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      Basic mechanisms of urgency: roles and benefits of pharmacotherapy

      research-article
      1 , , 2
      World Journal of Urology
      Springer-Verlag
      Urgency, Urge to void, Bladder sensation

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          Abstract

          Introduction

          Since urgency is key to the overactive bladder syndrome, we have reviewed the mechanisms underlying how bladder filling and urgency are sensed, what causes urgency and how this relates to medical therapy.

          Materials and methods

          Review of published literature.

          Results

          As urgency can only be assessed in cognitively intact humans, mechanistic studies of urgency often rely on proxy or surrogate parameters, such as detrusor overactivity, but these may not necessarily be reliable. There is an increasing evidence base to suggest that the sensation of ‘urgency’ differs from the normal physiological urge to void upon bladder filling. While the relative roles of alterations in afferent processes, central nervous processing, efferent mechanisms and in intrinsic bladder smooth muscle function remain unclear, and not necessarily mutually exclusive, several lines of evidence support an important role for the latter.

          Conclusions

          A better understanding of urgency and its causes may help to develop more effective treatments for voiding dysfunction.

          Related collections

          Most cited references66

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          Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder.

          To assess in a phase 3a trial the efficacy of solifenacin succinate, a once-daily oral antimuscarinic agent in development at 5-mg and 10-mg dosage strengths, for the treatment of overactive bladder (OAB) (Yamanouchi Pharmaceutical Co. Ltd, Tokyo, Japan) compared with placebo in patients with symptoms of OAB, i.e. urgency, incontinence, and frequency, with additional objectives being to assess the safety and tolerability of solifenacin and to compare the efficacy and safety of solifenacin with tolterodine 2 mg twice daily. The study was an international, multicentre, randomized, double-blind, tolterodine- and placebo-controlled trial conducted at 98 centres. Adult patients with symptomatic OAB for > or = 3 months were eligible; after a single-blind 2-week placebo run-in period patients were randomized equally to a 12-week double-blind treatment with either tolterodine 2 mg twice daily, placebo, solifenacin 5 mg or 10 mg once daily. Efficacy variables included change from baseline in the mean number of urgency, incontinence and urge incontinence episodes, and change from baseline in voids/24 h and mean volume voided/void. In all, 1281 patients were enrolled, 1081 randomized and 1077 treated; 1033 were evaluated for efficacy. Compared with placebo, the change from baseline (-1.41, -32.7%) in the mean number of urgency episodes per 24 h was statistically significantly lower with solifenacin 5 mg (-2.85, -51.9%) and 10 mg (-3.07, -54.7%; both P < 0.001), but not with tolterodine (-2.05, -37.9%; P = 0.0511). There was a statistically insignificant decrease in episodes of incontinence with tolterodine (-1.14; P = 0.1122) but a significant decrease in patients treated with solifenacin 5 (-1.42; P = 0.008) and 10 mg (-1.45; P = 0.0038). Compared with placebo (-1.20, -8.1%) the mean number of voids/24 h was significantly lower in patients receiving tolterodine (-1.88, -15%; P = 0.0145), solifenacin 5 (-2.19, -17%) and 10 mg (-2.61, -20%; both P < 0.001). The mean volume voided/void was also significantly higher with all three active treatments (P < 0.001). Solifenacin was well tolerated; compared with placebo (4.9%), dry mouth (the most common side-effect), mostly mild, was reported in 18.6% of patients receiving tolterodine, 14.0% receiving 5 mg and 21.3% receiving 10 mg solifenacin. Solifenacin 5 and 10 mg once daily improved urgency and other symptoms of OAB, and was associated with an acceptable level of anticholinergic side-effects. Solifenacin demonstrated significantly favourable efficacy to side-effect ratio in treating symptomatic OAB.
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            Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity/neurogenic overactive bladder: a systematic literature review.

            This systematic literature review discusses the efficacy and safety of botulinum toxin type A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity (NDO) and urinary incontinence or overactive bladder symptoms of neurogenic origin (NOAB). A MEDLINE and EMBASE search for clinical studies with botulinum toxin A injected into the detrusor of adults with NDO was performed. For several efficacy and safety variables data were extracted by one person and independently quality-controlled by another person. Extracted data were reviewed to propose recommendations for use in clinical practice based on level of evidence and expert opinion. A total of 18 articles evaluating the efficacy or safety of Botox in patients with NDO and incontinence/NOAB resistant to antimuscarinic therapy, with or without clean intermittent self-catheterisation (CIC), were selected. The amount of Botox injected was mostly 300 U, usually as 30 injections of 10 U/ml in the bladder (excluding the trigone) under cystoscopic guidance and with different types of anaesthesia. Most of the studies reported a significant improvement in clinical (approximately 40-80% of patients became completely dry between CICs) as well as urodynamic (in most studies mean maximum detrusor pressure was reduced to < or =40 cm H(2)O) variables and in the patients' quality of life, without major adverse events. Botox injections into the detrusor provide a clinically significant improvement in adults with NDO and incontinence/NOAB refractory to antimuscarinics. It seems to be very well tolerated. However, more adequately powered, well-designed, randomised, controlled studies evaluating the optimal dose, number and location of injections, impact on antimuscarinic regimen and CIC use, duration of effect, and when to perform repeat injections are warranted.
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              Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder.

              To determine the efficacy, tolerability, and safety of fesoterodine in subjects with overactive bladder (OAB). This was a multicentre, randomised, double-blind, placebo- and active-controlled trial with tolterodine extended release (ER) to assess the efficacy and safety of fesoterodine. Eligible subjects (> or =18 yr) with increased micturition frequency and urgency and/or urgency urinary incontinence (UUI) were randomised to placebo, fesoterodine 4 mg, fesoterodine 8 mg, or tolterodine ER 4 mg for 12 wk. The primary efficacy variable was a change from baseline to week 12 in micturitions per 24 h. Co-primary end points included change from baseline to week 12 in UUI episodes per 24 h and Treatment Response ("yes" or "no," based on four-point treatment benefit scale). Secondary efficacy variables included mean volume voided per micturition, continent days per week, and number of urgency episodes. At the end of treatment, subjects taking fesoterodine 4 and 8 mg had significant (p<0.05) and clinically relevant improvements versus placebo in the primary, co-primary, and most secondary efficacy variables. Tolterodine ER (active control) also provided significantly greater improvement than placebo for most efficacy variables, confirming the sensitivity of the study design. A more pronounced effect was observed with fesoterodine 8 mg at most end points. Both doses of fesoterodine were significantly better than placebo in improving the symptoms of OAB and produced a significantly greater Treatment Response versus placebo. Efficacy was more pronounced with fesoterodine 8 mg compared with the other treatments. Active treatments were well tolerated.
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                Author and article information

                Contributors
                +31-20-5666762 , +31-20-6965976 , m.c.michel@amc.nl
                Journal
                World J Urol
                World Journal of Urology
                Springer-Verlag (Berlin/Heidelberg )
                0724-4983
                1433-8726
                9 July 2009
                December 2009
                : 27
                : 6
                : 705-709
                Affiliations
                [1 ]Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
                [2 ]Department of Urology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, S10 2JF UK
                Article
                446
                10.1007/s00345-009-0446-5
                2780647
                19588154
                95350558-b761-412b-81f6-78a829032f95
                © The Author(s) 2009
                History
                : 19 May 2009
                : 19 June 2009
                Categories
                Topic Paper
                Custom metadata
                © Springer-Verlag 2009

                Urology
                bladder sensation,urge to void,urgency
                Urology
                bladder sensation, urge to void, urgency

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