparative study indicated that additive treatment with tolterodine ER in older men with BPH/BOO and significant storage symptoms is a beneficial and safe therapeutic option., (Copyright © 2011 Wiley-Liss, Inc.)

Aims: To assess the efficacy and safety of pregabalin alone or in combination with tolterodine extended release (ER) in subjects with idiopathic OAB., Methods: This 26-week, multicenter, randomized, double-blind, placebo-controlled, three-period crossover study enrolled women aged ≥ 18 years that were diagnosed with OAB and reported ≥ 8 micturitions/24 hr and ≥ 4 urgency episodes/week on 5-day bladder diary at baseline. Subjects were randomized to 1 of 10 treatment sequences and received three of five treatments, each for 4 weeks with 4-week washout periods: standard-dose pregabalin/tolterodine ER (150 mg twice daily [BID]/4 mg once daily [QD], n=102), pregabalin alone (150 mg BID, n=105), tolterodine ER alone (4 mg QD, n=104), low-dose pregabalin/tolterodine ER (75 mg BID/2 mg QD, n=105), and placebo (n=103). Subjects completed 5-day diaries at the end of treatment and washout periods. The primary endpoint was change from baseline to week 4 in mean voided volume (MVV) per micturition. The primary comparison was standard-dose pregabalin/tolterodine ER versus tolterodine ER alone; secondary comparisons were pregabalin alone versus tolterodine ER alone and versus placebo., Results: Baseline-adjusted changes in MVV were significantly greater after treatment with standard-dose pregabalin/tolterodine ER (39.5 ml) versus tolterodine ER alone (15.5 ml; P<0.0001), and with pregabalin alone (27.4 ml) versus tolterodine ER alone (P=0.005) and placebo (11.9 ml; P=0.0006). Treatments were generally well tolerated; discontinuation rates due to adverse events were 4%, 2%, 5%, 0%, and 1% with standard- and low-dose pregabalin/tolterodine ER, pregabalin, tolterodine ER, and placebo, respectively., Conclusions: Pregabalin, alone or with tolterodine ER may offer an alternative treatment option for idiopathic OAB in women., (Copyright © 2010 Wiley-Liss, Inc.)

Objective: To determine whether the efficacy and safety of a combination of tolterodine extended-release (ER) plus α-blocker treatment varies with high or low levels of serum prostate-specific antigen (PSA) in men who have persistent overactive bladder (OAB) symptoms after any α-blocker monotherapy., Patients and Methods: Men aged ≥ 40 years were eligible if they reported ≥ 8 micturitions/24 h, including ≥ 1 urgency episode/24 h with or without urgency urinary incontinence (UUI), and at least some moderate bladder-related problems at baseline despite receiving treatment with an α-blocker for ≥ 1 month. Exclusion criteria included a postvoid residual urine volume (PVR) of ≥ 200 mL and history of acute urinary retention requiring catheterization. Subjects were randomly assigned to tolterodine-ER 4 mg or placebo for 12 weeks; all subjects continued their α-blocker treatment throughout the study. Subjects completed 5-day bladder diaries at baseline and week 12, in which they recorded all micturitions and rated the sensation associated with each micturition using the 5-point Urinary Sensation Scale (USS). For this post hoc analysis, efficacy, safety, and tolerability data were stratified by the study median PSA concentration at baseline (1.41 ng/mL)., Results: In the tolterodine-ER +α-blocker and placebo +α-blocker groups, 160 and 159 men, respectively, had PSA levels of <1.41 ng/mL, and 166 and 160 men, respectively, had PSA levels of ≥ 1.41 ng/mL. Men with higher PSA levels were slightly older and had higher PVR at baseline compared with men with lower PSA levels. At week 12, improvements in daytime micturitions, 24-h urgency episodes, and daytime urgency episodes were significantly greater with tolterodine-ER +α-blocker vs placebo +α-blocker both in men with PSA levels of ≥ 1.41 ng/mL and those with PSA levels of < 1.41 ng/mL (P < 0.05). Among men with PSA levels of < 1.41 ng/mL, improvements in 24-h micturitions and frequency-urgency sum (sum of USS ratings for all micturitions) were also significantly greater with tolterodine-ER +α-blocker vs placebo +α-blocker (P < 0.05). There were no significant treatment differences in change in UUI episodes in either PSA group (although only 19% of subjects reported UUI at baseline), nor in nocturnal micturitions or nocturnal urgency episodes. Among men with PSA levels of ≥ 1.41 ng/mL, there was a statistically significant increase in PVR (P = 0.036) and decrease in maximum urinary flow rate (Q(max); P = 0.038) with tolterodine-ER +α-blocker vs placebo +α-blocker; these changes were not considered clinically meaningful. There were no treatment differences for changes in PVR or Q(max) among men with PSA levels of < 1.41 ng/mL. One subject receiving tolterodine-ER +α-blocker (PSA concentration of ≥ 1.41 ng/mL) and two subjects receiving placebo +α-blocker (one each in the PSA concentration subgroups of ≥ 1.41 ng/mL and < 1.41 ng/mL) had acute urinary retention requiring catheterization., Conclusion: In a 12-week study, the addition of tolterodine-ER to α-blocker therapy improved key OAB symptoms and appeared to be well tolerated compared with placebo +α-blocker in men with persistent OAB symptoms, regardless of subjects' prostate size as judged by serum PSA concentration., (© 2010 DRUG SAFETY RESEARCH UNIT.)

