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PubMed2005

Efficacy of botulinum-A toxin in adults with neurogenic overactive bladder: initial results.

INTRODUCTION AND OBJECTIVES: To study the effects of intradetrusor botulinum-A toxin (BTA) (BOTOX) injections in adult patients with detrusor overactivity who failed to respond to anticholinergic medications or developed intolerable side-effects. MATERIALS AND METHODS: Ten patients (average age 41 years, range 19-76 years) with neurogenic bladder and detrusor overactivity who were using clean intermittent catheterization 4 to 7 times a day with anticholinergic therapy were included in our study. Their history, physical examination, abdominal ultrasound, urine analysis, serum creatinine and electrolytes, as well as multichannel urodynamic evaluation were documented before administration of BTA injections. Anticholinergic medication was stopped at the time of injection. Three hundred to 400 U of BTA were injected into 30 to 40 different sites in the detrusor muscle under cystoscopic guidance. Clinical assessment and urodynamic testing were repeated 3 months after injection. RESULTS: Five patients were tetraplegic and five were paraplegic at the thoracic or lumbar level. Three patients had incontinence episodes between catheterizations before treatment, and only one patient continued to have incontinence episodes between catheterizations after treatment. Reflex volume increased by 63.08% from 180 +/- 44.99 ml to 293.7 +/- 208.42 ml (p < 0.02). Maximal bladder capacity was augmented by 73.63% from 290 +/- 131.64 ml to 518.20 +/- 273.35 ml (p < 0.03). Maximal detrusor pressure decreased by 15.52% from 69.60 +/- 39.19 cmH(2)O to 58.80 +/- 33.95 cmH(2)O (p < 0.2). No patients complained of side effects. CONCLUSION: BTA appears to be an effective and safe therapeutic option for overactive bladder in patients with spinal cord injury failing anticholinergic therapy and delays more invasive treatments. These initial results confirm European literature reports.

Adult↗
PubMed2005

Urgency of micturition and detrusor contractility in men with prostatic obstruction and overactive bladders.

AIMS: In men with prostatic obstruction and detrusor overactivity (DO), to ascertain whether urgency of micturition affects bladder contractility. MATERIALS AND METHODS: We urodynamically assessed five groups of 20 men each who had bladder outflow obstruction (BOO) from benign prostatic enlargement-Groups 1 (with no DO and no urgency), 2 (with DO and no urgency), 3A (with DO and moderate urgency), 3B (with DO and severe urgency), and 4 (with DO, severe urgency and chronic ischemic cerebral lesions). Urgency was graded as moderate or severe by the ability to avert an urgent void at cystometry for > or =2 or <2 min, respectively. BOO was assessed by the "Abrams-Griffiths number" (AG) and bladder contractility by the parameters PIP and WF(max). RESULTS: AG did not differ significantly in Groups 2, 3A, and 3B, proved higher in such groups than in Group 1, and was nearly the same in Groups 1 and 4. PIP and WF(max) were significantly higher in Groups 2, 3A, and 3B than in Groups 1 and 4, had the highest levels in Group 3B, and did not differ significantly in Groups 1-4 and 2-3A. CONCLUSIONS: In DO patients with prostatic obstruction there seems to be a DO-related facilitation of bladder contractility. In the same patients, severe urgency of micturition might over-amplify (i.e., enhance a DO-related facilitation of) bladder contractility, provided there are no neurogenic (chronic ischemic cerebral) lesions.

Aged↗
PubMed2004

Effect of cyclohexenonic long-chain fatty alcohol on rat overactive bladder induced by bladder neck obstruction.

