Neurogenic detrusor overactivity in adults: a review on efficacy, tolerability and safety of oral antimuscarinics.

OBJECTIVES: This review analyzed efficacy, tolerability and safety of oral antimuscarinic (AM) drugs in adults suffering from neurogenic detrusor overactivity (NDO). METHODS: A comprehensive search of major literature bases was conducted to identify all references. RESULTS: Thirty studies, thereof 16 randomized controlled trials (RCT), enrolling 1479 patients were identified and included in the review. Results were grouped in dose-finding, placebo- and active-controlled, flexible dose and combined high-dose AM drugs, and various studies. Key urodynamic outcome parameters, such as maximum detrusor pressure and maximum cystometric bladder capacity, demonstrated the efficacy of AM in NDO, following 2-3 weeks of treatment. Contrary to idiopathic detrusor overactivity (IDO), no placebo effects manifested. Other important parameters, such as impact on the upper urinary tract function and morphology, issues of continence, post-void residual urine, catheterisation, urinary tract infections and quality of life, were investigated to a limited extent only. Incidence rates of adverse events were comparable for NDO and IDO. Most of the studies, especially RCT, were undertaken with oxybutynin immediate release (IR), trospium chloride IR, propiverine IR and propiverine extended release. In NDO, these drugs are best investigated. CONCLUSIONS: AM drugs are effective in NDO, they normalize the intravesical pressure and increase cystometric bladder capacity. However, other important parameters are not adequately investigated so far and should be recognized in future studies.

Efficacy and tolerability of propiverine hydrochloride extended-release compared with immediate-release in patients with neurogenic detrusor overactivity.

STUDY DESIGN: Double-blind, randomised, multicentre study. OBJECTIVES: Efficacy and tolerability of propiverine extended-release (ER) compared with immediate-release (IR) were evaluated in patients with proven neurogenic detrusor overactivity (NDO). SETTING: Six Spinal Cord Injury Units located in Austria, Germany and Romania. METHODS: Propiverine ER 45 mg s.i.d. or IR 15 mg t.i.d. were administered in patients with proven NDO. Outcomes were assessed at baseline (V1), and after 21 days of treatment (V2): Reflex volume served as primary, leak point volume and maximum detrusor pressure as secondary efficacy outcomes, treatment-related adverse events as tolerability outcomes. RESULTS: Sixty-six patients with proven NDO were enrolled. Reflex volume (ml) increased significantly in the IR (V1: 100.9, V2: 202.9) and in the ER (V1: 89.8, V2: 180.3) group, no significant intergroup difference. Leak point volume increased, and maximum detrusor pressure decreased significantly in both groups, no significant intergroup differences. The percentage of patients presenting with incontinence was reduced by 14% in the IR and by 39% in the ER group, the difference is significant. Treatment-related adverse events manifested in 42 and 36% following propiverine IR and ER, respectively. CONCLUSION: The urodynamic efficacy outcomes demonstrated both galenic formulations to be equieffective. However, following propiverine ER 45 mg s.i.d. higher continence rates compared with propiverine IR 15 mg t.i.d. were achieved, possibly indicative of more balanced plasma-levels. A slight tendency for superior tolerability outcomes of propiverine ER compared with IR was demonstrated.

Desmopressin treatment regimens in monosymptomatic and nonmonosymptomatic enuresis: A review from a clinical perspective.

OBJECTIVE: To evaluate outcomes of desmopressin treatment in monosymptomatic enuresis (ME) and nonmonosymptomatic enuresis (NME). MATERIALS AND METHODS: PubMed was searched for all studies investigating enuresis, up to July 2009, in which desmopressin was administered alone or combined with other treatments. Each study was graded according to its respective level of evidence. RESULTS: Altogether, 99 studies enrolling 7422 patients were identified as fulfilling the inclusion criteria. In 76 studies, desmopressin was administered as monotherapy; in 29 it was combined with other treatments such as antimuscarinics and enuresis alarm. CONCLUSION: Studies incorporating a minor invasive versus a non-invasive diagnostic approach seem to achieve superior long-term success rates. Primary efficacy outcomes following desmopressin treatment are more favourable in ME than NME. Desmopressin administered with adjunct measures achieves superior outcomes compared to monotherapy, especially in NME. Compared to sudden withdrawal, the structured withdrawal programs show better long-term success and lower relapse rates. So far, no superiority has been shown for either time- or dose-dependent structured withdrawal programs. Most studies incorporated only small case series; only 25 studies with level of evidence 1 or 2 have been conducted. The broad range of mono- and adjunct treatments were evaluated according to the evidence based criteria recommended by the European Association of Urology.

[A suggested treatment algorithm in nocturnal enuresis with emphasis on partial responders]. / Therapiealgorithmus bei Enuresis nocturna.

