Urodynamic effects of propiverine in children and adolescents with neurogenic bladder: results of a prospective long-term study.

OBJECTIVE: To evaluate prospectively the efficacy and tolerability of propiverine for long-term treatment of neurogenic detrusor overactivity (NDO) in children. MATERIALS AND METHODS: 17 children and adolescents with NDO (10 female, 7 male; average age at last consultation 13.0 years) were evaluated during long-term treatment with propiverine (0.8 mg/kg body weight/day). Outcome measurements included urodynamic parameters, continence, hydronephrosis and tolerability of propiverine. RESULTS: Average follow-up was 3.6 years (range 2.0-5.9). The average maximum detrusor pressure was 33.2 ± 4.8 cmH(2)O and bladder compliance was 20.0 ± 5.4 ml/cmH(2)O at the last follow-up visit. Maximum cystometric bladder capacity (MCBC) within the normal range was attained in 11 patients; it was still reduced (average of 61% of expected MCBC) in the remaining 6. Incontinence occurred on average once per day. Hydronephrosis was classified for each renal unit separately: grade 0 was measured in 26 and 22 cases, grade 1 or 2 in 6 and 8 cases, grade 3 or 4 in 2 and 4 cases pre and post treatment, respectively. In 6/17 patients adjuvant intravesical oxybutynin was applied, in 4 out of these 6 patients more invasive procedures, such as untethering, augmentation cystoplasty or botulinum toxin injections, were necessitated. Propiverine monotherapy was well tolerated in 11/17 patients. No serious adverse events were encountered during the study period. CONCLUSION: Long-term efficacy and tolerability of propiverine for NDO in children and adolescents is promising: clinically relevant improvements in key urodynamic outcomes were paralleled by improvements in incontinence score.

The muscarinic receptor antagonist propiverine exhibits α(1)-adrenoceptor antagonism in human prostate and porcine trigonum.

PURPOSE: Combination therapy of male lower urinary tract symptoms with α(1)-adrenoceptor and muscarinic receptor antagonists attracts increasing interest. Propiverine is a muscarinic receptor antagonist possessing additional properties, i.e., block of L-type Ca(2+) channels. Here, we have investigated whether propiverine and its metabolites can additionally antagonize α(1)-adrenoceptors. METHODS: Human prostate and porcine trigone muscle strips were used to explore inhibition of α(1)-adrenoceptor-mediated contractile responses. Chinese hamster ovary (CHO) cells expressing cloned human α(1)-adrenoceptors were used to determine direct interactions with the receptor in radioligand binding and intracellular Ca(2+) elevation assays. RESULTS: Propiverine concentration-dependently reversed contraction of human prostate pre-contracted with 10 µM phenylephrine (-log IC(50) [M] 4.43 ± 0.08). Similar inhibition was observed in porcine trigone (-log IC(50) 5.01 ± 0.05), and in additional experiments consisted mainly of reduced maximum phenylephrine responses. At concentrations ≥1 µM, the propiverine metabolite M-14 also relaxed phenylephrine pre-contracted trigone strips, whereas metabolites M-5 and M-6 were ineffective. In radioligand binding experiments, propiverine and M-14 exhibited similar affinity for the three α(1)-adrenoceptor subtypes with -log K (i) [M] values ranging from 4.72 to 4.94, whereas the M-5 and M-6 did not affect [(3)H]-prazosin binding. In CHO cells, propiverine inhibited α(1)-adrenoceptor-mediated Ca(2+) elevations with similar potency as radioligand binding, again mainly by reducing maximum responses. CONCLUSIONS: In contrast to other muscarinic receptor antagonists, propiverine exerts additional L-type Ca(2+)-channel blocking and α(1)-adrenoceptor antagonist effects. It remains to be determined clinically, how these additional properties contribute to the clinical effects of propiverine, particularly in male voiding dysfunction.

Efficacy, tolerability and safety of propiverine hydrochloride in comparison to oxybutynin in children with urge incontinence due to overactive bladder: Results of a multicentre observational cohort study.