We attempted to clarify the preventive effects of cyclohexenonic long-chain fatty alcohol on detrusor overactivity induced by mild bladder neck obstruction. Bladder neck obstruction was created by partial ligation of the urethra. Female Sprague-Dawley rats were divided into three groups: those with bladder neck obstruction treated without long-chain fatty alcohol, those with bladder neck obstruction with long-chain fatty alcohol (8 mg/kg, i.p., every day) and the sham-operated control group (A, B, and C groups, respectively). Six weeks after the induction of bladder neck obstruction, voiding behavior was observed in the metabolic cage, and a cystometrogram was performed in the experimental animals. Furthermore, Hematoxylin and Eosin, Azan-Mallory, and Bodian stainings were performed in these bladders. Bladder weight, voiding behaviors and a cystometry indicated that rats in the A group showed detrusor overactivity, which was improved by treatment with long-chain fatty alcohol. The proportion of connective tissue and the density of bundles of neurofibers in the bladder of the A group was significantly less than that in the other bladders. Mild bladder neck obstruction induces detrusor overactivity, which is improved by treatment with long-chain fatty alcohol.

Animals↗
PubMed2002

Muscarinic receptor subtypes and management of the overactive bladder.

Anticholinergic agents are the most widely used therapy for urge incontinence despite exerting adverse effects, such as constipation, tachycardia, and dry mouth, that limit their use. These adverse effects result from a lack of selectivity for the bladder over other organs. Although M2-muscarinic receptors are the predominant cholinoreceptor present in urinary bladder, the smaller population of M3-receptors appears to be the most functionally important and mediates direct contraction of the detrusor muscle. M2-receptors modulate detrusor contraction by several mechanisms and may contribute more to contraction of the bladder in pathologic states, such as bladder denervation or spinal cord injury. Prejunctional inhibitory M2-receptors or M4-receptors and prejunctional facilitatory M1-muscarinic receptors in the bladder have also been reported, but their relevance to the clinical effectiveness of muscarinic antagonists is unknown. In clinical studies, tolterodine, a nonselective muscarinic antagonist, has been reported to be equally effective to oxybutynin but to induce less dry mouth. Controlled-release and intravesical, intravaginal, and rectal administrations of oxybutynin have all been reported to cause fewer adverse effects. Conversely, darifenacin, a new M3-selective antagonist, has been reported to have selectivity for the bladder over the salivary gland in vivo. Whether M3-selective or nonselective muscarinic antagonists will be the most clinically effective for the overactive bladder-preserving the best balance between efficacy and tolerability-has yet to be established, and comparative clinical trials between compounds, such as darifenacin (M3 selective) and tolterodine (nonselective) will be required.

Cholinergic Antagonists↗
PubMed2006

Expression of smoothelin in the normal and the overactive human bladder.

PURPOSE: We established the expression pattern of smoothelin, a marker protein for contractile smooth muscle cells, in the human detrusor and investigated its possible impact on bladder overactivity. MATERIALS AND METHODS: Detrusor samples of 13 overactive bladders (sensory urge and detrusor instability) were obtained before botulinum toxin injection and compared to those of 8 normally contractile, nonobstructed bladders obtained during radical cystectomy. Smoothelin mRNA expression patterns were investigated by Northern blot and variant specific reverse transcriptase-polymerase chain reaction as well as by quantitative reverse transcriptase-polymerase chain reaction on laser capture, microdissected smooth muscle. At the protein level smoothelin was investigated by standard and quantitative immunohistochemistry. RESULTS: The bladder muscularis expressed vascular and visceral smoothelin isoforms, and 2 of the known splice variants. In the smooth muscle of patients with detrusor instability and sensory urge a significant 2.4 and 2.2-fold increase, respectively, in smoothelin variant 1 mRNA was observed in comparison to that of normal controls. Analyses at the smoothelin protein level confirmed significant up-regulation in these bladder dysfunctions by a factor of 2.3 and 1.8, respectively. No significant difference in smoothelin expression was observed between detrusor instability and sensory urge. CONCLUSIONS: Increased expression of smoothelin in patients with detrusor instability and sensory urge implies that the etiology of these dysfunctions includes changes in myogenic parameters. In addition, our data support the new classification of the International Continence Society for overactive bladder proposing that sensory urge and detrusor instability represent a single clinical entity.

Cytoskeletal Proteins↗
PubMed1998

Effects of MK-801 on bladder overactivity in rats with cerebral infarction.