Monotherapeutic strategies often have only partial success in primary nocturnal enuresis (PNE). This analysis evaluated whether adjuvant treatment strategies improve outcomes. PNE children were submitted to a distinct therapeutic strategy including urotherapy (behavioral modifications), a first-line and, if necessary, a second-line treatment period. Outcome was the relief of bedwetting, the follow-up was 3-79 months. Urotherapy was applied. Nonresponders were assigned to desmopressin as first-line treatment. For complete responders a structured withdrawal program was applied. Partial responders were assigned to adjuvant second-line treatment according to their individual symptomatology, masked at basic investigations, incorporating either anticholinergics (propiverine hydrochloride), biofeedback, alpha-blocker (alfuzosin), alarm or psychotherapy, in addition to desmopressin. Nonresponders were referred to specialized management. The study included 259 children suffering from PNE (92 girls, 167 boys, aged 5-18 years): 42 children were relieved from bedwetting after urotherapy and 136 children had a complete response to desmopressin. Three nonresponders were assigned to specialized management, 61 partial responders had adjuvant treatments, and 17 partial responders had no further treatment. The suggested treatment algorithm resulted in 227 complete responders, 29 partial responders, and 3 nonresponders. The need for preliminary urotherapy is evident. The proposed desmopressin monotherapeutic strategy, incorporating a structured withdrawal program, is more effective than the standard desmopressin treatment module. Applying adjuvant treatment modules improves the complete response rate up to 88%. In partial responders overall efficacy rates are improved further. Nonresponders (1.2%) will be referred to specialized management, but many partial responders will gain improvement sufficient to refrain from invasive procedures.

Efficacy, tolerability and safety profile of propiverine in the treatment of the overactive bladder (non-neurogenic and neurogenic).

Propiverine hydrochloride (propiverine) is a compound that has neurotropic and musculotropic effects on the urinary bladder smooth muscle. Controlled clinical trials have shown its effectiveness in treating detrusor hyperreflexia and in treating patients with symptoms of an overactive bladder: this is true not only for adults but in children and the elderly as well. European and Japanese studies have also documented that propiverine is well tolerated. It is better tolerated than oxybutynin (particularly in regard to frequency and severity of dryness of the mouth). In several Japanese studies authors demonstrated that propiverine is well tolerated on a long-term basis. Voigt reported an adverse event incidence rate of 13% in a follow-up investigation during 10 years of treatment. A post-marketing drug surveillance consisting of 4390 patients provided additional data concerning efficacy and safety of propiverine. It is one of the few drugs recommended for the treatment of detrusor overactivity by the Committee on Pharmacological Treatment during the First International Consultation on Incontinence.

Efficacy and cardiac safety of propiverine in elderly patients - a double-blind, placebo-controlled clinical study.

The study investigated the efficacy and cardiac safety of propiverine in the elderly, because the induction of life-threatening ventricular arrhythmia has been reported for some drugs prescribed in the therapy of urinary incontinence. Ninety-eight patients (21 male, 77 female; 67.7+/-6.3 years of age) suffering from urgency, urge incontinence or mixed urge-stress incontinence were included in the double-blind, multicentre, placebo-controlled, randomized study. After a 2-week placebo run-in period, the patients received propiverine (15 mg t.i.d.) or placebo (t.i.d.) for 4 weeks. Before (V1, V2) and during the treatment period (V3, V4), standard ECGs and 24-hour long-term ECGs were recorded. Propiverine caused a significant reduction of the micturition frequency (V2: 8.7+/-4.2, V4: 6.5+/-3.2 ml; p< or =0.01), reflected in a significant increase in the average micturition volume (V2: 163.5+/-65.9, V4: 216.3+/-101.5 ml; p< or =0.01) and a significant decrease in episodes of incontinence (-54%; p = 0.048). These findings were confirmed by the overall assessment at V4, in which approximately 90% of patients under propiverine either had no urge incontinence or urge symptoms, or showed improvement. Resting and ambulatory electrocardiograms indicated no significant changes. Neither the frequency-corrected Q-T interval nor other cardiac parameters were relevantly altered. The frequency of cardiac events (Lown classes IVa/b) was random, revealing no difference between placebo and propiverine. The incidence of adverse events was very low (2% dryness of the mouth under propiverine) and confirmed by the findings from the quality of life questionnaires. A favourable benefit-risk ratio without the induction of any cardiac arrhythmia in the treatment of elderly patients suffering from urgency, urge incontinence or combined urge-stress incontinence is therefore proven for propiverine.

Trospium chloride versus oxybutynin: a randomized, double-blind, multicentre trial in the treatment of detrusor hyper-reflexia.