Objective: To evaluate the efficacy of extended-release (ER) tolterodine 4mg/day for the treatment of neurogenic detrusor overactivity (NDO) and/or low-compliance bladder by assessing urodynamic parameters., Methods: Forty-six patients (25 male, 21 female; mean age 57.6±20.7years) with NDO (n=39) and/or low-compliance bladder (n=7) were included in this 12-week single-arm study. Twenty-one patients (46%) were on clean intermittent catheterization and other patients could void on their own. A video urodynamic study was performed before and at 3 months after treatment. Changes in Overactive Bladder Symptom Score (OABSS), International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and King's Health Questionnaire (KHQ) as well as changes in number of voids, amount of each void, and number of leaks in 24h according to the 3-day voiding diary were also evaluated before treatment and at weeks 4 and 12 after treatment., Results: Bladder capacity at first sensation and maximum cystometric capacity increased significantly, by an average of 36.8mL (P=0.0402) and 82.3mL (P<0.0001), respectively. Maximum cystometric capacity increased by more than 50mL in 19 patients (49%) following treatment. Detrusor overactivity disappeared in three of 32 patients (9%), bladder capacity at first involuntary contraction increased significantly (P=0.0009), and amplitude of detrusor overactivity decreased significantly (P=0.0025). In patients with low-compliance bladder, bladder compliance increased significantly (P=0.0156). Overactive bladder symptom score, International Consultation on Incontinence Questionnaire-Short Form score, number of voids (per 24h and night-time), number of urgency episodes in 24h, number and amount of leaks in 24h, and amount of mean and maximum voided volumes all decreased significantly after treatment., Conclusion: Tolterodine is effective and well tolerated for the treatment of NDO and/or low-compliance bladder in patients with neurogenic bladder., (© 2010 The Japanese Urological Association.)

Purpose: To investigate the potential effect of tolterodine on the human heart rate variability (HRV). Oral antimuscarinic treatment for overactive bladder might significantly alter HRV, which is an important predictor for cardiac and all-cause mortality. Yet, little information exists regarding the influence of oral antimuscarinics on the HRV., Methods: Healthy female volunteers were randomly assigned to either placebo, tolterodine extended release (ER) 4 or 8 mg. Before and 4 h post treatment, a 10 min electrocardiogram (ECG) was recorded in supine position. Frequency domain and time domain analysis of both ECG measurements resulted in very low frequency (VLF), low frequency (LF), and high frequency (HF) data, the root mean square of differences of successive NN (= normal to normal, i.e. interval between two R-peaks) intervals (RMSSD), and the standard deviation of the NN intervals (SDNN)., Results: Thirty subjects (mean age: 23.7 ± 2.3 years) were investigated. Placebo caused no significant HRV changes. Tolterodine 4 mg significantly increased heart rate (HR) and significantly decreased VLF. Tolterodine 8 mg significantly decreased HF, VLF, RMSSD and SDNN and significantly increased HR and LF/HF ratio. The changes observed with 4 mg were not significantly different versus placebo, but 8 mg significantly increased LF/HF as compared to placebo., Conclusions: A single dose of 8 mg tolterodine ER, but not 4 mg seems to reduce resting HRV versus placebo in young healthy subjects. This might be particular relevant for patients with pre-existing cardiac conditions on daily overactive bladder drug treatment and should be further investigated in larger trials.

Objectives: To investigate the symptomatic and quality of life (QoL) response to treatment with tolterodine extended release (ER) in subgroups of male patients with Overactive Bladder Syndrome (OAB) and LUTS suggestive of non-obstructive benign prostatic hyperplasia (BPH) according to age, symptom severity, diabetes mellitus status, and concomitant treatment for LUTS., Methods: Patients treated with tolterodine ER 4 mg/day for OAB symptoms, alone or added to unsuccessful alpha-blocker treatment of > or =6 weeks duration, and presumed non-obstructive BPH (Q (max) > or = 15 ml/s) were observed for 12 weeks in a non-interventional study. Patients completed the International Prostate Symptom Score (IPSS) and Overactive Bladder Questionnaire (OAB-q) at baseline and after 12 weeks., Results: 52.4% of 741 patients were aged < or =65 years; 4, 64, and 32% had mild, moderate, and severe symptoms, respectively, according to IPSS; 14% had diabetes mellitus, and in 42% tolterodine was added to alpha blockers. In the various subgroups, mean IPSS total scores improved by 2.8-11.1 points, IPSS QoL scores by 1.8-2.4 points, and all OAB-q subscores by more than 14 points. Only IPSS and OAB-q baseline scores had a relevant impact on changes during treatment, benefits were greatest in patients with more severe symptoms and bother., Conclusions: In men with symptoms of OAB and LUTS suggestive of non-obstructive BPH of all IPSS severity classes, aged < or =65 years or above, with or without concomitant diabetes or alpha-blockers, symptoms and QoL improved markedly during treatment with tolterodine ER.

Unlabelled: INTRODUCTION & HYPOTHESIS: Determine if treatment of urge incontinence with tolterodine results in changes in bladder and/or urethral sensation using Current Perception Threshold (CPT) testing., Methods: Women with >or=1 incontinence episode on 7-day diary were treated with 4 mg of long-acting tolterodine for 2-months. At baseline and 2-months, participants had CPT testing of the urethral and bladder at 3 frequencies 2000, 250, and 5 Hz. Baseline and post-treatment measures were compared using Wilcoxon Signed Rank Test., Results: Seventeen women underwent baseline CPT testing. Four discontinued medication due to side effects and did not have repeated testing. Urethral CPT at 250 Hz was lower after treatment (median 1.3 [Interquartile range .69-2.1] and .75 [.45-1.2], p = .003) and at 5 Hz trended toward a significant decrease (1.1 [1-1.9] and .84 [.32-1.1], p = .06)., Conclusions: Urethral sensitivity improves after 2-months of tolterodine, suggesting it may restore urethral sensory nerves in addition to known motor effects., ((c) 2009 Wiley-Liss, Inc.)