PURPOSE: Our objective was to evaluate the underlying mechanisms of neurogenic voiding dysfunction following cerebral infarction. MATERIALS AND METHODS: The left middle cerebral artery (MCA) was occluded using 4-0 monofilament nylon thread in male S-D rats. Cystometric examination was performed in unanesthetized and urethane-anesthetized rats through a catheter chronically implanted in the dome of the bladder. RESULTS: Bladder capacity of unanesthetized or urethane anesthetized rats was significantly reduced just after occlusion of the left MCA; 2 weeks after the occlusion, the capacity was less than half that in sham-operated rats. Intravenous administration of N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 to the unanesthetized sham-operated rats led to a marked dose-dependent decrease in bladder capacity. Its administration to unanesthetized rats with cerebral infarction resulted in a slight decrease in bladder capacity. In the urethane-anesthetized state, the bladder capacity of the rats with cerebral infarction was significantly increased by MK-801, 0.1 mg./kg., without inhibiting the contraction pressure or increasing the amount of residual urine. A high dose (1 mg./kg.) of MK-801 was required to increase the bladder capacity of sham-operated rats. This led to an inhibition of contraction pressure and an increase in residual urine. CONCLUSION: Results in urethane anesthetized rats indicate that NMDA glutamatergic transmission is important in the overactivity of the bladder following a cerebral infarction. This model is useful in studying the neurogenic voiding dysfunction observed in patients with cerebrovascular disease.

Anesthesia↗
PubMed2005

Propiverine versus tolterodine: efficacy and tolerability in patients with overactive bladder.

OBJECTIVES: Propiverine and tolterodine were compared with respect to efficacy, tolerability and impact on the quality of life in the treatment of patients with idiopathic detrusor overactivity. METHODS: In a randomised, double-blind, multicentre clinical trial, patients with idiopathic detrusor overactivity were treated with 15 mg propiverine twice daily or 2mg tolterodine twice daily over a period of 28 days. The maximum cystometric capacity was determined at baseline and after 4 weeks of therapy. The difference of both values was used as the primary endpoint. Secondary endpoints were voided volume per micturition, evaluation of efficacy (by the investigator), tolerability, post void residual urine, and quality of life. RESULTS: The mean maximum cystometric capacity increased significantly (p < 0.01) in both groups. The volume at first urge and the frequency/volume chart parameters also showed relevant improvements during treatment. 42/100 patients in the propiverine group and 43/102 in the tolterodine group experienced adverse events. The most common adverse event, dry mouth, occurred in 20 patients in the propiverine group and in 19 patients in the tolterodine group. The scores for the quality of life improved comparably in both groups. CONCLUSION: The study demonstrates comparable efficacy, tolerability, and improvement in the quality of life of 15 mg propiverine twice-daily and 2mg tolterodine twice-daily in the treatment of the symptoms of idiopathic detrusor overactivity.

Adult↗
PubMed1997

Capsaicin-induced bladder overactivity and nociceptive behaviour in conscious rats: involvement of spinal nitric oxide.

To investigate the role of nitric oxide (NO) in spinal regulation of lower urinary tract function and bladder nociceptive behaviour, cystometry was performed in conscious rats. The effects of intra-arterial and intrathecal administration of the NO synthase (NOS)-inhibitor, L-NG-nitroarginine methyl ester (L-NAME), were studied on volume- and capsaicin-induced micturitions. The incidence of nociceptive behaviour after intravesical capsaicin was investigated in the absence and presence of L-NAME. Intrathecal L-NAME (0.5 mg) had no effect on the normal, volume-induced micturition. Intravesical capsaicin (30 microM) increased the micturition pressure (p < 0.01), the basal pressure (p < 0.01) and decreased the bladder capacity (p < 0.01) and the micturition volume (p < 0.01). Administration of L-NAME intrathecally (0.5 mg) or intra-arterially (25 mg/kg) had no effects on the capsaicin-induced bladder activity. During capsaicin-infusion, the rats showed signs of distress such as licking and head-turning directed toward the abdomen. This nociceptive behaviour was shown during 31 +/- 3% (n = 6) of the observation period. The capsaicin-induced nociceptive behaviour was markedly reduced by intrathecal and to a less extent by intra-arterial, administration of L-NAME. The percentage time spent licking and head-turning was reduced to 11 +/- 2%, n = 6 (p < 0.001) and 18 +/- 3%, n = 6 (p < 0.05) in rats treated with intrathecal and intra-arterial L-NAME, respectively. The results suggest that NO is not involved in the spinal regulation of the volume- or capsaicin-induced micturition. In contrast, the nociceptive behaviour evoked by intravesical capsaicin seems to involve spinal NO.

