Tolterodine Tartrate Loaded Cationic Elastic Liposomes for Transdermal Delivery: In Vitro, Ex Vivo, and In Vivo Evaluations.

OBJECTIVE: Tolterodine tartrate (TOTA) is a first-line therapy to treat overactive urinary bladder (OAB). Oral delivery causes high hepatic clearance, xerostomia, headache, constipation, and blurred vision. We addressed Hansen solubility parameter (HSP) and Design Expert oriented optimized cationic elastic liposomes for transdermal application. METHODS: The experimental solubility was conducted in HSPiP predicted excipients to tailor formulations using surfactants, stearylamine, ethanol, and phosphatidylcholine (PC). These were evaluated for formulation characteristics. The optimized OTEL1 and OTEL1-G (gel) were compared against the drug solution (DS) and liposomes. In vitro and ex vivo studies were accomplished to investigate the insights into the mechanistic understanding of TOTA release and permeation ability. Finally, confocal laser scanning microscopy (CLSM) supported ex vivo results. RESULTS: HSP values of TOTA were closely related to tween-80, stearylamine, and human's skin. The size (153 nm), %EE (87.6%), and PDI (0.25) values of OTEL1 were in good agreement to the predicted values (161 nm, 80.4%, and 0.31) with high desirability (0.963). Spherical and smooth OTEL1 (including OTEL1-G and liposomes) vesicles followed non-Fickian drug release as compared to DS (Fickian) as evidence with n > 0.5 (Korsmeyer and Peppas coefficient). OTEL1 (containing lipid and surfactant as 90 mg and 13.8 mg, respectively) exhibited 2.6 and 1.8-folds higher permeation flux than DS and liposomes, respectively. Biocompatible cationic OTEL1 was safe and non-hemolytic. CONCLUSIONS: OTEL1 was promised as a lead vesicular approach and an alternative to conventional oral therapy to treat OAB in children and advanced age patients.

HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus-Based In Vivo Prediction in Humans: Part I.

Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral delivery. Hansen solubility parameters (HSP, HSPiP program), experimental solubility (T = 298.2 to 318.2 K and p = 0.1 MPa), computational (van't Hoff and Apelblat models), and thermodynamic models were used to the select solvent(s). HSPiP predicted PEG400 as the most suitable co-solvent based on HSP values (δd = 17.88, δp = 4.0, and δh = 8.8 of PEG400) and comparable to the drug (δd = 17.6, δp = 2.4, and δh = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (xe = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δp and δh interacting forces. The activity coefficient (ϒi) was found to be increased with temperature. The higher values of r2 (linear regression coefficient) and low RMSD (root mean square deviation) indicated a good correlation between the generated "xe" data for crystalline TOTA and the explored models (modified Apelblat and van't Hoff models). TOTA solubility in "PEG400 + water mixture" was endothermic and entropy-driven. IR (immediate release product) formulation can be tailored using 60% PEG400 in buffer solution for 2 mg of TOTA in 0.25 mL (dosing volume). The isotonic binary solution was associated with a pH of 7.2 suitable for sub-Q delivery. The approach would be a promising alternative with ease of delivery to children and aged patients.

HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus­Based In Vivo Prediction in Humans: Part II.

In part I, we reported Hansen solubility parameters (HSP, HSPiP program), experimental solubility at varied temperatures for TOTA delivery. Here, we studied dose volume selection, stability, pH, osmolality, dispersion, clarity, and viscosity of the explored combinations (I-VI). Ex vivo permeation and deposition studies were performed to observe relative diffusion rate from the injected site in rat skin. Confocal laser scanning microscopy (CLSM) study was conducted to support ex vivo findings. Moreover, GastroPlus predicted in vivo parameters in humans and the impact of various critical factors on pharmacokinetic parameters (PK). Immediate release product (IR) contained 60% of PEG400 whereas controlled release formulation (CR) contained PEG400 (60%), water (10%) and d-limonene (30%) to deliver 2 mg of TOTA. GastroPlus predicted the plasma drug concentration of weakly basic TOTA as function of pH (from pH 2.0 to 9). The cumulative drug permeation and drug deposition were found to be in the order as B-VI˃ C-VI˃A-VI across rat skin. This finding was further supported with CLSM. Moreover, IR and CR were predicted to achieve Cmax of 0.0038 µg/ mL and 0.00023 µg/mL, respectively, after sub-Q delivery. Added limonene in CR extended the plasma drug concentration over period of 12 h as predicted in GastroPlus. Parameters sensitivity analysis (PSA) assessment predicted that sub-Q blood flow rate is the only factor affecting PK parameters in IR formulation whereas this was insignificant for CR. Thus, sub-Q delivery CR would be promising alternative with ease of delivery to children and aged patient.