Aims: There is evidence that antimuscarinic drugs have depressant influence not only on bladder muscle activity, but also on bladder sensations. The aim of this study was to evaluate the effect of a single dose tolterodine extended release (ER) 4 and 8 mg on bladder sensations during filling cystometry., Methods: After approval of the local ethics committee, 30 healthy female subjects (23.7 +/- 2.3 years) were included and randomly assigned to three groups: (A) placebo, (B) tolterodine ER 4 mg, and (C) tolterodine ER 8 mg in a double blind manner. Measurements were performed at baseline and 4 hr postmedication in each group, consisting of: (1) Filling cystometry with 25 ml/min at which subjects had to indicate first sensation of filling (FSF), first desire to void (FDV), and strong desire to void (SDV). (2) Uroflowmetry and ultrasound control for residual urine., Results: In the placebo group, filling volumes at FDV and SDV decreased significantly posttreatment. This effect could not be observed for the tolterodine 8 mg group and only at SDV in the 4 mg group. No significant difference between groups was found regarding uroflowmetry parameters and postvoid residual volume., Conclusions: No increase of filling volumes in healthy subjects could be observed with tolterodine. However, the results suggest that tolterodine is able to alleviate irritation caused by repeated catheterization and cystometry. There was no significant influence of tolterodine ER 4 or 8 mg on voiding function., ((c) 2009 Wiley-Liss, Inc.)

Purpose: The efficacy of alpha1-adrenoceptor (alpha1-AR) antagonist and anticholinergic agent combined therapy for patients with benign prostatic hyperplasia (BPH) together with overactive bladder (OAB) has been controversial. The purpose of this study was to evaluate the effect of tolterodine combined with alpha1-AR antagonist for patients with BPH and OAB after insufficient efficacy by monotherapy with alpha1-AR antagonist. The adverse event of this combined therapy was also assessed., Materials and Methods: The study included 47 patients with BPH, whose OAB symptom persisted (OAB symptom score; OABSS > or =3) after monotherapy with alpha1-AR antagonist for more than 4 weeks. The mean age was 72.9 years and the mean prostate volume was 29.8 ml. Four mg/day of tolterodine with alpha-AR antagonist was administered for 8 weeks to patients. International prostate symptom score (IPSS), quality of life (QOL) index, OABSS, King's Health Questionnaire (KHQ) and residual urine volume (RUV) were assessed before and after combined therapy., Results: Six patients were dropped out from this study because of dry mouth, constipation, onset of other disease and insufficient efficacy by self-judgment. IPSS (from 15.1 +/- 6.8 to 11.0 +/- 7.9; P < 0.01), QOL index (from 4.3 +/- 1.1 to 3.6 +/- 1.3; P < 0.01) and OABSS (from 7.0 +/- 3.0 to 5.4 +/- 2.9; P < 0.01) of 41 patients improved significantly by combined therapy. The storage symptom of IPSS subscore improved significantly (from 8.0 +/- 2.9 to 6.5 +/- 2.8; P < 0.01), whereas the voiding symptom did not improve. Regarding KHQ, the score of 3 domains (impact on life, role limitation, and physical limitation) improved significantly (P < 0.05). RUV did not change and no serious adverse event including urinary retention was found in this study., Conclusions: This study reveals that the combined therapy of alpha-AR antagonist and tolterodine represents an effective and safe treatment modality for patients with BPH and OAB, whose OAB symptom was not improved by antecedent monotherapy with alpha-AR antagonist.

Aim: A retrospective study was performed to investigate whether the improvement of symptoms achieved with 0.2 % sodium chondroitin sulfate in treating overactive bladder (OAB) persists after 24 months., Materials and Methods: Two years ago, a total of 82 patients with chronic OAB were randomly assigned to receive either anticholinergic treatment (Tolterodin; group A, n = 41) or 0.2 % sodium chondroitin sulfate (Gepan instill; group B, n = 41). Diagnostic assessment included a gynecological examination and history, urodynamic test-ing, introital ultrasound, and cystoscopy. Duration of treatment was 12 months. The patients underwent repeat follow-up after 24 months and the findings were compared with the results at 12 months., Results: In group A, 15 / 35 (43 %) women reported an improvement of symptoms after 12 months as opposed to only 5 / 35 (14 %) after 24 months. In group B, there was an improvement in 23 / 32 (72 %) at 12 months and in 18 / 32 (56 %) after 24 months (p = 0.001). The subjective results were corroborated by means of urodynamic test-ing, pad counts, voiding frequency and nycturia (voiding diary)., Conclusion: Our findings suggest that instillation treatment with 0.2 % sodium chondroitin sulfate results in a more sustained improvement or cure of the symptoms of overactive bladder due to development of a glycosaminoglycan layer. Long-term results are needed for confirmation., (Georg Thieme Verlag Stuttgart * New York.)

