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Registered at clinicaltrials.gov (NCT00966004). Objective• To evaluate the efficacy and safety of the β3-adrenoceptor agonist mirabegron, in a Japanese population with overactive bladder (OAB). Patients and Methods• This randomised, double-blind, placebo-controlled phase III study enrolled adult patients experiencing OAB symptoms for ≥24 weeks. Patients with ≥ 8 micturitions/24 h and ≥1 urgency episode/24 h or ≥1 urgency incontinence episode/24 h were randomised to once-daily placebo, mirabegron 50 mg or tolterodine 4 mg (as an active comparator, without testing for non-inferiority of efficacy and safety) for 12 weeks.• The primary endpoint was the change in the mean number of micturitions/24 h from baseline to final assessment. Secondary endpoints included micturition variables related to urgency and/or incontinence and quality-of-life domain scores on the King's Health Questionnaire.• Safety assessments included adverse events (AEs), post-void residual urine volume, laboratory variables, vital signs and 12-lead electrocardiogram. Results• A total of 1139 patients were randomised to receive placebo (n = 381), mirabegron 50 mg (n = 380) or tolterodine 4 mg (n = 378). Demographic and baseline characteristics were similar among the treatment groups.• At final assessment, mirabegron was significantly superior to placebo in terms of mean [SD] Conclusions• Mirabegron 50 mg once daily is an effective treatment for OAB symptoms, with a low occurrence of side effects in a Japanese population.

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* See Appendix for complete list of contributors.reductions in mean ( SD ) voids/24 h with solifenacin 5 mg, at − 1.93 (1.97), and 10 mg, at − 2.19 (2.09), and propiverine 20 mg, at − 1.87 (2.70), than with placebo, at − 0.94 (2.29) ( P < 0.001 for all). Solifenacin (5 and 10 mg) was superior to placebo, and no worse than propiverine 20 mg, for this variable. There were significantly fewer mean ( SD ) urgency, incontinence and urgency incontinence episodes with solifenacin and propiverine than with placebo, with respective changes on placebo of − 1.28 (2.90), − 0.72 (1.95) and − 0.69 (2.00); solifenacin 5 mg, − 2.41 (2.88), − 1.59 (2.12) and − 1.45 (1.89) ( P < 0.001 for all), and 10 mg, − 2.78 (2.82), − 1.60 (1.81) and − 1.52 (1.77) ( P < 0.001 for all), and propiverine 20 mg, − 2.30 (3.08), − 1.25 (2.79) and − 1.19 (2.20) ( P < 0.001, = 0.002 and = 0.002 respectively). All active treatments vs placebo improved the volume voided ( P < 0.001 for all) and QoL; solifenacin 10 mg reduced nocturia episodes ( P = 0.021) and significantly improved urgency episodes ( P = 0.012) and volume voided ( P = 0.009) vs propiverine 20 mg, and solifenacin 5 mg caused less dry mouth ( P = 0.003). Solifenacin 10 mg caused more dry mouth ( P = 0.012) and occurrences of constipation ( P = 0.004) than propiverine 20 mg, but discontinuation rates between both treatment groups were similar. Continence was restored at endpoint in more than half of the patients on active treatment. CONCLUSIONSolifenacin 5 and 10 mg once daily significantly improved the symptoms of OAB compared with placebo. Solifenacin therapy at 5 mg once daily is well-tolerated; 10 mg can be given if additional efficacy is required. KEYWORDSoveractive bladder, solifenacin succinate, propiverine hydrochloride, efficacy, tolerability, quality of life Study Type -Therapy (RCT) Level of Evidence 1b OBJECTIVESTo compare solifenacin succinate (5 and 10 mg once-daily) to placebo and propiverine hydrochloride (20 mg once-daily), respectively, in Japanese patients with overactive bladder syndrome (OAB). PATIENTS AND METHODSA multicentre, 12-week, double-blind phase III trial randomized men and women aged ≥ 20 years with OAB to solifenacin 5 or 10 mg, propiverine 20 mg, or placebo. Changes at endpoint in number of voids/24 h, urgency, incontinence, urgency incontinence and nocturia episodes, volume voided/void, restoration of continence and quality of life (QoL) were examined. RESULTSOf 1593 patients randomized, 1584 were treated; at the endpoint there were greater

Our data show that the brainstem as well as more rostral regions are involved in voluntary urine storage and these regions are functionally separated from those associated with bladder cold perception in healthy individuals.

The organization of vesicourethral reflex mechanisms in the male rat was studied by monitoring intraurethral pressure and the external urethral sphincter (EUS) electromyogram. EUS striated and urethral smooth muscle activities were elicited by reflex isovolumetric bladder contractions evoked by bladder filling or electrical stimulation of nerves in the bladder wall. Evoked EUS bursting activity in normal rats was eliminated in chronic spinal rats and replaced by tonic activity. Reflex urethral smooth muscle activity mediated by an increase in urethral pressure after paralysis of the EUS with alpha-bungarotoxin occurred in normal and chronic spinal rats. The response was significantly larger in chronic spinal (21.3 +/- 3.0 cmH2O) than in normal rats (4.2 +/- 0.7 cmH2O). NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor, 20 mg/kg i.v.) increased the smooth muscle response in normal (5.9 +/- 1.3 cmH2O) and chronic spinal rats (6.9 +/- 1.8 cmH2O). This increase in urethral pressure was not changed by sympathetic nerve transection or prazosin (0.2-0.3 mg/kg i.v.) but was abolished by hexamethonium and reduced 74-89% by atropine. These results indicate that coordinated EUS function (bursting activity) in the male rat is dependent on supraspinal pathways and that the urethral smooth muscle response during voiding is composed of a predominant cholinergic, atropine-sensitive contraction as well as a nitric oxide-mediated relaxation. Both are mediated by activation of parasympathetic pathways and are maintained or significantly larger after spinal cord injury, indicating that they are dependent on spinal reflex pathways.

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