Search

Background: Overactive bladder (OAB) is highly prevalent and is associated with considerable morbidity and reduced health-related quality of life. β3-adrenergic receptor (β3-AR) stimulation is a novel alternative to antimuscarinic therapy for OAB., Objective: The objective of this analysis was to assess the cost effectiveness of the β3-AR agonist mirabegron relative to tolterodine extended release (ER) in patients with OAB from a UK National Health Service (NHS) perspective., Methods: A Markov model was developed to simulate the management, course of disease, and effect of complications in OAB patients over a period of 5 years. Transition probabilities for symptom severity levels and probabilities of adverse events were estimated from the results of the randomised, double-blind SCORPIO trial in 1,987 patients with OAB. Other model inputs were derived from the literature and on assumptions based on clinical experience., Results: Total 5-year costs per patient were £1,645.62 for mirabegron 50 mg/day and £1,607.75 for tolterodine ER 4 mg/day. Mirabegron was associated with a gain of 0.009 quality-adjusted life-years (QALYs) with an additional cost of £37.88. The resulting incremental cost-effectiveness ratio (ICER) was £4,386/QALY gained. In deterministic sensitivity analyses in the general OAB population and several subgroups, ICERs remained below the generally accepted willingness-to-pay (WTP) threshold of £20,000/QALY gained. The probability of mirabegron 50 mg being cost effective relative to tolterodine ER 4 mg was 89.4 % at the same WTP threshold., Conclusions: Mirabegron 50 mg/day is likely to be cost effective compared with tolterodine ER 4 mg/day for adult patients with OAB from a UK NHS perspective.

Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas., (© 2014, The American College of Clinical Pharmacology.)

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.)

Introduction: Participatory patient-centered, web-based methods could streamline and improve the convenience of clinical trial participation. We used an entirely web-based approach to conduct a randomized, placebo-controlled, Phase 4 (REMOTE) trial under an Investigational New Drug (IND) application to evaluate tolterodine extended release (ER) 4 mg for overactive bladder., Methods: The trial was designed to replicate previous clinic-based trials of tolterodine ER but was conducted via the web from one clinical site overseen by physicians. Participants were recruited via the web, screened for eligibility using web-based questionnaires, had laboratory testing in their community, and entered a run-in phase requiring bladder e-diaries. Informed consent was obtained using an interactive web-based method with physician countersignature. Study medication was shipped directly to participants., Results: With a goal of 283 randomized participants, 5157 registered on the trial website. Of 456 who passed initial screening, identification verification, and signed consent, 237 passed additional medical screening and were countersigned by the investigator. After laboratory testing, 118 entered the placebo run-in; only 18 passed e-diary assessments and were randomized to treatment. At week 12, the mean change from the baseline in micturitions/24 hours (primary endpoint) was -2.4 for tolterodine ER versus -0.8 for placebo [treatment difference (95% CI): -1.6 (-3.9, 0.6)]., Conclusion: The REMOTE trial is the first entirely web-based trial conducted under an IND application. The efficacy observed was consistent with results from conventional trials. With simplification of multi-step screening and testing, web-based trials or their component parts should provide a participant-friendly approach to many clinical trials., (Copyright © 2014 Elsevier Inc. 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 study included 95 female patients of 65 to 74 years (average age 67,1 years), who previously (more than 6 months before this study) took a course of monotherapy with hydrochloride trospium in higher dosages with unstable or weak effect. In this study, all patients were divided into three groups and were treated with two antimuscarinic drugs. The majority of older women suffering from OAB and treatment-resistant taking one antimuscarinic drug in high doses showed a significant positive progress in a state by adding a second antimuscarinic agent. The received side effects do not exceed thereof in comparison with treatment with a single drug.

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.