Overactive bladder (OAB) is a common problem. Affected individuals suffer decreased quality of life and productivity. The mainstay of pharmacological treatment of OAB is antimuscarinic agents. Tolterodine was the first antimuscarinic drug designed specifically for treating OAB. Compared with the immediate-release (IR) drug, once-daily tolterodine extended-release (ER) releases the drug in a steady but constant manner lowering peak and trough drug levels. This translates to more constant serum concentrations and theoretically better patient tolerability. The dry mouth rate for the ER formulation has been reported to be lower than for the IR formulation. Recent literature strongly supports the efficacy and safety of tolterodine ER in carefully selected older men with OAB symptoms. Tolterodine ER is well tolerated and withdrawal rates are similar to those in placebo. Fesoterodine is a new antimuscarinic that shares the same active metabolite as tolterodine and may provide less pharmacokinetic variability. We support tolterodine ER for treating for OAB. It has proven efficacy and tolerability.

Objectives: To investigate the tolerability of tolterodine extended release (ER) in older subjects with overactive bladder (OAB)., Methods: This was a retrospective analysis of pooled data from five large, randomised, double-blind, placebo-controlled trials. Subjects with OAB symptoms, including urinary frequency and urgency (and nocturia in two studies) with or without urgency urinary incontinence, received qd treatment with tolterodine ER (4 mg) or placebo for 8-12 weeks. Data were stratified post hoc by age group: < 65 (n = 2531), 65-74 (n = 1059) and > or = 75 years (n = 573). Tolerability was assessed by evaluating the occurrence of adverse events (AEs). AE occurrences from each study were mapped to the MedDRA coding dictionary of preferred terms., Results: Discontinuation rates were slightly higher among subjects > or = 75 years of age vs. those < 65 years of age; however, this was observed in subjects treated with placebo as well as tolterodine ER. Overall, there were no significant differences in the occurrence of dry mouth, headache, constipation, nausea, urinary tract infection, blurred vision, dry eye, dizziness and micturition disorder in older (65-74 or > or = 75 years) vs. younger (< 65 years) subjects treated with tolterodine ER relative to placebo (treatment x age; all p > 0.1). Dry mouth was the only AE consistently associated with tolterodine ER treatment (< 65 years, 17%; 65-74 years, 16%; > or = 75 years, 15%). The occurrence of all other AEs was < or = 5% in most age and treatment cohorts. Most AEs were mild or moderate in all age and treatment cohorts., Conclusion: The nature and frequency of AEs associated with tolterodine ER treatment were similar across age groups in subjects with OAB, suggesting that tolterodine ER was not associated with an increased risk of AEs in older vs. younger subjects and, thus, is a suitable first-line pharmacotherapy treatment for OAB in this population.

The aim of the present investigation was to evaluate the percutaneous absorption of tolterodine (TOL) using O-acylmenthol derivatives as enhancers as well as to correlate their enhancing activity under in vitro and in vivo conditions. The in vitro permeation studies of TOL were conducted in isopropyl myristate (IPM) solution or from patches in side-by-side diffusion cells. TOL pharmacokinetic parameters were determined after intravenous administration and topical application of patches without enhancer or with l-menthol and (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate (M-OA) as enhancers in rats. The in vitro permeation studies indicated that M-OA was the most promising enhancer for transdermal delivery, as 2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate (M-LA) was merely effective in IPM solution. There was no significant difference between the control and l-menthol group in terms of the flux before patches were removed, while the skin reservoir effects of the enhancer-containing groups were significantly greater than that of the control group. The mean steady-state plasma concentrations after applying patches without enhancer or with l-menthol and M-OA as enhancers were 0.89, 0.84 and 1.47 microg/mL, respectively. The in vivo results observed from the three types of patches in rats were in good agreement with the plasma concentrations predicted from the in vitro data.

Improvements in overactive bladder (OAB) symptoms and health-related quality of life (HRQL) were assessed during a 24-week study of tolterodine extended release (TOL ER) in sexually active women with OAB and urgency urinary incontinence (UUI). A 12-week, double-blind, randomized, placebo-controlled trial was followed by a 12-week open-label phase. Sexually active women reported symptoms for >or=3 months. Subjects completed bladder diaries and HRQL measures at baseline and weeks 12 and 24. One hundred sixty-one women received TOL ER for 24 weeks. Women reported significant improvements in all end points at week 12 that were maintained or improved at 24 weeks. At week 24, 70% of subjects reported no UUI episodes. TOL ER resulted in improvements in OAB symptoms and HRQL that were maintained or greater with 6 months of use. Long-term compliance with OAB pharmacotherapy may be important for optimal treatment outcomes.