Efficacy and Safety of Tolterodine and Pilocarpine in Patients with Overactive Bladder.

PURPOSE: We evaluated the efficacy and safety of a combination of 2 mg tolterodine and 9 mg pilocarpine, vs tolterodine monotherapy in patients with overactive bladder. MATERIALS AND METHODS: We enrolled patients with overactive bladder symptoms in a multicenter, randomized, double-blind, parallel, active control study. Patients were randomized to the combination or 2 mg tolterodine twice daily for 12 weeks. After the double-blind period finished all patients were started on the combination for 12 weeks. Study co-primary end points were the change from baseline in the mean number of daily micturitions and cumulative incidence of dry mouth at the end of 12 weeks. Secondary end points were other overactive bladder symptoms, the total xerostomia inventory score and results of a visual analogue scale for dry mouth at the end of 12 and 24 weeks. RESULTS: The mean change in the number of daily micturitions from baseline to 12 weeks was -1.49 and -1.74 in the combination and tolterodine monotherapy groups, respectively. The mean difference was -0.26 (95% CI -0.79-0.27), confirming noninferiority. At 12 weeks the incidence of dry mouth was lower in the combination group than in the tolterodine monotherapy group (30.0% vs 42.9%, p = 0.009). All secondary and other efficacy outcomes related to overactive bladder symptoms improved in each group with no significant differences between the groups at 12 weeks. Changes from baseline in the total xerostomia inventory score and the visual analogue scale for dry mouth were significantly lower in the combination group than in the tolterodine monotherapy group. CONCLUSIONS: Tolterodine and pilocarpine alleviated dry mouth in patients with overactive bladder while maintaining anticholinergic efficacy similar to that of tolterodine.

Muscarinic receptor binding of fesoterodine, 5-hydroxymethyl tolterodine, and tolterodine in rat tissues after the oral, intravenous, or intravesical administration.

The present study aimed to characterize muscarinic receptor binding of fesoterodine, 5-hydroxymethyl tolterodine (5-HMT), and tolterodine in bladder and other tissues of rats after their oral, intravenous, or intravesical administration. Muscarinic receptors in tissues were measured by using [N-methyl-3H]scopolamine methyl chloride ([3H]NMS). The in vitro binding affinity for muscarinic receptors was the highest by 5-HMT, followed by tolterodine and fesoterodine. Fesoterodine exhibited lower affinity in rat submaxillary gland than in detrusor muscle and urothelium. Muscarinic binding affinities of 5-HMT and tolterodine were similar among tissues. The duration of binding of oral fesoterodine to muscarinic receptors was longer in bladder than in submaxillary gland, heart, and lung, and its binding was little observed in colon and cerebral cortex. Binding activity of intravenous 5-HMT to muscarinic receptors was significantly observed in all tissues, except cerebral cortex, with a longer duration in bladder. Significant binding of bladder detrusor and urothelial muscarinic receptors was observed following intravesical instillation of 5-HMT. This selectivity may be attributed to the direct blockade of bladder receptors by excreted urinary 5-HMT. Thus, fesoterodine may be efficacious as a treatment for patients with overactive bladder.

Long-term safety and efficacy of antimuscarinic add-on therapy in patients with overactive bladder who had a suboptimal response to mirabegron monotherapy: A multicenter, randomized study in Japan (MILAI II study).

OBJECTIVES: To evaluate the long-term safety (primary objective) and efficacy (secondary objective) of antimuscarinic add-on therapy in patients receiving mirabegron. METHODS: During a 2-week screening period, patients (aged ≥20 years, mirabegron treatment for ≥6 weeks, residual overactive bladder symptoms) received mirabegron 50 mg once daily. These patients were subsequently randomized to 52 weeks' treatment with mirabegron 50 mg/day plus an antimuscarinic (solifenacin 5 mg, propiverine 20 mg, imidafenacin 0.2 mg, or tolterodine 4 mg) with the potential to double the antimuscarinic dose (except for tolterodine) at week 8. Safety assessments included treatment-emergent adverse events, vital signs, 12-lead electrocardiograms, post-void residual volume, and laboratory evaluations. Efficacy was assessed using changes from baseline in overactive bladder symptom score total score; overactive bladder questionnaire short form score; micturitions, urgency episodes, urinary incontinence episodes, and urgency urinary incontinence episodes/24 h; mean volume voided per micturition; and number of night-time micturitions. RESULTS: Overall, 80.2% of patients (88.1% women, mean age 65 years) experienced at least one treatment-emergent adverse event, with similar rates for all treatments. The adverse events most commonly reported were dry mouth, nasopharyngitis, and constipation. No marked change was observed in systolic or diastolic blood pressure for any treatment, although pulse rate increased slightly in the mirabegron and propiverine, and mirabegron and tolterodine groups. For all treatments, significant improvements were observed in all efficacy parameters, including overactive bladder symptom score total and questionnaire short form scores. CONCLUSIONS: Antimuscarinic add-on therapy is well tolerated and effective after initial treatment with mirabegron in patients with overactive bladder symptoms.