Objective: To carry out a cost-utility analysis comparing initial treatment with solifenacin 5 mg/day vs oxybutynin immediate-release (IR) 15 mg/day for the treatment of patients with overactive bladder (OAB) from the perspective of the U.K. National Health Service (NHS)., Methods: A Markov model with six health states was developed to follow a cohort of OAB patients treated with either solifenacin or oxybutynin during a 1-year period. Costs and utilities were accumulated as patients transited through the health states in the model and a drop-out state. Some of the solifenacin patients were titrated from 5 mg to 10 mg/day at 8 weeks. A proportion of drop-out patients were assumed to continue treatment with tolterodine ER. Utility values were obtained from a Swedish study and pad use was based on a multinational clinical trial. Adherence rates for individual treatments were derived from a U.K. database study. For pad use and utility values, the drop-out state was split between those patients who were no longer receiving treatment and those on second-line therapy. Patients on second-line therapy who drop-out were referred for a specialist visit. Results were expressed in terms of incremental cost-utility ratios., Results: Total annual costs for solifenacin and oxybutynin were £504.30 and £364.19, respectively. First-line drug use represents 49% and 4% of costs and pad use represent 23% and 40% of costs for solifenacin and oxybutynin, respectively. Differences between cumulative utilities were small but were greater for solifenacin (0.7020 vs. 0.6907). The baseline incremental cost-effectiveness ratio was £12,309/QALY., Conclusion: Under the baseline assumptions, solifenacin would appear to be cost-effective with an incremental cost-utility of less than £20,000/QALY. However, small differences in utility between the alternatives and the large number of drop-outs means that the results are sensitive to small adjustments in the values of utilities assigned to the drop-out state.

We performed a randomized, prospective study to assess the possible role of combined tamsulosin and tolterodine therapy for the relief of vesical irritability and in facilitating the spontaneous expulsion of intramural ureteral stones. Patients were randomized to one of three treatment groups. Treatment group 1 patients received tamsulosin 0.4 mg/day, group 2 patients received tamsulosin 0.4 mg/day plus tolterodine 2 mg (twice a day), and group 3 patients received tolterodine 2 mg (twice a day). Subjects rated the urgency associated with each micturition using the Urinary Sensation Scale. Pain descriptions were recorded by the patients using the Visual Analog Scale. Stone expulsion was observed in 30 patients in group 1, 29 patients in group 2 and 18 patients in group 3. Kaplan-Meier curves were plotted to access the expulsion rate of each group over time. A significant difference was shown for the expulsion rate between the tolterodine group and the other two groups. (P = 0.003 by log rank test). Average time to expulsion for groups 1, 2 and 3 was 7.62 ± 2.42, 7.79 ± 2.11 and 10.57 ± 2.71 days, respectively (P = 0.000). In groups 1, 2 and 3, the mean number of pain episodes was 2.27 ± 0.91, 1.39 ± 1.34 and 1.38 ± 1.20, respectively (P = 0.023). Treatment with tamsulosin and tolterodine appears to be beneficial in intramural ureteral stone clearance, particularly in intramural ureter stone with symptoms of vesical irritability.

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.)

Objective: The aim of this study was to compare the changes in urinary symptoms and urodynamic parameters after administration of tolterodine in women with an overactive bladder (OAB)., Materials and Methods: Thirty-eight women diagnosed with OAB and treated with tolterodine were reviewed. Urinalysis, pelvic examination, 3-day bladder diary, urodynamic study, and a personal interview to identify urinary symptoms prior to and 3 months after treatment were recorded and interpreted., Results: Most of our patients were menopausal (76.3%; mean age 55.7 years) and multiparous (mean parity 3.3) women. Urinary symptoms such as urinary frequency, urgency, urge incontinence, and nocturia were decreased significantly (p < 0.05). All urodynamic parameters did not change significantly except for the maximum cystometric capacity (p < 0.05), showing a significant increase after 3 months of medication., Conclusions: Tolterodine, at a recommended dose, improves the symptoms of OAB syndrome without causing urine retention, as proved by the changes of urodynamic parameters., (Copyright © 2013. Published by Elsevier B.V.)