OBJECTIVE: To compare, in a retrospective observational cohort study, the efficacy, tolerability and safety of propiverine and oxybutynin in children with urge incontinence (UI) due to overactive bladder. PATIENTS AND METHODS: Medical records were scrutinized for children with UI. As a primary efficacy outcome variable the achievement of continence after treatment with variable doses of propiverine or oxybutynin was assessed. Weekly UI episodes and daily voiding frequency were evaluated as secondary efficacy outcomes. Tolerability was evaluated by the rate of adverse events, adverse drug reactions caused by antimuscarinics and premature treatment termination. RESULTS: At 16 study centres, 621 children aged 5-14 years with UI due to overactive bladder were enrolled. After anticholinergic treatment (437 propiverine, 184 oxybutynin) continence was achieved in 61.6% and 58.7% of the patients after 186 and 259 days, respectively. There were clinically relevant improvements in voiding frequency across treatment groups. Daily doses of propiverine were markedly below the recommendations (0.54 vs 0.8 mg/kg body weight), daily doses of oxybutynin were according to the recommendations (0.31 vs 0.2-0.4 mg/kg body weight) at treatment initiation. There was a significantly more favourable tolerability to propiverine than oxybutynin for the overall rate of adverse events (3.9% vs 16.3%, odds ratio 4.813), adverse drug reactions caused by propiverine or oxybutynin (2.8% vs 9.2%) and premature treatment termination due to adverse drug reactions (1.6% vs 4.4%). CONCLUSION: Propiverine and oxybutynin are effective in children with UI due to overactive bladder. Sufficient treatment periods of at least 2, preferably 3-4, months are the crucial factors for a successful treatment. The tolerability profile of propiverine is better than for oxybutynin.

Failure of monotherapy in primary monosymptomatic enuresis: a combined desmopressin and propiverine treatment regimen improves efficacy outcomes.

OBJECTIVE: To evaluate, in a prospective study, the combination of the antimuscarinic propiverine and the antidiuretic hormone-agonist desmopressin in children and adolescents not responsive to previous monotherapy, as in primary monosymptomatic enuresis (PME), combined treatments are considered a second-line approach after the failure of monotherapy. PATIENTS AND METHODS: The study included 122 children and adolescents (mean age 10.8 years, range 5-21) with PME and so far unresponsive to single or multiple monotherapy. Propiverine (body weight <30 kg, 15 mg/day; >or=30 kg, 20 mg/day) and desmopressin (0.4 mg/night) were administered over 3 months, followed by successive structured withdrawal programmes for propiverine and desmopressin, depending on the amount of loss of urine at night before treatment. RESULTS: The re-evaluation of unresponsive patients, incorporating video-urodynamics, showed neurogenic detrusor overactivity, isolated detrusor sphincter dyssynergia and vesicorenal reflux in 12.3% (15/122) of patients, so far falsely treated as enuresis. In 107 of 122 patients the diagnosis of PME was confirmed. The primary efficacy outcome, continence at night, was achieved in 104 of 107 patients (97.2%). During the individual follow-up periods (3-12 months), 23 of 107 (21.5%) patients relapsed after withdrawal of both medications. Adverse events of moderate intensity were rare (3.7%). CONCLUSION: Re-evaluation of patients after monotherapy has failed is justified, because other entities can be discovered in patients so far treated unsuccessfully for enuresis. The combination of propiverine and desmopressin is highly effective in children with PME. Our results support the case for further optimizing the inaugurated treatment algorithm of PME for treatment duration, dose-titration and structured withdrawal programmes, thus possibly further decreasing relapse rates.

Propiverine vs oxybutynin for treating neurogenic detrusor overactivity in children and adolescents: results of a multicentre observational cohort study.

OBJECTIVE: To compare, in a retrospective observational cohort study, the efficacy, tolerability, safety and clinical effectiveness of propiverine and oxybutynin in children and adolescents with neurogenic detrusor overactivity (NDO). PATIENTS AND METHODS: In all, 255 children and adolescents (aged 1-18 years) with NDO (199 myelomeningocele, 46 spinal cord injury, 10 other diagnoses) were enrolled at 14 study centres. To evaluate the efficacy of propiverine and oxybutynin, urodynamic and clinical variables were assessed before and after at least 12 month of the antimuscarinic agents administered at variable doses. RESULTS: In all, 127 patients given propiverine and 128 given oxybutynin were enrolled. The primary efficacy outcome, i.e. reductions in urodynamically assessed individual maximum detrusor pressure (P(detmax)), was assumed to indicate success in 74.2% of those on propiverine vs 49.6% on oxybutynin. The mean P(detmax) was significantly reduced during treatment, from 59.8 to 36.7 cmH(2)O in the propiverine and from 65.2 to 54.9 cmH(2)O in the oxybutynin groups. The mean maximum cystometric bladder capacity increased from 146 to 242 mL in the propiverine and from 222 to 310 mL in the oxybutynin group. Propiverine was better tolerated than oxybutynin, having fewer adverse drug reactions (9.4% vs 17.2%, odds ratio 2.04), and for its severity grades and premature treatment termination (none vs 11 cases). CONCLUSION: In this non-interventional study, reflecting 'real-life' clinical practice, comparing the efficacy, tolerability and safety of propiverine and oxybutynin in children and adolescents with NDO, propiverine was at least as effective as oxybutynin, but better tolerated, resulting in superior clinical effectiveness than for oxybutynin.