Tolterodine ER reduced increased bladder wall thickness in women with overactive bladder. A randomized, placebo-controlled, double-blind, parallel group study.

AIMS: We evaluated the effect of Tolterodine extended release (TER) versus placebo on bladder wall thickness (BWT) using transvaginal ultrasound in women with overactive bladder (OAB). MATERIALS AND METHODS: We recruited 79 women with symptoms of OAB with a mean age of 47 years who had a BWT of at least 5 mm and a post-micturition volume of less than 50 mL at screening. Subjects received TER 4 mg or placebo once daily for the first 12 weeks of the study. For the subsequent 12 weeks, all subjects received TER 4 mg once daily. BWT was measured at screening, weeks 12 and 24. Subjects recorded number of micturitions, incontinence episodes and urgency episodes, and volume voided per micturition at regular intervals during the study. RESULTS: Treatment with TER for 12 weeks produced a statistically significant decrease from baseline in BWT (mean [SD] = 0.9 [1.4] mm; P < 0.05) that was not evident following treatment with placebo (0.2 [1.6] mm; P = 0.54). However, the treatment difference did not reach statistical significance (LS Mean = -0.4; 95%CI: -1.2, 0.3; P = 0.25). After 12 weeks of treatment, subjects who had taken TER showed an improvement in each bladder diary variable compared to placebo-treated subjects. CONCLUSIONS: TER may have a direct effect on BWT in women with OAB. Larger studies are warranted to further investigate the effect of behavioral interventions and antimuscarinics, such as TER, on BWT in women with OAB and increased BWT.

Patient-reported outcomes in patients with overactive bladder treated with mirabegron and tolterodine in a prospective, double-blind, randomized, two-period crossover, multicenter study (PREFER).

BACKGROUND: The PREFER study was an assessment of medication tolerability, treatment preference and symptom improvement during treatment with mirabegron (M) and tolterodine (T) extended release (ER) in patients with overactive bladder (OAB). In this analysis of PREFER, patient-reported outcomes (PROs) were assessed during treatment. METHODS: PREFER was a two-period, 8-week crossover, double-blind, phase IV study (NCT02138747) of treatment-naïve adults with OAB ≥3 months randomized to 1 of 4 treatment sequences (M/T; T/M; M/M; T/T), separated by a 2-week washout. Tolterodine ER was dosed at 4 mg for 8 weeks and mirabegron was dosed at 25 mg for 4 weeks then increased to 50 mg for the next 4 weeks. At each visit, PROs related to treatment satisfaction, quality of life and symptom bother were assessed using the OAB Satisfaction (OAB-S; 3 independent scales/5 single-item overall assessments), OAB-q (total health-related QoL [HRQoL] and subscales [Sleep, Social, Coping, Concern] and Symptom Bother scale) and Patient Perception of Bladder Condition (PPBC) questionnaires. Responder rates were reported for OAB-q subscales based on a minimal important difference (MID; ≥ 10-point improvement) and OAB-S Medication Tolerability score ≥ 90. RESULTS: In total, 358 randomized patients received ≥1 dose of double-blind study medication and completed ≥1 post-baseline value (OAB-S scale, OAB-q, PPBC): M/T (n = 154), T/M (n = 144), M/M (n = 30) or T/T (n = 30). At end of treatment (EoT), mirabegron and tolterodine ER were associated with similar mean improvements in 7 of the 8 OAB-S scores investigated, OAB-q scales and PPBC. A higher percentage of patients achieved clinically relevant improvements (MID) in OAB-q scales and OAB-S Medication Tolerability score during treatment with mirabegron than tolterodine ER. CONCLUSIONS: On average, patients with OAB experienced improvements in treatment satisfaction, HRQoL and symptom bother that were of a similar magnitude during treatment with mirabegron or tolterodine ER. However, during mirabegron treatment, patients were more likely to achieve clinically relevant improvements in tolerability and HRQoL (as measured by the MID for the OAB-q or an OAB-S Medication Tolerability score ≥ 90) than during tolterodine ER treatment. TRIAL REGISTRATION: NCT02138747 ; registered May 13, 2014.