Purpose: The objective of the study was to evaluate the synergistic transdermal permeation effect of chemical enhancers and iontophoresis technique on tolterodine tartrate (TT) transdermal gel and to evaluate its pharmacokinetic properties., Materials and Methods: Taguchi robust design was used for optimization of formulations. Skin permeation rates were evaluated using the Keshary-chein type diffusion cells in order to optimize the gel formulation. In-vivo studies of the optimized formulation were performed in a rabbit model and histopathology studies of optimized formulation were performed on rats., Results: Transdermal gels were formulated successfully using Taguchi robust design method. The type of penetration enhancer, concentration of penetration enhancer, current density and pulse on/off ratio were chosen as independent variables. Type of penetration enhancer was found to be the significant factor for all the responses. Permeation parameters were evaluated when maximum cumulative amount permeated in 24 hours (Q24) was 145.71 ± 2.00µg/cm² by CIT4 formulation over control (91.89 ± 2.30µg/cm²). Permeation was enhanced by 1.75 fold by CIT4 formulation. Formulation CIT4 containing nerolidol (5%) and iontophoretic variables applied (0.5mA/cm² and pulse on/off ratio 3:1) was optimized. In vivo studies with optimized formulation CIT4 showed increase in AUC and T1/2 when compared to oral suspension in rabbits. The histological studies showed changes in dermis indicating the effect of penetration enhancers and as iontophoresis was continued only for two cycles in periodic fashion so it did not cause any skin damage observed in the slides., Conclusion: Results indicated that iontophoresis in combination with chemical enhancers is an effective method for transdermal administration of TT in the treatment of overactive bladder.

Objective: To design and optimize a drug-in-adhesive (DIA) type transdermal patch for tolterodine (TOL) based on acrylic and silicone matrixes., Methods: Initial in vitro studies were conducted to optimize the formulations. Two types of adhesive matrixes, drug loading, and enhancers were evaluated on the TOL transport across rabbit skin. For in vivo studies, patches were administered to rabbit abdominal skin. Pharmacokinetic assessments were performed based on plasma level of TOL up to 28 h for acrylic patch and 52 h for silicone patch after topical application., Results: The final formulation of acrylic adhesive type patch consisted of 10% TOL (w/w) and 5.8 × 10(-4) mol isopropyl myristate (IPM) and 2.9 × 10(-4) mol Span 80 in per unit gram (mol/g) of adhesive, while 2.5% TOL (w/w) and 2.9 × 10(-4) mol/g IPM for silicone adhesive type patch. Comparison of the pharmacokinetic parameters between two types of patches showed that the steady-state concentration of silicone type patch was 2-fold higher than that of acrylic type patch being 0.97 mg/L versus 0.49 mg/L, and the absolute bioavailability was 27.5% for silicone type patch and 6.3% for acrylic type patch, respectively. In addition, the prediction of in vivo drug level from the in vitro permeation data of silicone adhesive formulation was in good agreement with actual observed concentration data in rabbits., Conclusion: These results indicate that the silicone type of TOL patch is an appropriate delivery system for the treatment of overactive bladder (OAB).

Background: Previous randomized studies have demonstrated that fesoterodine significantly improves the Overactive Bladder (OAB) symptoms and their assessment by patients compared with tolterodine extended-release (ER). This study aimed to assess the effect of aging and dose escalation on patient-reported treatment benefit, after changing their first Overactive Bladder (OAB) therapy with tolterodine-ER to fesoterodine in daily clinical practice., Methods: A post-hoc analysis of data from a retrospective, cross-sectional and observational study was performed in a cohort of 748 OAB adults patients (OAB-V8 score ≥8), who switched to fesoterodine from their first tolterodine-ER-based therapy within the 3-4 months before study visit. Effect of fesoterodine doses (4 mg vs. 8 mg) and patient age (<65 yr vs. ≥65 yr) were assessed. Patient reported treatment benefit [Treatment Benefit Scale (TBS)] and physician assessment of improvement with change [Clinical Global Impression of Improvement subscale (CGI-I)] were recorded. Treatment satisfaction, degree of worry, bother and interference with daily living activities due to urinary symptoms were also assessed., Results: Improvements were not affected by age. Fesoterodine 8 mg vs. 4 mg provides significant improvements in terms of treatment benefit [TBS 97.1% vs. 88.4%, p < 0.001; CGI-I 95.8% vs. 90.8% p < 0.05)], degree of worry, bother and interference with daily-living activities related to OAB symptoms (p <0.05)., Conclusions: A change from tolterodine ER therapy to fesoterodine with dose escalation to 8 mg in symptomatic OAB patients, seems to be associated with greater improvement in terms of both patient-reported-treatment benefit and clinical global impression of change. Improvement was not affected by age.

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.)

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.