Treatment with propiverine in children suffering from nonneurogenic overactive bladder and urinary incontinence: results of a randomized placebo-controlled phase 3 clinical trial.

BACKGROUND: Until now no confirmatory clinical trial in children suffering from nonneurogenic overactive bladder (OAB) and urinary incontinence could demonstrate superiority for antimuscarinics over placebo. OBJECTIVES: The following study was conducted to prove efficacy and tolerability of propiverine compared to placebo. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled phase 3 trial with parallel-group design in children aged 5-10 yr was performed. Prior to the 8-wk medical therapy urologic baseline diagnostics, a 3-wk lifestyle advice (urotherapy) was established. INTERVENTION: After re-evaluation of in- and exclusion criteria and uroflowmetry, only children fulfilling the requested criteria were allocated to a body-weight-adjusted therapy (10 or 15 mg propiverine twice daily or corresponding placebo). MEASUREMENTS: Efficacy parameters derived from bladder diary and a micturition volume protocol. Decrease in voiding frequency per day was chosen as primary efficacy parameter; secondary endpoints included voided volume and incontinence episodes. A safety assessment was conducted. RESULTS AND LIMITATIONS: Of 171 randomized children, 87 were treated with propiverine and 84 with placebo. The primary efficacy parameter showed a decrease in voiding frequency (-2.0 episodes for propiverine versus -1.2 for placebo; p=0.0007). Superiority could also be demonstrated for voided volume (31.4 vs. 5.1 ml; p<0.0001) and incontinence episodes (-0.5 vs. -0.2 episodes per d; p=0.0005). The trial design did not allow for separate evaluation of the effect of urotherapy prior to medical treatment. Propiverine was well-tolerated in children. Altogether 23% of side-effects were reported for propiverine and 20% for placebo. CONCLUSIONS: This clinical trial showed superior efficacy of propiverine over placebo and good tolerability for the treatment of children suffering from OAB and urinary incontinence. An important additional factor for the success of the trial was a modified trial design with previous urotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00603343.

Muscarinic receptor expression and receptor-mediated detrusor contraction: comparison of juvenile and adult porcine tissue.

Urinary bladder function is known to mature during fetal and postnatal development, including changes in neurotransmitter regulation of detrusor contraction. However, only few experimental data are available about muscarinic receptor antagonist function in the urinary bladder from young animals. In the present study, we compare the muscarinic receptor-mediated contractions in juvenile and adult porcine detrusor and the effects of antimuscarinic compounds. Urinary bladders from young (8-12 weeks; 12- to 35-kg body weight) and mature pigs (>40 weeks; >100 kg) were compared. Muscarinic receptor expression was assessed by real time polymerase chain reaction and radioligand binding. Muscle contraction was measured with a force transducer; L-type Ca2+ currents (ICa,L) of isolated detrusor myocytes were recorded with standard voltage clamp technique. Juvenile and adult detrusor expressed similar quantities of the messenger RNA of M2 and M3 receptors. The number of [3H]QNB-binding sites and their affinity for the radioligand were also similar between juvenile and adult detrusor. In contrast, maximum contractile responses to the muscarinic receptor agonist carbachol were slightly larger in juvenile than adult bladders. On the other hand, carbachol was slightly less potent in juvenile than in adult tissue. The M3 antagonist DAU 5884 and the spasmolytic drug propiverine inhibited contractile responses with comparable efficacies and potencies in juvenile and adult tissue. ICa,L was somewhat smaller in juvenile than in adult cells. Taken together, these data suggest that expression and function of M2 and M3 receptors are similar in the detrusor of juvenile and mature pigs. Therefore, similar responses to antimuscarinic compounds could be expected in young and adult patients.