Background: Fesoterodine is a new antimuscarinic agent developed for the treatment of overactive bladder. Fesoterodine itself is inactive and is rapidly and extensively converted by ubiquitous esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is formed via biotransformation of both fesoterodine and tolterodine, albeit by different metabolising enzymes, viz. esterases and CYP2D6 respectively. Tolterodine is a potent muscarinic receptor antagonist and has been used for the treatment of overactive bladder for over ten years. The objective of this study was to establish the pharmacokinetic profile of fesoterodine and to highlight ist potential pharmacokinetic advantages over tolterodine., Design: Single-centre, open-label, randomised, 4-way crossover study in a total of 24 healthy male volunteers. Single oral doses of 4, 8, or 12 mg fesoterodine were administered after an overnight fast. In addition, the 8 mg dose was also administered after a standard high-fat and high-calorie breakfast. Blood and urine samples for the analysis of 5-HMT were collected before and multiple times after drug administration for pharmacokinetic analysis., Results: The mean peak plasma concentration (Cmax) of 5-HMT and the mean area under the time versus concentration curve (AUC) increased proportionally with the fesoterodine dose. These two parameters were some 2-fold higher in CYP2D6 poor metabolisers, whereas the time to peak plasma concentration (tmax) and half life (t1/2) were not influenced by the dose or the CYP2D6 metaboliser status. If fesoterodine was taken following a high-fat breakfast, we observed small increases in Cmax and AUC. In spite of these modest genetic influences and food effects on the pharmacokinetics of fesoterodine, the overall interindividual variability in Cmax levels was relatively little compared to previously published reports using tolterodine., Conclusions: Due to the esterase-mediated cytochrome P450-independent formation of 5-HMT and involvement of multiple metabolic and renal excretion pathways in the elimination of 5-HMT, the effects of patient-intrinsic and -extrinsic factors on the pharmacokinetics of fesoterodine are only modest, with some 2-fold higher 5-HMT exposure. Therefore, in contrast to tolterodine, no reduction of fesoterodine dosage is required under conditions of reduced elimination. In most cases of drug interaction or renal/hepatic impairment, the fesoterodine dose may be increased to 8 mg/day based on individual patients' response, or patients may be required to remain at the initial recommended dose of 4 mg/day.

Background: No authors have investigated whether the administration of local oestrogens in addition to antimuscarinics could have a synergistic effect in the therapy of overactive bladder (OAB)., Objectives: To compare the efficacy of antimuscarinics alone versus antimuscarinics in combination with local oestrogens for OAB; to verify whether risk factors for lower antimuscarinic efficacy can be overcome by the concomitant use of local oestrogens., Design, Setting, and Participants: Some 229 postmenopausal women with symptomatic urodynamically proven detrusor overactivity were prospectively enrolled at a tertiary level urogynaecology centre and divided into two groups., Intervention: Women in group 1 (n=129) were prescribed tolterodine extended release (ER) 4 mg once daily; women in group 2 (n=100) were prescribed both tolterodine ER 4 mg and concomitant oestriol cream application once daily., Measurements: All women underwent clinical evaluation and urodynamics in accordance with the Good Urodynamic Practices Guidelines. After 12 wk of treatment the two groups were compared in terms of subjective efficacy for OAB symptom improvement using a three-point scale. Nonresponders were compared to the patients who improved or were cured in order to identify risk factors for resistance to therapy., Results and Limitations: There was no significant difference between the two groups in terms of efficacy of therapy: 80.6% in group 1 versus 82% in group 2 (p=0.86). Patients with urodynamically proven detrusor overactivity (DO) occurring during provocative manoeuvres and patients with coital incontinence during orgasm reported a higher failure rate both in the overall study population and in group 2. A possible limitation of the study is the nonrandomised design., Conclusions: No synergistic effect of local oestrogens and antimuscarinics in the treatment of OAB was found. Antimuscarinic treatment has lower cure rates in women with symptomatic DO complaining of incontinence at orgasm or in patients with DO following provocative manoeuvres. The association of local oestrogens does not influence the role of the two mentioned risk factors.

After lifestyle and behavioral measures to control overactive bladder, the mainstay of pharmacological treatment is the use of antimuscarinic therapy. Overactive bladder predominantly affects older people, who experience the most severe disease, and are also at a greater risk of side effects from antimuscarinic therapy. Thus it is imperative that data are available on the efficacy and tolerability of this group of drugs when used in older people. This article reviews the pathophysiology of the condition, its effect on the elderly and the evidence for the use of extended release tolterodine in the elderly using data from placebo and active drug controlled studies.

Objective: The purpose of the present analysis was to analyze and compare the cost-effectiveness of solifenacin flexible dosing (5-10 mg) with tolterodine 4 mg sustained release (SR) or placebo (assumed to be comparable to no treatment) for patients with overactive bladder (OAB) symptoms., Design: A decision-analytic model was constructed., Methods: Costs and effects were evaluated for the three treatment options in a one-year timeframe. Costs included were treatment costs, cost of pad use, and patients productivity loss based on data from the Nordic countries., Sample: Results from two randomized controlled trials were used as input data in the cost-effectiveness analysis., Main Outcome Measures: Quality adjusted life years and incremental cost-effectiveness ratio., Results: Solifenacin flexible dosing was more effective with respect to reducing OAB symptoms compared to both placebo and tolterodine 4 mg. Treatment with both solifenacin and tolterodine was more costly compared to placebo, but treatment with solifenacin was a less costly alternative compared to tolterodine 4 mg SR. Sensitivity analyses revealed that the conclusions were robust., Conclusion: Solifenacin flexible dosing was a cost-effective treatment alternative compared to tolterodine 4 mg SR.