Administration, Intravesical↗
PubMed2001

Model of peripheral autonomous modules and a myovesical plexus in normal and overactive bladder function.

Normal bladder function is controlled by the central nervous system (CNS) and any peripheral contribution to bladder control is believed to be small. Nevertheless, anatomically and functionally, such a contribution might exist. Taking account of this evidence, we propose that the detrusor muscle is arranged into modules, which are circumscribed areas of muscle active during the filling phase of the micturition cycle. These modules might be controlled by a peripheral myovesical plexus, consisting of intramural ganglia and interstitial cells. Detrusor overactivity is the occurrence of abnormal increases in pressure during bladder filling, which the patient cannot inhibit. This disorder is thought to be a consequence of abnormal expression of the micturition reflex or changes in the properties of the smooth muscle. We propose that detrusor overactivity results from exaggerated symptomatic expression of peripheral autonomous activity, resulting from a shift in the balance of excitation and inhibition in smooth muscle modules. These structures responsible for origin and spread of peripheral autonomous activity could be targeted to help develop new therapeutic strategies.

Humans↗
PubMed1997

Ice water test in patients with overactive bladder due to cerebrovascular accidents and bladder outlet obstruction.

To investigate the factors which influence the results of the ice-water test (IWT) in patients with cerebrovascular accidents or infravesical obstruction, IWT was performed on these patients with urge urinary incontinence. Thirty-two patients with cerebrovascular lesions (group 1) and 16 patients with benign prostatic hyperplasia (group 2) who demonstrated overactive detrusor function on cystometry were evaluated. Ice-chilled sterile saline was infused into the empty bladder through a balloon catheter, and detrusor pressure was simultaneously recorded. Twenty of the 32 patients (62.5%) in group 1 showed positive IWT. In the positive IWT group, threshold volume at involuntary detrusor contraction was significantly lower than that of the negative IWT group (p < 0.05). The incidence of a positive IWT appeared to be higher in patients with pontine lesions than in those with multiple cerebral infarctions. In group 2 IWT was only positive in 1 patient (6.3%). The location of cerebral lesion and the threshold volume at mechanoreceptor-induced involuntary detrusor contraction appeared to influence the results of the IWT.

Administration, Intravesical↗
PubMed2003

Role of 5-HT receptors in treatment of overactive bladder.

Normal bladder function requires coordinated detrusor relaxation and urethral sphincter contraction during the filling phase and the reverse during micturition. This is achieved by the integration of excitatory, inhibitory, and sensory nerve activity in control centers in the spinal cord, pons, and forebrain. It is possible that much of bladder pathology is related to disturbances in the vesical ganglia, sensory reflex loops, and central control of micturition. Experimental studies in animals have revealed that spinal reflex circuits involved in voiding function exhibit a dense serotonergic innervation, multiple 5-HT receptors, and sensitivity to 5-HT receptor agonists and antagonists, and 5-HT reuptake inhibitors. Activity in the serotonergic pathway generally enhances urine storage by facilitating the vesical sympathetic reflex pathway and inhibiting the parasympathetic voiding pathway. Thus, 5-HT receptor antagonists and reuptake inhibitors represent important targets for the development of new treatments of detrusor overactivity and urinary incontinence. Among the drugs modulating the bladder function through 5HT receptor, duloxetine, a potent and selective inhibitor of 5-HT and NE reuptake, is presently undergoing clinical trials for stress urinary incontinence after being shown to be effective in animal models of this condition.

Animals↗
PubMed2006

Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction.

