Detrol
Pharmacological effects of tolterodine on human isolated urinary bladder.

Yono M, Yoshida M, Wada Y, Kikukawa H, Takahashi W, Inadome A, Seshita H, Ueda S.

Department of Urology, Kumamoto University School of Medicine, Japan.

Tolterodine, (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine+ ++, is an antimuscarinic drug developed for the treatment of overactive bladder with symptoms of frequency, urgency and urge incontinence. We investigated the effects of tolterodine and its major active metabolite, DD 01 (PNU-200577), (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropa namine, on the contractions induced by carbachol, KCl, CaCl2 and electrical field stimulation in human isolated urinary bladder smooth muscles, using the muscle bath technique. Specimens of human urinary bladder were obtained from 20 patients who underwent total cystectomy due to malignant bladder tumor. The detrusor preparations were taken from the intact part of the dome region of the bladder. Carbachol (10(-9)-10(-2) M) caused concentration-dependent contraction of human detrusor smooth muscles. Tolterodine (10(-9)-10(-6) M), DD 01 (10(-9)-10(-6) M), oxybutynin (10(-8)-10(-6) M), propiverine (10(-8)-10(-6) M), atropine (10(-9)-10(-6) M), pirenzepine (10(-8)-10(-5) M), methoctramine (10(-8)-10(-5) M) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) (10(-9)-10(-6) M) caused typical shifts to the right of the concentration-response curves for carbachol, except for higher concentrations (10(-5) M) of oxybutynin and propiverine, which caused a decrease of about 30% of the maximum contractile responses to carbachol. All the slopes of the regression lines of Schild plots were close to unity, and the rank order of pA2 values was: atropine = DD 01 = tolterodine = 4-DAMP = oxybutynin > propiverine = pirenzepine > methoctramine. Tolterodine (10(-9)-10(-6) M) and DD 01 (10(-9)-10(-6) M) did not inhibit the KCl-induced (80 mM) and CaCl2-induced (5 mM) contractions, while oxybutynin (10(-8)-10(-5) M) and propiverine (10(-8)-10(-5) M) significantly inhibited the contractions. Electrical field stimulation (2-60 Hz) caused frequency-dependent contraction of human detrusor smooth muscles, which were significantly inhibited by various drugs. In the presence of 10(-6) M atropine, tolterodine and DD 01 did not inhibit the residual contractions induced by electrical field stimulation at any of the frequencies, while oxybutynin (10(-5) M) and propiverine (10(-5) M) significantly inhibited the atropine-resistant part of the contractions. The results suggest that the inhibitory effects of tolterodine and DD 01 are mediated only by their antimuscarinic action, which is equal to that of oxybutynin and significantly greater than that of propiverine, and that tolterodine and DD 01 have neither Ca2+ channel antagonist action nor inhibitory effect on the atropine-resistant part of the contractions in human detrusor smooth muscles. These findings support the usefulness of tolterodine as a therapeutic drug for overactive bladder with symptoms of frequency, urgency and urge incontinence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10193658&dopt=Abstract tolterodine Detrol



Detrol
Cost-effectiveness analysis of extended-release formulations of oxybutynin and tolterodine for the management of urge incontinence.

Hughes DA, Dubois D.

Centre for the Economics of Health, IMSCaR, University of Wales, Bangor, Wales. d.a.hughes bangor.ac.uk

INTRODUCTION: Oxybutynin and tolterodine are two drugs widely used for the management of overactive bladder and urge urinary incontinence. The once-daily, extended-release formulations benefit from being well tolerated and efficacious. However, their costs, compared with generic immediate-release (IR) oxybutynin, are significantly greater. This study compared the cost effectiveness of oxybutynin extended-release (Oxy-XL), tolterodine extended-release (Tol-ER), tolterodine immediate-release (Tol-IR) and oxybutynin immediate-release (Oxy-IR). STUDY DESIGN: A cost-effectiveness model. METHODS: A systematic review that identified appropriate randomised clinical trials provided evidence on efficacy. Empirical models of drug effects (number of incontinent-free weeks) and persistence (proportion of patients still on therapy) were constructed in order to determine clinical effectiveness which was combined with cost data (direct medical costs to the UK NHS, year 2001 values) to calculate the drugs' cost-effectiveness from the perspective of the NHS. Univariate sensitivity analyses were conducted to test the robustness of the results. PATIENTS: Hypothetical cohort of patients with urge incontinence associated with overactive bladder. MAIN OUTCOME MEASURES AND RESULTS: The incremental cost per incontinent-free week for Oxy-IR (versus no treatment) ranged from pound sterling 2.58 to pound sterling 16.59. Oxy-XL and Tol-ER were more effective than Oxy-IR but at additional costs per incontinent-free week. Tol-IR did not appear to be a cost-effective option as it was less effective and more costly than the extended-release formulations. Uncertainty surrounding the health and cost consequences of early discontinuation affected these results, although the model results were robust to parameter uncertainty. CONCLUSION: Oxy-IR, Oxy-XL and Tol-ER appear to be cost-effective options for the management of urge incontinence from the NHS perspective. A decision among the treatments depends on the acceptable cost per additional incontinent-free week.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15524493&dopt=Abstract tolterodine Detrol



Detrol
Impact of urodynamics in treatment of primary nocturnal enuresis persisting into adulthood.