Objective: To evaluate the efficacy of tolterodine extended release (ER) versus placebo at 1 and 12 weeks using questionnaires and diary measures., Research Design and Methods: Subjects with overactive bladder (OAB) were randomized to receive tolterodine ER (4 mg) or placebo for 12 weeks. This double-blind study is registered with ClinicalTrials.gov (identifier: NCT00143377)., Main Outcome Measures: Subjects completed the Patient Perception of Bladder Condition (PPBC) and 3-day bladder diaries at baseline and weeks 1 and 12, and the Overactive Bladder Questionnaire (OAB-q) at baseline and week 12. PPBC score changes were analyzed using 2-category (improvement, no improvement), 3-category (improvement, no change, deterioration), and 4-category (>or=2-point improvement, 1-point improvement, no change, deterioration) stratifications. Categorical change in PPBC scores from baseline to week 12 was the primary endpoint., Results: A total of 617 subjects were randomized (tolterodine ER, n = 410; placebo, n = 207). At week 1, a significantly higher percentage of subjects receiving tolterodine ER reported improvement on the PPBC compared with placebo (p < 0.05). Subjects receiving tolterodine ER also had a significantly greater reduction in all OAB symptoms versus placebo (all p < 0.05). At week 12, a higher percentage of tolterodine ER subjects reported PPBC improvement versus placebo subjects. This was significant in the 3- and 4-category analyses (both p < 0.05) but not in the 2-category analysis (the prespecified method of analysis; p = 0.098). Compared with the placebo group, the tolterodine ER group reported significantly greater week 12 improvements in all bladder diary variables (all p < 0.01) as well as in OAB-q Symptom Bother, total Health-Related Quality of Life, Coping, and Concern scores (all p

Objective: We evaluated long-term (> or =12 months) efficacy and safety of tolterodine in children with neurogenic detrusor overactivity., Subjects and Methods: Subjects successfully completed one of three 12-week, open-label studies and had stable neurologic disease and urodynamic evidence of neurogenic detrusor overactivity requiring intermittent catheterization. Drug formulation and dosing were based on age (4 months-4 years, tolterodine oral solution 0.2-2mg twice daily; 5-10 years, tolterodine oral solution 0.5-4 mg twice daily; 11-16 years, tolterodine extended-release capsules 2, 4, or 6 mg once daily). Daily doses were individualized for each subject. Efficacy was evaluated urodynamically and using parent-completed 3-day bladder diaries., Results: Thirty subjects were enrolled. Functional bladder capacity (volume at first leakage, first sensation of bladder fullness or 40 cm H(2)O pressure) increased by month 12 in the younger age groups but not in the oldest subjects. Volume to first detrusor contraction >10 cm H(2)O pressure and detrusor leak point pressure did not change in any age group. The number of incontinence episodes per 24h decreased in all subjects, as did the number of catheterizations per 24h. Mean volume per catheterization increased in all subjects. Seven treatment-related adverse events were reported., Conclusions: Both tolterodine formulations were effective and well tolerated in children with neurogenic detrusor overactivity.

Objectives: To evaluate the efficacy of tolterodine extended release (ER), tamsulosin, and tolterodine ER plus tamsulosin in men with symptoms of overactive bladder and benign prostatic hyperplasia stratified by prostate-specific antigen (PSA) level., Methods: We performed a post hoc analysis of data from men >or=40 years old with frequency and urgency (with or without urge urinary incontinence), postvoid residual urine volume <200 mL, maximal urinary flow rate >5 mL/s, International Prostate Symptom Score (IPSS) of >or=12, and quality-of-life score of >or=3. They had been randomized to placebo, tolterodine ER (4 mg), tamsulosin (0.4 mg), or tolterodine ER plus tamsulosin for 12 weeks. The men were stratified by the median baseline PSA level (>or=1.3 vs <1.3 ng/mL). Assessments included changes in bladder diary variables and IPSSs. The men rated the urgency level of each micturition, and the frequency-urgency sum was defined as the total of these ratings., Results: The PSA level correlated significantly with prostate size. Men with a PSA level of >or=1.3 ng/mL receiving tolterodine ER plus tamsulosin showed significantly greater improvements in 24-hour frequency, daytime frequency, the frequency-urgency sum, total IPSS, and IPSS storage score compared with those receiving placebo. Tamsulosin significantly improved the IPSS voiding scores, but tolterodine ER was ineffective. In men with a PSA level <1.3 ng/mL, tolterodine ER alone and tolterodine ER plus tamsulosin significantly improved the 24-hour frequency, daytime frequency, frequency-urgency sum, and IPSS storage scores compared with those receiving placebo; tamsulosin alone was ineffective. No significant changes were found in the postvoid residual urine volume or maximal urinary flow rate in any group, and the acute urinary retention rates were low., Conclusions: The results of our study have shown that tolterodine ER was efficacious in men with lower urinary tract symptoms, including overactive bladder, who had lower PSA levels (<1.3 ng/mL).

Objective: Desmopressin is an approved medical therapy for the treatment of monosymptomatic primary nocturnal enuresis. In cases of limited response to desmopressin, we have added anticholinergic therapy to desmopressin (combination therapy). To evaluate this treatment strategy, we examined the efficacy of combination therapy for primary nocturnal enuresis in desmopressin-nonresponders., Methods: Only patients with primary nocturnal enuresis refractory to the maximal dosage of desmopressin were enrolled. Children with lower urinary tract symptoms or bowel dysfunction were excluded, on the basis of a 3-day, 24-hour, frequency-volume chart and elimination record. Children continued to take desmopressin and were assigned randomly, in a double-blind manner, to receive either extended-release anticholinergic medication or placebo. Patients were reassessed after 1 month of therapy, with a 1-week nocturnal record., Results: Forty-one desmopressin-nonresponders were enrolled, and 7 patients were excluded because of noncompliance. The treatment groups were equally matched with respect to age, gender, functional bladder capacity, and number of wet nights per week. After 1 month of treatment, there was a significant reduction in the mean number of wet nights in the combination therapy group, compared with the placebo group. With a generalized estimating equation approach, there was a significant 66% decrease in the risk of a wet episode, compared with the placebo group., Conclusions: This study represents the first prospective, placebo-controlled trial examining the effect of desmopressin in combination with long-acting, anticholinergic, bladder-relaxing therapy for monosymptomatic primary nocturnal enuresis.

