Kate H. Moore

Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review

Abstract Objective: To determine the effectiveness of anticholinergic drugs for the treatment of overactive bladder syndrome. Design: Systematic review of randomised controlled trials. Data sources: Published papers and abstracts. Study selection: Randomised controlled trials with anticholinergic drug treatment in one arm and placebo in another. Data extraction: Primary outcomes of interest were patient perceived cure or improvement in symptoms, differences in number of incontinent episodes and number of voids in 24 hours, and side effects. Secondary outcomes of interest were urodynamic measures of bladder function (volume at first contraction, maximum cystometric capacity, and residual volume) and adverse events. Data synthesis: 32 trials were included, totalling 6800 participants. Most trials were described as double blind but were variable in other aspects of quality. At the end of treatment, cure or improvement (relative risk 1.41, 95% confidence interval 1.29 to 1.54), differences in incontinent episodes in 24 hours (estimated mean difference 0.6, 0.4 to 0.8), number of voids in 24 hours (0.6, 0.4 to 0.8), maximum cystometric capacity (54 ml, 43 ml to 66 ml), and volume at first contraction (52 ml, 37 ml to 67 ml), were significantly in favour of anticholinergics (P<0.0001 for all). Anticholinergics were associated with significantly higher residual volumes (4 ml, 1 ml to 7 ml; P=0.02) and an increased rate of dry mouth (relative risk 2.56, 2.24 to 2.92; P<0.0001). Sensitivity analysis, although affected by small numbers of studies, showed little likelihood of an effect of age, sex, diagnosis, or choice of drug. Conclusions: Although statistically significant, the differences between anticholinergic drugs and placebo were small, apart from the increased rate of dry mouth in patients receiving active treatment. For many of the outcomes studied, the observed difference between anticholinergics and placebo may be of questionable clinical significance. None of these studies provided data on long term outcome. What is already known on this topic Anticholinergics are the first line medical treatment for overactive bladder The effectiveness of these drugs is unclear What this study adds Anticholinergics produce significant improvements in overactive bladder symptoms compared with placebo The benefits are, however, of limited clinical significance

Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial.

To further assess, in a phase 3 study, treatment with duloxetine for women with stress urinary incontinence (SUI) in other geographical regions, including Argentina, Australia, Brazil, Finland, Poland, South Africa and Spain, as previous trials in North America and Europe provided evidence for the safety and efficacy of duloxetine as a pharmacological treatment for SUI in women.

Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing.

1 We investigated muscarinic receptors in the detrusor and mucosa of the human bladder body. Radioligand‐binding studies with [3H]QNB were conducted using specimens collected from patients (36–77 years) with normal bladder function, undergoing surgery. For RT–PCR, biopsies of normal bladder were obtained from patients (30–88 years) undergoing check cystoscopy. 2 Binding of [3H]QNB in detrusor (n=20) was of high affinity (KD 77.1 (55.2–99.0) pM) and capacity (Bmax 181±7 fmol mg protein−1). Similar values were obtained in mucosa (n=6) (KD 100.5 (41.2–159.9) pM; Bmax 145±9 fmol mg protein−1). 3 Competition‐binding experiments in detrusor membranes with muscarinic receptor antagonists including trospium, darifenacin, 4‐DAMP, methoctramine, AQ‐RA 741, AF‐DX 116 and pirenzepine indicated a receptor population of 71% M2, 22% M3 and 7% M1. In the mucosa, 75% of sites were M2 receptors, with 25% M3/M5. 4 Using RT–PCR, expression of M1, M2, M3 and M5 mRNA was demonstrated in both detrusor and mucosa. 5 The presence of a high density of mainly M2 muscarinic receptors in the mucosa appears to be a novel finding and raises the question of their physiological significance and the source of their endogenous ligand. 6 There was a negative correlation of receptor number (Bmax) with age in detrusor muscle from male patients (P=0.02). Quantitative competitive RT–PCR demonstrated a selective age‐related decrease in mRNA for muscarinic M3 but not M2 receptors, in both male (P<0.0001) and female (P=0.019) detrusor. These findings correspond with reports of decreased detrusor contractility with ageing.

Host–pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection

Bladder infections affect millions of people yearly, and recurrent symptomatic infections (cystitis) are very common. The rapid increase in infections caused by multidrug-resistant uropathogens threatens to make recurrent cystitis an increasingly troubling public health concern. Uropathogenic Escherichia coli (UPEC) cause the vast majority of bladder infections. Upon entry into the lower urinary tract, UPEC face obstacles to colonization that constitute population bottlenecks, reducing diversity, and selecting for fit clones. A critical mucosal barrier to bladder infection is the epithelium (urothelium). UPEC bypass this barrier when they invade urothelial cells and form intracellular bacterial communities (IBCs), a process which requires type 1 pili. IBCs are transient in nature, occurring primarily during acute infection. Chronic bladder infection is common and can be either latent, in the form of the quiescent intracellular reservoir (QIR), or active, in the form of asymptomatic bacteriuria (ASB/ABU) or chronic cystitis. In mice, the fate of bladder infection, QIR, ASB, or chronic cystitis, is determined within the first 24 h of infection and constitutes a putative host-pathogen mucosal checkpoint that contributes to susceptibility to recurrent cystitis. Knowledge of these checkpoints and bottlenecks is critical for our understanding of bladder infection and efforts to devise novel therapeutic strategies.