Plasma concentration profile of tolterodine and 5-hydroxymethyl tolterodine following transdermal administration of tolterodine in rats.

In this study, the plasma concentration profiles of tolterodine and its active metabolite, 5-hydroxymethyl tolterodine (5-HM tolterodine) were investigated in rats with tolterodine transdermal patches using liquid chromatography-tandem mass spectrometry. The plasma samples were extracted by a liquid-liquid extraction method, with an n-hexane/isopropyl alcohol mixture (9:1, v/v). Tiropramide was used as an internal standard (IS). Chromatographic separation was achieved using a C18 column (2.0 mm × 150 mm, 5 µm), with a mobile phase consisting of 5 mM ammonium acetate in distilled water/acetonitrile (50:50, v/v). The precursor-product ion pairs used for multiple reaction monitoring were m/z 326 → 284 (tolterodine), m/z 342 → 223 (5-HM tolterodine), and m/z 468 → 367 (IS). Subsequently, the plasma concentration levels of tolterodine and 5-HM tolterodine were measured in rat plasma after oral or transdermal administration of tolterodine and the pharmacokinetic parameters were calculated. The Cmax of the patch was less than that of the oral administration but their AUC values were comparable. The resulting data suggested that a transdermal dose of tolterodine 3 times higher (9 mg/12 cm2) could yield comparable efficacy to a 10 mg/kg oral dose in rats. These results would provide useful information on dose optimization of tolterodine transdermal patch for further clinical studies.

Results of a randomized, double-blind, active-controlled clinical trial with propiverine extended release 30 mg in patients with overactive bladder.

OBJECTIVE: To compare the efficacy and safety of the 30 mg extended release (ER) formulation of propiverine hydrochloride with the 4 mg ER formulation of tolterodine tartrate in patients with overactive bladder (OAB) in a non-inferiority trial. PATIENTS AND METHODS: Eligible patients, aged 18-75 years and with symptoms of OAB, were enrolled in this multicentre, randomized, double-blind, parallel-group, active-controlled study. After a 2-week screening period, patients were randomized at a 1:1 ratio to receive either propiverine ER 30 mg or tolterodine ER 4 mg daily during the 8-week treatment period. Efficacy was assessed using a 3-day voiding diary and patient's self-reported assessment of treatment effect. Safety assessment included recording of adverse events, laboratory test results, measurement of post-void residual urine and electrocardiograms. RESULTS: A total of 324 patients (244 female and 80 male) were included in the study. Both active treatments improved the variables included in the voiding diary and in the patient's self-reported assessment. The change from baseline in the number of voidings per 24 h was significantly greater in the propiverine ER 30 mg group compared with the tolterodine ER 4 mg group after 8 weeks of treatment (full analysis set [FAS] -4.6 ± 4.1 vs -3.8 ± 5.1; P = 0.005). Significant improvements were also observed for the change of urgency incontinence episodes after 2 weeks (P = 0.026) and 8 weeks (P = 0.028) of treatment when comparing propiverine ER 30 mg with tolterodine ER 4 mg. Both treatments were well tolerated, with a similar frequency of adverse drug reactions in both the propiverine ER 30 mg and tolterodine ER 4 mg groups (FAS 40.7 vs 39.5%; P = 0.8). More patients treated with tolterodine ER 4 mg discontinued the treatment because of adverse drug reactions compared with propiverine ER 30 mg (7.4 vs 3.1%). CONCLUSIONS: Propiverine ER 30 mg was confirmed to be an effective and well-tolerated treatment option for patients with OAB symptoms. This first head-to-head study showed non-inferiority of propiverine ER 30 mg compared with tolterodine ER 4 mg.

A retrospective study of treatment persistence and adherence to α-blocker plus antimuscarinic combination therapies, in men with LUTS/BPH in the Netherlands.