In this study, poly(d,l-lactide-co-glycolide) (PLGA) microspheres of tolterodine depot formulation were prepared using oil in water (o/w) method to investigate their potential pharmacokinetic and pharmacodynamic advantages over tolterodine l-tartrate tablets. Morphological studies of the microspheres showed a spherical shape and smooth surface with mean size of 50.69-83.01 microm, and the encapsulation efficiency was improved from 62.55 to 79.10% when the polymer concentration increased from 180 to 230 mg/ml. The addition of stearic or palmitic acids could significantly raise the drug entrapment efficiency but only slightly affected the in vitro release. A low initial burst followed by a proximately constant release of tolterodine was noticed in the in vitro release profiles. The in vivo study was carried out by intramuscular (i.m.) administration of tolterodine-loaded microspheres on beagle dogs, and a sustained release of drug from the PLGA microspheres was achieved until the 18th day with a low initial burst. Since the absence of hepatic first pass metabolism, only a single active compound-tolterodine was detected in the plasma. This avoided the coexistence of two active compounds in plasma in the case of oral administration of tolterodine, which may lead to a difficulty in dose control due to the different metabolic capacity of patients. In the pharmacodynamic study, the influence of tolterodine PLGA microspheres on the inhibition of carbachol-induced rat urinary bladder contraction was more significant than that of tolterodine l-tartrate tablets. There were invisible changes in rat bladder slices between tolterodine-loaded PLGA microspheres group and tolterodine l-tartrate tablets group. These results indicate that the continuous inhibition of muscarinic receptor may offer an alternative therapy of urge incontinence., (Crown Copyright 2010. Published by Elsevier B.V. All rights reserved.)

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.)

Objective: To assess if oxybutynin and tolterodine have an effect on simple reaction time in healthy volunteers., Methods: Simple reaction time was evaluated before and 90 minutes after the oral administration of oxybutynin and tolterodine in a cross-over design. Twenty seven healthy volunteers, aged 26 to 48 years, were included in the study. The electromyographic activity of the flexor digitorum superficialis muscle that was used for the response was recorded, and premotor time was measured., Results: The mean age of the study group was 33.1 ± 7.4 years. Mean premotor times before oxybutynin and before tolterodine administration were statistically non-significant. Mean premotor times after the administration of oxybutynin and tolterodine were significantly longer than the initial premotor times (p = 0.003)., Conclusions: The results of the study showed that oxybutynin and tolterodine prolonged the simple reaction time. The prolonged simple reaction time may suggest a perceptive impairment. The potential for perceptive impairment as a side effect of oxybutynin and tolterodine might suggest a negative impact on the rehabilitation interventions and the activities of daily living because of central nervous system effects.

Aim: To evaluate the effects of tolterodine extended release (ER) and alfuzosin for the treatment of Double-J stent-related lower urinary tract symptoms., Materials and Methods: Fifty-two patients (33 men and 19 women; mean age 52.0 years) who underwent insertion of a Double-J stent after urological surgery were prospectively randomized into three groups. Group 1 included 20 patients who received 10 mg of alfuzosin, once daily for 6 weeks; group 2 included 20 patients who received 4 mg of tolterodine ER, once daily for 6 weeks; group 3 included 12 patients who received a placebo for the same protocol. All patients completed a validated Ureteral Stent Symptom Questionnaire at 6 weeks after the stent placement., Results: The mean urinary symptom index was 22.1 in group 1, 22.1 in group 2, and 28.1 in the placebo group (p = 0.032). The mean pain scores were 8.2, 11.7, and 16.2, respectively (p = 0.020). There were no significant differences in urinary symptoms and pain between the alfuzosin and tolterodine ER groups. In addition, there was no significant difference in the general health, work performance, and sexual performance scores among the groups., Conclusions: Tolterodine ER and alfuzosin improve stent-related urinary symptoms and body pain.

Purpose: The aim of this work was to investigate the feasibility of using nanosized microemulsion for transdermal delivery of tolterodine tartrate., Methods: The effect of three microemulsions formed by Labrasol: Plurol (3:1), isopropyl myristate and water on the permeation of tolterodine through miniature pig skin was studied in vitro using Franz diffusion cell. For comparison purpose, the effect of different vehicles on the permeation was also studied. Drug pharmacokinetics was studied after transdermal application to human volunteers compared to the commercial oral dosage form using a newly developed LC-MS/MS assay., Results: The vehicle PEG 400:Phosphate buffer pH 7.4 in the ratio of 1:1 significantly enhanced tolterodine permeation across pig skin. The microemulsion system (ME3) containing the highest amount of water (50%) significantly enhanced permeation with Q(24) of 0.746 mg.cm(-2). In contrast to oral delivery, a sustained activity was observed over a period of 72 h after transdermal application of this microemulsion to human volunteers with significant lower C(max) (1.06 ng/ml), delayed T(max) (3.17 h) and higher MRT value (147.82 h) (p < 0.05)., Conclusion: This sustained activity was due to the controlled release of drug into the systemic circulation with expected increase in the patient compliance and prevention of nocturnal enuresis.