CLINICAL EFFICACY AND SAFETY OF TOLTERODINE COMPARED TO PLACEBO IN DETRUSOR OVERACTIVITY

PURPOSE We evaluated the efficacy, patient acceptability and side effect profile of tolterodine, a new antimuscarinic agent for treating bladder overactivity. MATERIALS AND METHODS In our randomized, placebo controlled, parallel group study 123, 129 and 64 patients 18 years old or older with proved detrusor overactivity (idiopathic detrusor instability or detrusor hyperreflexia) were randomized to receive 1 or 2 mg. tolterodine, or placebo, respectively, twice daily for 12 weeks. Main outcome measures were number of voids per 24 hours, urine volume per void and episodes of urge incontinence per 24 hours on a frequency-volume chart with detailed recording of side effects. RESULTS After 12 weeks of treatment mean number of voids per 24 hours plus or minus standard deviation decreased from 11.2 +/- 3.1 to 9.0 +/- 2.6 with the 2 mg. dosage (p = 0.0045 versus placebo). At this dose mean urine volume per void increased from 155 +/- 52 to 190 +/- 70 ml. (p <0.0001 versus placebo), while mean number of incontinence episodes per 24 hours decreased from 3.6 +/- 4.0 to 1.8 +/- 3.1 (p = 0.19 versus placebo). Similar efficacy was observed in patients receiving the 1 mg. dose. Severe dry mouth was reported by only 2, 1 and 2% of patients given the 1 and 2 mg. dose, and placebo, respectively. There was no clinical or electrocardiographic evidence of significant cardiac adverse events. CONCLUSIONS Tolterodine administration resulted in a significant decrease in the frequency of voiding and improved voided volume but it was seldom associated with troublesome or severe side effects.

A urodynamic study of surface neuromodulation versus sham in detrusor instability and sensory urgency

PURPOSE We studied the effect of surface neuromodulation on cystometric pressure and volume parameters in women with detrusor instability or sensory urgency. Electrical current was delivered to the suprapubic region and third sacral foramina via a transcutaneous electrical nerve stimulator with sham neuromodulation control. MATERIALS AND METHODS A consecutive series of women with proved detrusor instability or sensory urgency were randomized to 3 surface neuromodulation groups. Volume and pressure parameters were the main outcomes of transcutaneous electrical nerve stimulation applied during second cystometric fill. RESULTS Sham transcutaneous electrical nerve stimulation did not alter the outcome measures. However, neuromodulation delivered across the suprapubic and sacral skin effected a reduction in mean maximum height of detrusor contraction. A current which inhibits motor activity was not superior to that which inhibits sensory perception in reducing detrusor pressure. Response in sensory urgency was poor. CONCLUSIONS Results from our sham controlled study suggest that short-term surface neuromodulation via transcutaneous electrical nerve stimulation may have a role in the treatment of detrusor instability. Future studies must examine the clinical effect of long-term surface neuromodulation.

Duloxetine compared with placebo for treating women with symptoms of overactive bladder

To evaluate duloxetine (a serotonin‐noradrenaline reuptake inhibitor) in women with symptoms of overactive bladder (OAB), as it has been shown to increase the bladder capacity in an animal model.

Crouching over the toilet seat: prevalence among British gynaecological outpatients and its effect upon micturition

Summary. This study investigated whether British women prefer to crouch over public toilet seats, and measured the effect of such a voiding position on urine flow rate and residual urine volume. Of 528 consecutive women who attended a general gynaecological clinic and completed an anonymous questionnaire, 85% usually crouched over the toilet when using a public convenience, 12% applied paper to the seat and 2% sat directly on public toilet seats. When using a friends bathroom 38% of the women voided by crouching. Results were similar for 155 patients attending a urodynamic clinic, 80 of whom were studied while voiding in both positions. There was a 21% reduction in average urine flow rate and a 149% increase in residual urine volume in the crouching position. Women undergoing urodynamic tests should be asked which voiding position they used before abnormal results are interpreted. Patients with a reduced functional bladder capacity may benefit from being encouraged to sit comfortably on the toilet whenever possible.

Inadequate repeatability of the one‐hour pad test: the need for a new incontinence outcome measure

Objective To assess the reproducibility of two one‐hour pad tests performed within one week using serial ultrasound scanning to obtain identical bladder volumes, and to measure the effect of patient anxiety upon test reproducibility.

Is the Urothelium Intelligent

The urothelium separates the urinary tract lumen from underlying tissues of the tract wall. Previously considered as merely an effective barrier between these two compartments it is now recognized as a more active tissue that senses and transduces information about physical and chemical conditions within the urinary tract, such as luminal pressure, urine composition, etc. To understand this sensory function it is useful to consider the urothelium and suburothelium as a functional unit; containing uroepithelial cells, afferent and efferent nerve fibers and suburothelial interstitial cells. This structure responds to alterations in its external environment through the release of diffusible agents, such as ATP and acetylcholine, and eventually modulates the activity of afferent nerves and underlying smooth muscles. This review considers different stresses the urothelium/suburothelium responds to; the particular chemicals released; the cellular receptors that are consequently affected; and how nerve and muscle function is modulated. Brief consideration is also to regional differences in the urothelium/suburothelium along the urinary tract. The importance of different pathways in relaying sensory information in the normal urinary tract, or whether they are significant only in pathological conditions is also discussed. An operational definition of intelligence is used, whereby a system (urothelium/suburothelium) responds to external changes, to maximize the possibility of the urinary tract achieving its normal function. If so, the urothelium can be regarded as intelligent. The advantage of this approach is that input–output functions can be mathematically formulated, and the importance of different components contributing to abnormal urinary tract function can be calculated. Neurourol. Urodynam. 29:598–602, 2010.