BACKGROUND: To assess treatment persistence and adherence in men ≥45 years of age with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), using prescription records from the Netherlands IMS Lifelink™ LRx database. METHODS: In this retrospective, observational cohort study, we identified men who received combination therapy with an α-blocker plus an antimuscarinic (e.g. solifenacin or tolterodine) between 1 November 2013 and 31 October 2014. Treatment could be received as a fixed-dose combination (FDC) tablet or as two drugs administered together (concomitant therapy), if both combination drugs were prescribed within 30 days. The primary objective was to assess treatment persistence, defined as the time from initiation of combination therapy until first discontinuation of the FDC or at least one of the drugs given concomitantly (i.e. ≥30 days without prescription renewal). Subgroup and sensitivity analyses were conducted to assess persistence by antimuscarinic agent, and with different gap lengths used to define discontinuation (45, 60 and 90 days), respectively. RESULTS: A total of 1891 men received an α-blocker plus an antimuscarinic (FDC, N = 665; concomitant therapy, N = 1226). Median time to discontinuation was significantly longer with FDC versus concomitant therapy (414 vs. 112 days; adjusted hazard ratio [HR] 2.04, 95% confidence interval 1.77, 2.35; p < 0.0001). Persistence at 12 months (51.3% vs. 29.9%) was also significantly greater with FDC compared with concomitant therapy. Assessment of antimuscarinic subgroups showed that median time to discontinuation was longest with solifenacin combinations (214 days) compared with other antimuscarinic combinations (range, 47-164 days; adjusted HR range, 1.27-1.77, p = 0.037). No observable impact on treatment persistence was found by adjusting the gaps used to define discontinuation. DISCUSSION: This study of real-world evidence of men with LUTS/BPH treated with α-blocker plus antimuscarinic combination therapy in the Netherlands showed that treatment persistence was significantly greater in those who received a FDC tablet compared with combination therapy given concomitantly. The study also shows that treatment persistence was extended in men who received combination therapy containing solifenacin compared with other antimuscarinics. CONCLUSIONS: Overall, these findings may be useful for prescribers, as improved persistence on-treatment may translate into improved outcomes for men with LUTS/BPH. Further study is warranted to establish the key drivers of persistence in men receiving combination therapy for LUTS/BPH.

Tolterodine treatment of women with overactive bladder syndrome: Comparison of night-time and daytime dosing for nocturia.

AIM: We aimed to clarify the impact of night-time dosing with tolterodine extended release (ER) on nocturia. METHODS: The bladder diaries, urodynamic studies, and medical records of female patients with overactive bladder syndrome who were diagnosed between January 2005 and December 2015, and treated with tolterodine ER 4 mg once per day (night-time or daytime dosing) for 12 weeks in the urogynecology outpatient clinics of two tertiary referral centers were reviewed retrospectively. RESULTS: A total of 72 female patients were reviewed. Thirty-six patients were in the daytime dosing group, and the other 36 patients were in the night-time dosing group. In the daytime dosing group, a decrease in the volume of fluid intake was found at 06.00-12.00, 12.00-18.00, and 18.00-24.00 hours, and a decrease in total voided volume was found at 12.00-18.00, 18.00-24.00, and 24.00-06.00 hours with a between-group difference at 18.00-24.00 hours (coefficient = 542 mL, P = 0.01). In the night-time dosing group, an increase in voided volume per micturition was found at 06.00-12.00 and 24.00-06.00 hours with a between-group difference at 24.00-6.00 hours (coefficient = 92 mL, P = 0.003) compared with the daytime dosing group. Nonetheless, pre-treatment proportions of nocturnal polyuria did not differ from post-treatment proportions (night-time: 20% vs 20%, P = 1.00; daytime: 48% vs 42%, P = 0.48). Decreases in the number of voiding and urgency episodes at nearly all time periods and increases in the volumes at strong desire to void were also found in both groups. CONCLUSION: Night-time dosing of tolterodine ER may benefit female patients suffering from nocturia due to a greater voided volume per micturition at midnight.

[A dosage regimen of M-receptor blocker after TURP for severe BPH with predominant urine storage symptoms].