To determine whether participants in the behavior enhances drug reduction of incontinence (BE-DRI) trial experienced reduction in the frequency of nocturia and/or nocturnal leakage during treatment with antimuscarinic phamacotherapy with or without additional behavioral therapy. We analyzed urinary diary data relating to nocturia and nocturnal incontinence before and after 8 weeks of study treatment in the BE-DRI trial, in which patients were randomly assigned to receive drug therapy with tolterodine tartrate extended-release capsules 4 mg alone or in combination with behavioral training. Chi-square tests assessed whether nocturia and nocturnal incontinence prevalence varied by treatment arm and paired t tests assessed the change in mean frequency of nocturia and nocturnal leakage. Among 305 women, 210 (69%) had an average of at least one nocturia episode at baseline. There were small but statistically significant differences (p < 0.001) in mean nocturia frequency and nocturnal incontinence frequency with both treatments after 8 weeks, but no significant difference between study treatment groups. Among these urge incontinent women, tolterodine with or without supervised behavioral therapy had little impact on either nocturic frequency or nocturnal incontinence.

Objective: To understand the pathophysiological mechanism of incontinence during orgasm and to compare women affected by symptomatic detrusor overactivity (DO) with and without incontinence at orgasm in terms of efficacy of antimuscarinic treatment., Methods: All consecutive sexually active women with incontinence during intercourse were prospectively included and divided into two groups: women with coital incontinence at orgasm or at penetration. The two forms of coital incontinence were correlated to the urodynamic finding of DO. Women complaining of overactive bladder (OAB) symptoms, with urinary incontinence at orgasm and urodynamically proven DO (cases), were prescribed tolterodine 4 mg extended release for at least 12 wk. The cases were compared in terms of efficacy of treatment on OAB symptoms to consecutive patients with symptomatic DO without coital incontinence (control group)., Results: Among the 1133 women who underwent urodynamic testings during the study period, 132 patients were eligible for final analysis. A significant difference in DO was observed in women with incontinence at orgasm (34 of 49; 69.4%) compared with women with incontinence during penetration (24 of 83; 28.9%) (p<0.0001). The 34 women with incontinence at orgasm associated with DO were given antimuscarinics treatment and were compared with 53 controls. Fourteen of 34 (41.2%) and 9 of 53 (17%) women did not respond to antimuscarinics in the cases and in the control group, respectively (p=0.023)., Conclusions: Incontinence at orgasm is associated with DO in the majority of cases. This is the first study showing an inferior efficacy of antimuscarinic treatment in women with DO complaining of incontinence at orgasm.

Objective: This study evaluated the use of solifenacin in patients experiencing residual urgency symptoms during treatment with tolterodine extended release (ER) 4 mg for overactive bladder (OAB)., Methods: This was a 12-week, multicenter, openlabel, flexible-dose study of the efficacy, tolerability, and effects on health-related quality of life (HRQL) of solifenacin in patients aged >or=18 years who had symptoms of OAB for >or=3 months, had been treated with tolterodine ER 4 mg for >or=4 weeks, and wished to switch therapy because of a lack of sufficient subjective improvement in urgency. At baseline (before washout of tolterodine), patients had to have >or=3 urgency episodes/24 hours. After >or=14 days' washout of tolterodine, all patients received oral solifenacin 5 mg/d, with the option of a dose increase to 10 mg at weeks 4 and 8. On 3 consecutive days before the prewashout, postwashout (no drug treatment for OAB), and week 4, 8, and 12 visits (during and at the end of treatment with solifenacin), patients used a bladder diary to document daily symptoms of urgency, urge incontinence, frequency, nocturia, and nocturnal voids. Changes in these measures at study end were compared with prewashout and postwashout values. The Patient Perception of Bladder Condition (PPBC) and Overactive Bladder Questionnaire (OAB-q) were used to assess patient-reported outcomes at prewashout, postwashout, and week 12. Tolerability was evaluated based on the nature, frequency, and severity of observed or reported adverse events (AEs)., Results: Of 606 patients screened, 441 received study medication (mean [SD] age, 61.4 [13.8] years; 88.9% white; 88.2% female). Diary-documented urgency changed from a mean of 6.0 episodes/24 hours at prewashout to 2.6 episodes/24 hours at study end, a mean decrease of 3.4 episodes/24 hours (95% CI, -3.8 to -3.0; P < 0.001). The frequency of all other diary variables was also significantly reduced from prewashout to study end (P < 0.001). The mean PPBC score changed from 4.2 points at prewashout to 3.0 points at study end, a mean improvement of 1.2 points (95% CI, -1.3 to -1.1; P < 0.001). Changes in all OAB-q scales and domains (symptom bother, coping, concern, sleep, social interaction, and total HRQL) from prewashout and postwashout to study end were also statistically significant (P < 0.001). Treatment-emergent AEs were mainly mild or moderate (237/261 [90.8%]) and led to few discontinuations (16/441 [3.6%]). Treatment-emergent AEs included anticholinergic AEs such as dry mouth (77 [17.5%]), constipation (51 [11.6%]), and blurred vision (10 [2.3%])., Conclusions: Among these patients with residual urgency after treatment with tolterodine ER 4 mg, solifenacin was associated with significant improvements in urgency and other diary-documented symptoms of OAB. Patients receiving solifenacin also had significant improvements in HRQL and the perceived bother of OAB.