Yucel S, Kutlu O, Kukul E, Baykara M.

Department of Urology, Akdeniz University School of Medicine, Kampus, Antalya, Turkey.

OBJECTIVES: To investigate the urodynamic profiles of adults with primary nocturnal enuresis (PNE) and the association of the urodynamic profile findings with the efficacy of desmopressin and/or tolterodine pharmacotherapy. At least 2% of adults are enuretic during the night. The diagnostic and treatment approach for PNE is empirically the same in children and adults. METHODS: A total of 20 nocturnal enuretic patients (12 women and 8 men) with a mean age of 27.1 years (range 20 to 42) were studied. They had wet their bed at least twice per week for the past 6 months. Urodynamic studies, including filling and voiding cystometry, pressure-flow study, and pelvic floor electromyography with superficial electrodes, were performed on all patients. Two of them had daytime symptoms, and two had prior failed desmopressin therapy. All patients began taking oral desmopressin 0.4 mg for 1 month. Their continence was assessed and tolterodine 4 mg was added for those in whom desmopressin alone failed. The patients responsive to desmopressin alone or desmopressin plus tolterodine were weaned from medication at 6 and 12 months to reassess continence. The mean follow-up period was 11.6 +/- 3.3 months (range 4 to 14). RESULTS: Urodynamic studies of 20 PNE adult patients revealed detrusor instability in 10 (50%), hypocompliance in 8 (40%), nonneurogenic detrusor-sphincter dyssynergy in 1 (5%), and no abnormality in 10 (50%). Of the 20 patients, 19 (95%) had no voiding bladder problems. Of the 10 patients responsive to desmopressin alone, 6 (60%) had a normal urodynamic profile; the remaining 4 (40%) had detrusor instability and/or hypocompliance. Of the 5 patients who received desmopressin and tolterodine, 3 achieved continence. The overall continence rate was 86% (13 of 15), and 12 (92%) of the 15 patients required maintenance therapy. In 2 patients (13.3%), desmopressin and tolterodine therapy failed. The efficacy of desmopressin alone and of desmopressin plus tolterodine were not related to the urodynamic profile findings (P >0.05). The urodynamic profile was also not related to the relapse rate after any form of pharmacotherapy (P >0.05). CONCLUSIONS: PNE persisting into adulthood may be associated with abnormal urodynamic findings. Patients may benefit from urodynamic studies, because if the findings are abnormal, they might have the best chance of successful treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15533498&dopt=Abstract tolterodine Detrol



Detrol
Impact of a health education intervention in overactive bladder patients.

Herschorn S, Becker D, Miller E, Thompson M, Forte L.

Sunnybrook Health and Women's College Health Sciences Centre, Toronto, Ontario, Canada.

OBJECTIVE: To assess a standardized and simple educational intervention in overactive bladder (OAB) patients to improve compliance with anticholinergic medication, increase the use of concomitant behavioral treatments, and improve patients' perception of bladder symptoms. MATERIALS AND METHODS: This is a 16-week open-label randomized trial of tolterodine combined with an education intervention for the experimental group versus tolterodine alone (no intervention) for the control group. The setting was in family medicine and urology clinics in Ontario. The participants were male and female adults with OAB symptoms. Both groups received tolterodine prescriptions. The intervention patients received printed information and an explanation about OAB, medication use, and behavioral treatments (kegel exercise, bladder stretching, fluid regulation). The primary outcomes were medication compliance and persistence at 16 weeks. Secondary outcomes were use of behavioral treatments and self-reported severity of symptoms. RESULTS: More patients in the intervention group (experimental) purchased their prescriptions (p<0.05). Compliance rate was greater for the intervention group (39%), versus the control group (31%) at 16 weeks although the difference was not significant (p>0.05). Significantly more patients started and/or continued non-drug treatments in the intervention group (82%) compared to the control group (53%) (p<0.05). Furthermore, more patients in this group reported improvement in severity of bladder symptoms (p<0.05). CONCLUSIONS: The simple education intervention resulted in a greater, but not significant, increase in compliance with medication compared to the control group. It also resulted in a significantly increased use of behavior modification therapies and better self-perception of treatment outcome.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15636668&dopt=Abstract tolterodine Detrol