OBJECTIVE: To study the dosage regimen of oral M-receptor blocker following transurethral resection of the prostate (TURP) for severe benign prostate hyperplasia (BPH) with predominant urine storage period symptoms (USPSs) and its clinical effect. METHODS: Severe BPH patients with predominant USPSs received oral tolterodine (2 mg q12d or 4 mg qd) 6 hours after TURP for 4 weeks. The medication continued for another 2 weeks in case of recurrence of USPSs or until the 12th week in case of repeated recurrence. Before and at 1, 4, 8 and 12 weeks after TURP, we analyzed the International Prostate Symptoms Score (IPSS), quality of life (QoL) score, maximum urinary flow rate (Qmax), and postvoid residual volume (PVR) of the patients. RESULTS: Complete clinical data were collected from 106 cases, of which 33 achieved successful drug withdrawal with no aggravation of USPSs at 4 weeks after TURP, 51 at 6－8 weeks, 13 at 10－12 weeks, and 9 needed medication after 12 weeks. Before and at 1, 4, 8 and 12 weeks after TURP, the total IPSSs were 25.33 ± 3.45, 19.33 ± 3.62, 11.56 ± 2.45, 8.38 ± 2.0 and 7.74 ± 1.87, those in the urine storage period were 11.97 ± 1.53, 10.76 ± 1.82, 6.16 ± 1.22, 4.08 ± 1.19 and 3.91 ± 1.15, those at urine voiding were 9.80 ± 1.60, 5.59 ± 1.45, 3.40 ± 0.92, 2.85 ± 0.71, and 2.61 ± 0.67, and the QoL scores were 4.70 ± 0.78, 3.92 ± 0.75, 2.55 ± 0.74, 1.83 ± 0.72 and 1.66 ± 0.75, respectively, with statistically significant differences between the baseline and the scores at 1 and 4 weeks (P <0.01) but not at 8 or 12 weeks (P >0.05). Qmax and PVR were improved progressively and significantly at 1 and 4 weeks (P <0.01) but not at 8 or 12 weeks (P >0.05). CONCLUSIONS: Four to eight weeks of oral administration of M-receptor blocker may be an effective dosage regimen for severe BPH with predominant USPSs after TURP.

Role of tolterodine in the management of postoperative catheter-related bladder discomfort: Findings in a Nigerian teaching hospital.

BACKGROUND: Patient discomfort secondary to an indwelling urethral catheter in the post operative period can be very distressing. These symptoms resemble the overactive bladder (OAB) syndrome. Muscarinic receptor blockers have been successful in the management of OAB. However, information on the use of these drugs in the management of the postoperative catheter-related bladder discomfort (CRBD) in sub-Saharan Africa is still relatively sparse. OBJECTIVE: To assess the efficacy of preoperative oral tolterodine in the management of CRBD in surgical patients in the immediate postoperative period. METHODS: This was a double-blind placebo-controlled study consisting of 56 patients in each arm who underwent general anesthesia. Each patient was given oral tolterodine or placebo 1 hour before the induction of anesthesia. The patient was later assessed at the recovery room at intervals after recovery from anesthesia. The presence of CRBD was noted and graded. RESULTS: The overall incidence of CRBD in both the tolterodine group and the control were 85.7% and 91.1%, respectively. Overall, tolterodine prophylaxis (TP) was associated with an absolute risk reduction (ARR) of 5.4%, relative risk reduction (RRR) of 5.8%, and a number needed to treat (NNT) of 19. The incidence of moderate-to-severe CRBD in the tolterodine and control groups were 10.7% and 78%, respectively, with an ARR of 74.5% with TP. CONCLUSION: TP does not significantly reduce the incidence of CRBD in the immediate postoperative period but appears to be efficient in the reduction of the severity of postoperative CRBD.

Acupuncture for overactive bladder in female adult: a randomized controlled trial.

PURPOSE: To assess the effectiveness of acupuncture in treating female adult with overactive bladder. MATERIALS AND METHODS: After we excluded other causes for storage symptoms, a total of 240 consecutive female patients with overactive bladder were enrolled and completed all aspects of this prospective randomized controlled trial, of which 118 cases were randomly assigned to receive a weekly acupuncture treatment (intervention group), while the other 122 cases were given a pharmacological treatment of oral tolterodine tartrate 2 mg twice daily (control group) for 4 weeks. Data on urgency, incontinence, micturition frequency, nocturia episodes and voided volume were collected and statistically analyzed before and after 4 weekly acupuncture treatments or 4 weeks' pharmacological treatment using a 3-day micturition diary. RESULTS: The two groups of female patients with overactive bladder were given treatment with weekly acupuncture (n = 118), oral tolterodine tartrate (n = 122) for 4 weeks respectively. At weeks 4, subjects in both intervention and control groups had significant decreases in number of urinary urgency episodes, incontinence episodes, daytime frequency, nocturia episodes and increase in volume voided per micturition without a significant difference in the changes of overactive bladder symptoms between the groups. There were no serious adverse events during the study. CONCLUSIONS: This randomized controlled trial demonstrates that acupuncture is safe with significant improvements in patient assessment of overactive bladder symptoms and may be considered a clinically alternative treatment for overactive bladder in female adult.