Objectives: To assess efficacy and tolerability of tolterodine extended release (ER) in continent and incontinent subjects with overactive bladder (OAB)., Methods: This was a post hoc analysis of data from a 12-week, double-blind, placebo-controlled trial of tolterodine ER (4 mg once daily). Subjects completed 7-day bladder diaries at baseline and week 12; those with one or more incontinence episode(s) in their diaries at baseline were considered incontinent. Subjects rated urgency associated with each micturition on a scale from 1 to 5, and micturitions were categorized post hoc by urgency rating as non-OAB (1-2), OAB (3-5), or severe OAB (4-5)., Results: At baseline, 40% of subjects were incontinent. Tolterodine ER (n = 429) reduced total, OAB, and severe OAB micturitions compared with placebo (n = 421) in continent and incontinent subjects. There was no difference between continent and incontinent subjects in terms of the magnitude of improvement with tolterodine ER relative to placebo for total, OAB, and severe OAB micturitions. Reductions in mean urgency and frequency-urgency sum ratings were significantly greater in the tolterodine ER group. Among incontinent subjects, tolterodine ER significantly reduced urgency urinary incontinence episodes and significantly increased the percentage of subjects achieving continence relative to placebo. Adverse event rates were low in both continent and incontinent subjects., Conclusions: Tolterodine ER reduced micturitions associated with urgency (OAB or severe OAB) in both continent and incontinent subjects. Tolterodine ER also reduced urgency urinary incontinence episodes in incontinent subjects. These data show that tolterodine ER is effective and well tolerated in both continent and incontinent subjects with OAB.

Purpose: We evaluated the efficacy of tolterodine extended release and/or tamsulosin on micturition related urgency episodes, urgency severity and patient reported outcomes in men who met entry criteria for prostatic enlargement and overactive bladder trials., Materials and Methods: Men 40 years old or older with an International Prostate Symptom Score of 12 or greater, frequency (8 or more voids per 24 hours) and urgency (3 or more episodes per 24 hours) with or without urgency urinary incontinence were randomized to placebo, 4 mg tolterodine extended release, 0.4 mg tamsulosin or tolterodine extended release plus tamsulosin for 12 weeks. Subjects completed 5-day diaries; the Patient Perception of Bladder Condition and Urgency Perception Scale at baseline, and weeks 1, 6 and 12; Overactive Bladder Questionnaire at baseline, and weeks 6 and 12; Perception of Treatment Satisfaction question at weeks 1, 6 and 12; and Willingness to Continue question at week 12. Subjects rated the urgency associated with each micturition on a 5-point scale and micturition related urgency episodes were those rated 3 or greater. Urgency severity was measured using frequency-urgency sum, defined as the sum of urgency ratings for all micturitions., Results: Compared with placebo, tolterodine extended release plus tamsulosin significantly reduced daytime and nocturnal micturition related urgency episodes as well as frequency-urgency sum at weeks 1, 6 and 12. It also improved Patient Perception of Bladder Condition scores at weeks 1, 6 and 12; improved Urgency Perception Scale and Overactive Bladder Questionnaire, Symptom Bother and Health Related Quality of Life scores at weeks 6 and 12; and increased the percentage of subjects who reported treatment satisfaction at weeks 6 and 12, and willingness to continue at week 12., Conclusions: Treatment with tolterodine extended release plus tamsulosin significantly improved urgency variables and patient reported outcomes in men meeting entry criteria for overactive bladder and prostatic enlargement trials.

Objective: Assess changes in resource utilization, work and activity impairment, and health utility among OAB patients continuing to have urgency symptoms with tolterodine ER 4 mg and willing to try solifenacin 5/10 mg., Research Design and Methods: This was an open-label, non-comparative, flexible-dosing, multicenter, 12-week study assessing the efficacy and safety of solifenacin 5/10 mg/day. Patients receiving tolterodine ER 4 mg/day for >/=4 weeks but continuing to experience residual urgency symptoms (>/=3 urgency episodes/24 h) were enrolled into the study. After a 14-day washout, patients began treatment with solifenacin 5 mg/day with dosing adjustments allowed at Weeks 4 and 8., Main Outcome Measures: Outcomes were assessed using the Work Productivity and Activity Impairment Questionnaire - Specific Health Problem (WPAI-SHP), Health Utilities Index (HUI), and a resource utilization questionnaire administered at Pre-Washout and Week 12., Results: Patients (n=440) reported significantly fewer physician office visits (p<0.0001), UTIs (p<0.0001), and pads/diapers (p=0.0009) during the study period while receiving solifenacin 5/10 mg/day, compared with the Pre-Washout period when receiving tolterodine ER 4 mg/day. After 12 weeks of treatment with solifenacin 5/10 mg/day, patients reported a reduction in work time missed (p=0.0017), less impairment while working (p<0.0001), less overall work impairment (p<0.0001) and a reduction in activity impairment (p<0.0001) compared to Pre-Washout. There was no significant difference in health utility scores. Treatment-emergent adverse events were mostly anticholinergic in nature, and were mild to moderate in severity., Conclusion: Overall, solifenacin 5/10 mg/day improved work productivity, activity participation, and reduced medical care use in OAB patients who continued to have urgency symptoms with tolterodine ER 4 mg/day and wished to switch to solifenacin 5/10 mg. This was an open-label, non-comparative study; therefore, further research is needed to confirm these results.