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.

Objective: To assess the effects of tolterodine extended release (ER) on patient-reported outcomes (PROs) in sexually active women with overactive bladder (OAB) and urgency urinary incontinence (UUI)., Research Design and Methods: This multicenter, double-blind, placebo controlled trial included 411 women aged > or =18 years reporting OAB symptoms for > or =3 months; > or =8 micturitions per 24 hours (including > or =0.6 UUI episodes and > or =3 OAB micturitions) in 5-day bladder diaries at baseline, and being in a sexually active relationship for > or =6 months. Subjects randomized to placebo or tolterodine ER completed validated OAB- or incontinence-specific questionnaires, including the Patient Perception of Bladder Condition (PPBC), Overactive Bladder Questionnaire (OAB-q), Urgency Perception Scale (UPS), and the Incontinence Impact Questionnaire (IIQ) at baseline and week 12, as well as the Perception of Treatment Benefit and Treatment Satisfaction questions at week 12. This study is registered with ClinicalTrials.Gov (identifier: NCT00143481)., Results: The mean age of enrolled women was approximately 48 years. Compared with placebo, the tolterodine ER group reported significant baseline to week 12 improvements in PPBC responses (p = 0.0048); OAB-q Symptom Bother, total Health-Related Quality of Life (HRQL), and HRQL domain scores (all p < 0.05); IIQ Emotional Health domain scores (p < 0.05); proportions of subjects reporting treatment benefit (79 vs. 54%; p < 0.0001) and satisfaction (78 vs. 59%; p < 0.0001). Improvements on the UPS were not significantly different., Conclusions: Tolterodine ER treatment was associated with improvements in multiple OAB- and incontinence-specific PROs in a sexually active, relatively young, and racially diverse population of women. The findings provide clinicians with new insights into the impact of OAB and its treatment on HRQL in this population, which has been underrepresented in previous OAB studies. Study limitations include a potential underestimation of the impact of OAB symptoms resulting from the exclusion of women who may not be sexually active because of their urinary symptoms.

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.

Background: Some men with lower urinary tract symptoms (LUTS) including overactive bladder (OAB) symptoms may benefit from antimuscarinic therapy, with or without an alpha-adrenergic antagonist., Objectives: To evaluate the safety and efficacy of tolterodine extended release (ER), tamsulosin, or tolterodine ER+tamsulosin in men meeting symptom entry criteria for OAB and prostatic enlargement trials, stratified by prostate size., Design, Setting, and Participants: Subjects with an International Prostate Symptom Score (IPSS) >or=12; frequency and urgency, with or without urgency urinary incontinence; postvoid residual volume (PVR) <200 mL; and maximum urinary flow rate (Q(max)) >5 mL/s were randomized to receive placebo, tolterodine ER (4 mg), tamsulosin (0.4 mg), or tolterodine ER+tamsulosin for 12 wk. Data were stratified by median baseline prostate volume (<29 mL vs >or=29 mL)., Measurements: Endpoints included week 12 changes in bladder diary variables, IPSS scores, and safety variables., Results and Limitations: Among men with larger prostates, tolterodine ER+tamsulosin significantly improved frequency (p=0.001); urgency (p=0.006); and IPSS total (p=0.001), storage (p<0.001), and voiding scores (p<0.013). Tamsulosin significantly improved IPSS voiding scores (p=0.030). Among men with smaller prostates, tolterodine ER significantly improved frequency (p=0.016), UUI episodes (p=0.036), and IPSS storage scores (p=0.005). Tolterodine ER+tamsulosin significantly improved frequency (p=0.001) and IPSS storage scores (p=0.018). Tamsulosin significantly improved nocturnal frequency (p=0.038) and IPSS voiding (p=0.036) and total scores (p=0.044). There were no clinically or statistically significant changes in Q(max) or PVR; incidence of acute urinary retention (AUR) was low in all groups (

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.