OBJECTIVE: To compare trospium chloride (TCl), a quaternary ammonium derivative with atropine-like effects and predominantly antispasmodic activity, with oxybutynin (Oxy) in terms of efficacy and adverse effects. PATIENTS AND METHODS: In a randomized, double-blind, multicentre trial, 95 patients with spinal cord injuries and detrusor hyper-reflexia were studied. Treatment consisted of three doses per day over a 2 week period, with either Oxy (5 mg three times daily) or with TCl (20 mg twice daily) with an additional placebo at midday. The results were evaluated with regard to changes in objective (urodynamic) data and subjective symptoms as well as the incidence/severity of adverse effects. RESULTS: With both drugs there was a significant increase in maximum bladder capacity, a significant decrease in maximum voiding detrusor pressure and a significant increase in compliance and residual urine; there were no statistically significant differences between the treatment groups. The percentage of patients who reported severe dryness of the mouth was considerably lower (4%) in those receiving TCl 2 x 20 mg/day than in those receiving Oxy (23%) 3 x 5 mg/day. Withdrawal from treatment was also less frequent in those receiving TCl (6%) than in those receiving Oxy (16%). CONCLUSION: Trospium chloride and oxybutynin, judged in terms of objective urodynamic parameters, are of substantially equal value as parasympathetic antagonists. However, assessment of tolerance in terms of adverse drug effects showed that TCl had certain advantages.

Safety and tolerance of trospium chloride in the high dose range.

The safety and tolerance of increasing single oral doses of 20, 40, 80, 120, 180, 240 and 360 mg trospium chloride (Spasmo-lyt, CAS 10405-0204) were investigated in 29 healthy male volunteers in a double-blind placebo-controlled study. Blood pressure, heart rate, ECG, pupillary diameter, salivary secretion, and subjective reports of tolerance revealed no essential differences between placebo and trospium chloride in doses up to 120 mg. Starting with single doses of 180 mg, anticholinergic effects were observed with increasing intensity, i.e., dilatation of the pupils, reduction of salivary flow, and increase of heart rate. While the highest administered dose of 360 mg trospium chloride did not cause any relevant changes of vital parameters (blood pressure, pulse, ECG), it was subjectively rated as quite unpleasant. The data show that trospium chloride is well tolerated in single oral doses well above the current therapeutic daily dose of up to 40 mg.

Ultrasound studies of the effect of trospium chloride on gall-bladder kinetics.

In a randomized double-blind study the effects of increasing doses of trospium chloride (Spasmo-lyt, CAS 10405-02-4), 0.2, 0.5, 1.0, and 1.5 mg i.v., on gall-bladder contractility were compared among themselves and against placebo and n-butylscopolamine bromide (20 mg i.v.) by an intraindividual 5-fold crossover technique. Gall-bladder volumes after drug-induced contraction (fat stimulus with sodium iopodate) were measured by ultrasound scanning conducted by a single examiner. Serial measurements, carried out in 6 female subjects without any evidence of gall-bladder disease, demonstrated a dose-dependent trend of inhibition of gall-bladder motility produced by trospium chloride. In the maximal doses employed (1.0 and 1.5 mg i.v.) trospium chloride effected almost total inhibition of motility. The response to n-butylscopolamine bromide tested in a nonblind comparison, showed a dose-effect ratio of roughly 40:1 between trospium chloride and n-butylscopolamine bromide given intravenously. This work confirms that ultrasound measurement of gall-bladder volume is a suitable pharmacodynamic model for testing the dose-effect relationships of antispasmodic agents.

[High-dose trospium chloride in therapy of detrusor hyperreflexia]. / Hochdosierte Applikation von Trospiumchlorid zur Therapie der Detrusorhyperreflexie.

The efficacy and tolerance of a high-dose treatment with trospium chloride (20 mg twice daily) were investigated in pilot studies carried out in three trial centres and involving a total of 29 patients suffering from reflex bladder due to transverse lesions of the spinal cord with paraplegia. In all three centres the trial procedure was the same. Urodynamic measurements (maximum bladder capacity, bladder compliance, maximum detrusor pressure during micturition, urinary flow and residual urine) were taken both before and after treatment with trospium chloride for a period of at least 2 weeks. In almost all patients there was a clear rise in maximum bladder capacity, a marked decrease in maximum detrusor pressure and an increase in bladder compliance. As a result the frequency of micturitions was lowered. In the majority of patients, urinary incontinence caused by detrusor hyperreflexia was brought under control through depression of detrusor activity, and urinary continence was achieved. If necessary, intermittent catheterization was continued to empty the bladder. Tolerance of the test preparation was good, and side-effects were rare and mild.

Effect of trospium chloride on urodynamic parameters in patients with detrusor hyperreflexia due to spinal cord injuries. A multicentre placebo-controlled double-blind trial.

In a multicentre placebo-controlled double-blind study 61 patients with spinal cord injuries and detrusor hyperreflexia were treated: 20 mg trospium chloride was given twice daily over a period of 3 weeks. Pre- and posttreatment urodynamic measurements demonstrated large improvements in maximum cystometric capacity (mean = 138.1 ml), decreased maximum detrusor pressure (mean = -37.8 cm H2O) and an increase in compliance (mean = 12.1 ml/cm H2O) in the treatment group. Urodynamic parameters in the placebo group remained substantially unchanged. Comparisons between the two groups revealed highly significant differences for these parameters (all, p less than 0.001). No effect on maximum flow rate and residual urine was detected in either group. The incidence of spontaneously reported side-effects was extremely low and comparable for both groups.