Tolterodine in the Treatment of Male LUTS.

Storage lower urinary tract symptoms (LUTS) in men are usually chronic, with a high prevalence and a substantial impact on quality of life; therefore, adequate therapies are desirable and crucial for these men. First line treatment for all patients with storage LUTS should always be behavioral. The gold standard for pharmacological treatment of overactive bladder/storage symptoms is a muscarinic receptor antagonist such as tolterodine. First-marketed antimuscarinics were limited by several adverse events such as dry mouth, constipation, tachycardia, accommodation disorder, and cognitive dysfunction, resulting in poor compliance and early treatment discontinuation in a large number of patients. In order to improve compliance with oral drug treatment, tolterodine was developed, providing a better efficacy/adverse event profile. Tolterodine is available in the following two formulations: the intermediate release (IR) and extended release form (ER). Tolterodine ER 4 mg administered once daily is pharmacokinetically equivalent to tolterodine IR 2 mg twice daily but has a lower incidence of adverse events and increased efficacy. Combination therapy of tolterodine and an alpha-blocker is significantly more efficacious than either monotherapy. Even when compared and added to tamsulosin, tolterodine shows a good safety profile. The incidence of acute urinary retention requiring catheterization and treatment withdrawals due to adverse events are low in all the studies included in the present review.

Cost-effectiveness of a fixed-dose combination of solifenacin and oral controlled adsorption system formulation of tamsulosin in men with lower urinary tract symptoms associated with benign prostatic hyperplasia.

BACKGROUND: Storage symptoms, associated with benign prostatic hyperplasia (BPH), often co-exist with voiding symptoms in men with lower urinary tract symptoms (LUTS). Storage symptoms are likely to be most bothersome, and may not be adequately resolved by treatment with α-blocker or antimuscarinic monotherapy. A recent randomised controlled phase 3 trial (NEPTUNE) demonstrated that a fixed-dose combination (FDC) of solifenacin 6 mg plus an oral controlled absorption system (OCAS™) formulation of tamsulosin (TOCAS, 0.4 mg) improved storage symptoms, as well as quality of life, compared with TOCAS alone in men with moderate-to-severe storage symptoms and voiding symptoms. This analysis aimed to assess the cost-effectiveness of a FDC tablet of solifenacin 6 mg plus TOCAS relative to tolterodine plus tamsulosin given concomitantly, from the perspective of the UK National Health Service (NHS). METHODS: A Markov model was developed for men aged ≥45 years with LUTS/BPH who have moderate-to-severe storage symptoms and voiding symptoms. The model calculated cost-effectiveness over an analytical time horizon of 1 year and estimated total treatment costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratio. RESULTS: The FDC tablet of solifenacin 6 mg plus TOCAS was associated with lower total annual costs (£860 versus £959) and increased QALYs (0.839 versus 0.836), and was therefore dominant compared with tolterodine plus tamsulosin. Time horizon, discontinuation or withdrawal rates, drug cost and utility values were the main drivers of cost-effectiveness. The probability that the FDC tablet of solifenacin 6 mg plus TOCAS is cost-effective was 100% versus tolterodine plus tamsulosin, at a willingness-to-pay threshold of £20,000/QALY gained. CONCLUSIONS: The FDC tablet of solifenacin 6 mg plus TOCAS provides important clinical benefits and is a cost-effective treatment strategy in the UK NHS compared with tolterodine plus tamsulosin for men with both storage and voiding LUTS/BPH.

Clinical safety, tolerability and efficacy of combination tolterodine/pilocarpine in patients with overactive bladder.

