Treatment of detrusor hyperreflexia in multiple sclerosis: a double-blind, crossover clinical trial comparing methantheline bromide (Banthine), flavoxate chloride (Urispas) and meladrazine tartrate (Lisidonil). [Intravesical instillation of trospium chloride, oxybutynin and verapamil for relaxation of the bladder detrusor muscle. A placebo controlled, randomized clinical test]. A meta-analysis comparing trials of antimuscarinic medications funded by industry or not. Combination therapy with desmopressin and an anticholinergic medication for nonresponders to desmopressin for monosymptomatic nocturnal enuresis: a randomized, double-blind, placebo-controlled trial. Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET). Desmopressin resistant enuresis: pathogenetic and therapeutic considerations. An objective comparison of the effects of parenterally administered drugs in patients suffering from detrusor instability. Placebo--the drug of choice in female motor urge incontinence? Efficacy of maintenance use of anticholinergic agents.
34 patients suffering from detrusor hyperreflexia due to multiple sclerosis entered the trial and 32 patients accomplished. The patients received each drug for a period of 14 days. The patients made records of relevant symptoms, urgency and urge incontinence and compared the treatment periods according to these symptoms. Registration of the number of micturitions was also made. Furthermore, the patients underwent cystometric studies. The following parameters were recorded and compared: residual urine, volume at the first bladder contraction, effective volume and amplitude of the first bladder contraction. The study showed that the patients preferred methantheline bromide. The entire cystometric pattern changed statistically significant with methantheline bromide, but only with concordance to the patients preferences in 60%. Decrease in number of micturitions and volume at the first bladder contraction were the only parameters showing accordance with the preferences. The drugs caused many various side effects. 12 treatment periods were discontinued due to side effects of meladrazine tartrate. The cystometric recordings seem to be of little use in evaluation of a drugs therapeutic effect, and it is difficult to find parameters which reflect the patients preference of the drugs. Therapy of detrusor hyperactivity with anticholinergic agents often is followed by adverse drug reactions. Intravesical application may be an interesting alternative. A randomised, single-blind, placebo-controlled, mono-centre clinical trial was carried out in 84 patients with urgency or urge incontinence. Due to intravesical administration of oxybutynin (CAS 5633-20-5) (n = 21) and trospium chloride (CAS 10405-02-4) (n = 21), respectively, a significant increase in maximum bladder capacity and decrease of detrusor pressure accompanied by an increase of residual urine were found in comparison to placebo in urodynamical investigations. Improvement of uninhibited bladder contractions occurred leading to higher filling volume. Under verapamil (CAS 152-11-4) (n = 21) no marked changes in the efficacy variables were found compared with placebo. All patients completed the study and were assessed with regard to efficacy and safety. No adverse events or marked changes in the vital signs were reported. The immediate onset of effect and the lack of adverse drug reactions suggest that treatment with topical oxybutynin or trospium chloride is an effective alternative in patients with intolerable side effects when orally treated. In addition, intravesical administration may be indicated in patients with bladder spasms due to indwelling catheter or in order to increase bladder capacity before percutaneous cystostomy. To determine if there is a significant difference in outcomes of clinical trials funded by industry or not of antimuscarinic medications used to treat overactive bladder (OAB) symptoms and detrusor overactivity (DOA).
                A Medline search was conducted from January 1966 to June 2003 to identify human clinical trials of oxybutynin and tolterodine published in English. Randomized controlled trials on subjects aged > or = 16 years who were being treated with oxybutynin or tolterodine for OAB symptoms or DOA; 24 studies were identified. The endpoints assessed were OAB symptoms or changes in uninhibited detrusor contractions on cystometrography. The outcome variables were dichotomized as 'improvement' or 'no improvement'. Odds ratios and 95% confidence intervals were calculated for each study based on data derived or extracted from tables and figures.
                Meta-analysis showed no significant difference in the outcomes trails funded by industry or not. Trials were then reviewed to determine their adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines for randomized trials.
                Clinical trials are important for clinicians when selecting medical therapies. In this analysis we found no difference in outcomes when comparing studies funded by industry or not for tolterodine and oxybutynin. The quality of all trials would be improved by close adherence to the CONSORT guidelines for randomized clinical trials. Desmopressin is an approved medical therapy for the treatment of monosymptomatic primary nocturnal enuresis. In cases of limited response to desmopressin, we have added anticholinergic therapy to desmopressin (combination therapy). To evaluate this treatment strategy, we examined the efficacy of combination therapy for primary nocturnal enuresis in desmopressin-nonresponders.
                Only patients with primary nocturnal enuresis refractory to the maximal dosage of desmopressin were enrolled. Children with lower urinary tract symptoms or bowel dysfunction were excluded, on the basis of a 3-day, 24-hour, frequency-volume chart and elimination record. Children continued to take desmopressin and were assigned randomly, in a double-blind manner, to receive either extended-release anticholinergic medication or placebo. Patients were reassessed after 1 month of therapy, with a 1-week nocturnal record.
                Forty-one desmopressin-nonresponders were enrolled, and 7 patients were excluded because of noncompliance. The treatment groups were equally matched with respect to age, gender, functional bladder capacity, and number of wet nights per week. After 1 month of treatment, there was a significant reduction in the mean number of wet nights in the combination therapy group, compared with the placebo group. With a generalized estimating equation approach, there was a significant 66% decrease in the risk of a wet episode, compared with the placebo group.