PURPOSE: Antimuscarinic therapy for men with OAB and BOO is perceived as a potential risk for urinary retention. Using pressure flow urodynamics, we evaluated the safety of tolterodine vs placebo in men with OAB and BOO. MATERIALS AND METHODS: Men (older than 40 years) with BOO and confirmed detrusor overactivity were randomized to tolterodine (2 mg twice daily in 149) or placebo (in 72) for 12 weeks. Primary end points were Qmax and pdetQmax. RESULTS: Median treatment differences in Qmax (-0.7 ml per second, 95% CI -1.6 to 0.4) and pdetQmax (-7 cm H2O, 95% CI -3 to 11) were comparable. Tolterodine significantly reduced the BOOI vs placebo (-9 vs 0, p < 0.02). There were significant treatment differences in volume to first detrusor contraction (+59 ml, 95% CI 19-100) and maximum cystometric capacity (+67 ml, 95% CI 35-103), favoring tolterodine over placebo (p < 0.003). Change in PVR was significantly greater among patients treated with tolterodine (+25 ml) than placebo (0 ml, p < 0.004). There were no significant between-group differences in the incidence of adverse events. Urinary retention was reported by 1 patient treated with placebo. CONCLUSIONS: Tolterodine did not adversely affect urinary function in men with OAB and BOO. Urinary flow rate was unaltered, and there was no evidence of clinically meaningful changes in voiding pressure and PVR or urinary retention. Tolterodine was well tolerated. These results suggest that antimuscarinics can be safely administered in men with BOO.

Aged↗
PubMed1993

Electrical pelvic floor stimulation in the management of urinary incontinence due to neuropathic overactive bladder.

Electrical pelvic floor stimulation employing a portable functional electrical stimulation system with percutaneously indwelling electrodes was carried out to improve detrusor urinary incontinence. Cyclic stimulation using negative going pulse trains of 20 Hz was applied 3 to 6 times daily to the bilateral pudendal nerves distributing to the pelvic floor muscles for the purpose of strengthening these muscles, including the urethral sphincter, and simultaneously, suppressing detrusor overactivity and increasing cystometric capacity. Electrical training for 4-8 weeks resulted in an improvement of urinary incontinence in five of six patients. In two of six cases incontinence had subjectively disappeared. Urodynamic investigations demonstrated an increase in detrusor reflex threshold and less tendency for abortive detrusor contraction. No apparent complications were encountered during these periods. This procedure appears to be efficient for the management of patients with detrusor incontinence who respond poorly to conservative therapies.

Adult↗
PubMed1997

Pharmacokinetics and pharmacodynamics of tolterodine in man: a new drug for the treatment of urinary bladder overactivity.

The aim of this study was to determine the pharmacokinetics, pharmacodynamics, and safety of tolterodine following single oral and intravenous doses in healthy volunteers. A secondary aim was to identify major urinary metabolites and determine mass balance. Single oral doses of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, and 12.8 mg of tolterodine (as the tartrate salt) were given to 17 healthy male volunteers. Two intravenous doses (0.64 and 1.28 mg) were administered to 8 of the volunteers and mass balance was studied after a single oral dose of 5 mg (14C)-tolterodine in 6 subjects. Tolterodine was rapidly absorbed following oral administration (time to peak serum concentration 0.9 +/- 0.4 h). The absolute bioavailability was highly variable, ranging from 10 to 70%. The volume of distribution at steady-state ranged from 0.9 to 1.6 l/kg and systemic clearance ranged from 0.23 to 0.52 l/h/kg, which resulted in a terminal half-life of 2-3 h. Tolterodine exhibited high first-pass metabolism and 2 hepatic metabolic pathways were identified: oxidation and dealkylation. Independent of route of administration, < 1% of the parent compound was excreted unchanged in urine. Five metabolites were structurally identified in urine. Following oral administration of (14C)-tolterodine, the excretion of radioactivity into urine and feces was 77 +/- 4.0% and 17 +/- 3.5%, respectively. Tolterodine decreased stimulated salivation after 3.2 mg, increased heart rate after 6.4 mg, and nearpoint of vision after 12.8 mg. Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg. The lack of a direct relationship between tolterodine serum concentrations and effects on stimulated salivation suggested the presence of pharmacologically active metabolite(s).

Adult↗