AIMS: The purpose of this study was to assess the safety, tolerability and impact on overactive bladder (OAB) symptoms of a novel combination of tolterodine immediate-release (IR) 2 mg and delayed-release pilocarpine 9 mg in patients with OAB. METHODS: Eligible patients with OAB were randomised to each of three treatments [tolterodine/pilocarpine (2/9 mg), tolterodine IR 2 mg or placebo] twice daily for 4 weeks in a double-blind, crossover fashion. At the end of the 12-week, double-blind treatment period, patients could enter an open-label extension during which they were re-randomised to either tolterodine/pilocarpine (3/13.5 mg) twice daily or tolterodine extended-release 4 mg once daily for 12 weeks. RESULTS: A total of 138 patients were randomised to double-blind medication. Both tolterodine/pilocarpine (2/9) and tolterodine IR 2 mg significantly reduced incontinence episodes and daily micturitions (p < 0.001 vs. placebo), with similar reductions in symptoms observed between active treatment groups. Tolterodine/pilocarpine (2/9) was associated with consistently lower Visual Analogue Scale (VAS) scores for all dry mouth parameters compared with tolterodine alone. Salivary flow over a 3 h period remained fairly constant after tolterodine/pilocarpine (2/9) administration, similar to placebo, but decreased markedly after administration of tolterodine alone. In the extension study, patients receiving tolterodine/pilocarpine (3/13.5) reported comparable dry mouth VAS scores to tolterodine extended-release alone without additional side effects or loss of efficacy. The combination was well tolerated, and the adverse effects observed were consistent with the known safety profiles of tolterodine and pilocarpine. CONCLUSIONS: A combination of tolterodine/pilocarpine (2/9) effectively reduced the incidence of dry mouth compared with tolterodine IR alone while maintaining treatment efficacy in OAB.

Efficacy and safety of fesoterodine 8 mg in subjects with overactive bladder after a suboptimal response to tolterodine ER.

AIMS: To assess fesoterodine 8 mg efficacy over time and vs. placebo in subjects with overactive bladder (OAB) who responded suboptimally to tolterodine extended release (ER) 4 mg. METHODS: In a 12-week, double-blind trial, subjects with self-reported OAB symptoms for ≥ 6 months, mean of ≥ 8 micturitions and ≥ 2 to < 15 urgency urinary incontinence (UUI) episodes/24 h, and suboptimal response to tolterodine ER 4 mg (defined as ≤ 50% reduction in UUI episodes during 2-week run-in) were randomised to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks) or placebo once daily. Change from baseline to week 12 in UUI episodes (primary end-point) was analysed in step-wise fashion: first, baseline vs. week 12 for fesoterodine; if significant, then change from baseline to week 12 for fesoterodine vs. placebo. RESULTS: By week 12, subjects receiving fesoterodine 8 mg had significantly greater improvement from baseline vs. placebo in UUI episodes, urgency episodes and scores on the Patient Perception of Bladder Control, Urgency Perception Scale and OAB Questionnaire Symptom Bother and Health-Related Quality of Life scales and domains (all p < 0.05). 50% and 70% UUI responder rates were also significantly higher with fesoterodine 8 mg vs. placebo at week 12 (p < 0.05). Dry mouth (placebo, 4%, 12/301; fesoterodine, 16.6%, 51/308) and constipation (placebo, 1.3%, 4/301; fesoterodine, 3.9%, 12/308) were the most frequent adverse events. CONCLUSIONS: Subjects who responded suboptimally to tolterodine ER 4 mg showed significant improvements in UUI and other OAB symptoms and patient-reported outcomes, with good tolerability, during treatment with fesoterodine 8 mg vs. placebo.

Hansen solubility parameters and quality-by-design oriented optimized cationic nanoemulsion for transdermal drug delivery of tolterodine tartrate.

Tolterodine tartrate (TOT) is a selective anti-muscarinic drug to treat urinary urgency and overactive urinary bladder (OAB) occurring in children, renal disease and elderly patients. Oral delivery is associated with several adverse effects. We addressed HSPiP and QbD (quality by design)-oriented TOT loaded cationic nanoemulsions for transdermal delivery. Hansen solubility parameters (HSP) screened excipients based on theoretical solubility whereas, QbD optimized cationic nanoemulsions (CNE-TOT-6). Formulation characteristic parameters were desirable to execute targeted in vitro drug release and ex vivo permeation profiles. In vitro hemolysis was conducted at varied concentrations whereas, histopathological study supported the safety aspect of CNE-TOT6. A comparative bioavailability was carried out in a rat model. Capmul PG8 (CAP), tween 80, and PEG 400 (polyethylene glycol 400) were screened based on HSP and experimental solubility data. QbD suggested optimized content of CAP, tween 80, and PEG 400 to achieve the lowest value of size (184 nm), maximum % entrapment efficiency (87.2 %), high zeta potential (+32.6 mV), optimum viscosity (47.19 cP), and high extrudability (96 %) as compared to its gel. High gel consistency slowed down the drug release and permeation flux as compared to CNE-TOT6 suspension. Hemocompatible CNE-TOT6 increased pharmacokinetic parameters as compared to the control and gel without causing skin toxicity after application. Thus, HSPiP and QbD oriented cationic nanoemulsions are promising carriers to treat overactive urinary bladder.