                This study represents the first prospective, placebo-controlled trial examining the effect of desmopressin in combination with long-acting, anticholinergic, bladder-relaxing therapy for monosymptomatic primary nocturnal enuresis. Treatment with the antimuscarinic agents tolterodine and oxybutynin is the mainstay of therapy for overactive bladder, a chronic and debilitating condition characterized by urinary urgency with or without urge incontinence, usually in combination with urinary frequency and nocturia. This study consisted of two trials; in one, patients with overactive bladder were randomized to 8 weeks of open-label treatment with either 2 mg or 4 mg of once-daily extended-release tolterodine (TER), and in the other to 5 mg or 10 mg of extended-release oxybutynin (OER). The study protocol and design were identical for the two trials and site selection ensured that there was no bias in either trial for the tendency of investigators to prescribe one drug rather than the other, or for geographical location. A total of 1289 patients were enrolled, 669 in the tolterodine trial (TER 2 mg, n = 333; TER 4 mg, n = 336) and 620 in the oxybutynin trial (OER 5 mg, n = 313; OER 10 mg, n = 307). Fewer patients prematurely withdrew from the trial in the TER 4 mg group (12%) than either the OER 5 mg (19%; p = 0.01) or OER 10 mg groups (21%; p = 0.002). More patients in the OER 10 mg group than the TER 4 mg group withdrew because of poor tolerability (13% vs 6%; p = 0.001). After 8 weeks, 70% of patients in the TER 4 mg group perceived an improved bladder condition, compared with 60% in the TER 2 mg group, 59% in the OER 5 mg group and 60% in the OER 10 mg group (all p < 0.01 vs TER 4 mg). Response to therapy was greater in a subgroup of patients whose perception of bladder condition was moderate to severe at baseline (TER 4 mg 77% vs OER 10 mg 65%; p < 0.01). Dry mouth was dose-dependent with both agents, although differences between doses only reached statistical significance in the oxybutynin trial (OER 5 mg vs OER 10 mg; p = 0.05). Patients treated with TER 4 mg reported a significantly lower severity of dry mouth compared with OER 10 mg. In conclusion, the greater efficacy and tolerability of tolterodine ER 4 mg suggests improved clinical effectiveness compared with oxybutynin ER 10 mg. We tested the role of the bladder in the pathogenesis of desmopressin resistant enuresis by evaluating the influence of urine production on the timing of the enuretic event and the response to anticholinergic medication.
                We gave 33 children with monosymptomatic nocturnal enuresis resistant to the standard 0.4 mg. oral dose of desmopressin 0.4 and 0.8 mg. desmopressin and placebo tablets for 5 nights each in a double-blind crossover fashion. The time of enuresis or nocturia was documented. All 9 children who had at least 1 dry treatment period during the randomized portion of the study then received open label treatment with 0.8 mg. desmopressin. Nonresponders to this regimen and the remainder of the children were offered anticholinergic treatment.
                Average time between bedtime and voiding was 5.0, 5.6 and 5.0 hours during the nights with placebo, and 0.4 and 0.8 mg. desmopressin, respectively (p = 0.12). Of the 9 children subsequently treated with 0.8 mg. desmopressin 5 became completely dry. Of the remaining 28 children given anticholinergic treatment 20 responded.
                Antidiuresis does not delay the enuretic event in children with desmopressin resistant enuresis. This finding and the favorable response to anticholinergic medication favor the hypothesis that these children have nocturnal bladder instability. A subgroup of enuretic children responds to high but not normal doses of desmopressin. Cystometric changes produced by 3 parenterally administered drugs, flavoxate hydrochloride, emepronium bromide and imipramine hydrochloride, have been evaluated in 15 female patients with detrusor instability. Each patient was given 2 of the 3 drugs and cystometric recordings were done 10 and 30 minutes after the administration of each drug. Emepronium bromide was found to be the only drug to cause a significant improvement in bladder capacity and reduction in detrusor pressure. In a randomised double-blind cross-over trial of 19 females with motor urge incontinence but without bladder suspension defect, the effects of 14 days' treatment with emepronium bromide 200 mg qid, flavoxate chloride 200 mg qid or placebo qid were compared by means of micturition charts, the patients' drug preferences and evaluation of side effects. Placebo was the only drug giving rise to a statistically significant decrease in the frequency of voidings, incontinence and nocturia. Forty-seven per cent of the patients preferred placebo and side effects were less frequent during treatment with this medication. No differences could be demonstrated between the effects of emepronium bromide and flavoxate chloride. Perhaps detrusor instability is not always the main reason for the voiding dysfunction in these patients, in whom the effect of placebo was equal or superior to the effect of "active drugs" and superior to no treatment at all. Twenty-seven long-term psychiatric inpatients maintained on neuroleptics with concomitant antiparkinsonian medication were entered into a study in which anticholinergic medication was gradually withdrawn in a randomized double-blind within-subjects design. The extrapyramidal symptoms of each patient were compared when taking their usual anticholinergic medication, when taking placebo and when taking no antiparkinsonian drug. The relapse rate on no medication was 14%, and if patients relapsed on no medication they also relapsed on placebo. The relapse rate was not significantly different on active medication. Nor were there significant differences in ratings of parkinsonism or dyskinesia. The lack of difference between double-blind and overt withdrawal does not mean that studies that find a much higher relapse rate are necessarily unaffected by nonspecific factors, as significant unblinding may occur in clinical trials.
Many of the drugs considered in trials in this review are no longer used in clinical practice (and this includes the most commonly tested - flavoxate). There is inadequate evidence as to determine whether any of the available druge are better or worse than anticholinergic medications. Larger randomised controlled trials in clinical settings are required to further establish the role of these medications in the management of overactive bladder syndrome.