Detrol
A pharmacoeconomic model comparing two long-acting treatments for overactive bladder.

Noe L, Becker R, Williamson T, Chen D.

Ovation Research Group, 600 Central Avenue Suite 265, Highland Park, IL 60035, USA.

OBJECTIVE: To compare the estimated first-line treatment costs of extended-release tolterodine versus controlled-release oxybutynin in patients with overactive bladder (OAB). METHODS: We developed a decision-analysis model to estimate the patterns of treatment, resource consumption, and cost impact of treating OAB with either controlled-release oxybutynin or extended-release tolterodine as first-line drug therapy. We used data from the published literature to develop the framework for the model and supplemented this information with expert opinion, where necessary. Based on recent clinical studies, we assumed equal efficacy between the comparators and reduced the model to a cost-minimization analysis. The model was constructed from the payer perspective, and all costs are given in 2000 U.S. dollars. RESULTS: A base-case analysis was generated showing that patients initiating therapy with extended-release tolterodine have probable average 3-month treatment costs of 1,207 dollars compared to 1,283 dollars for patients initiating with controlled-release oxybutynin, for a 6.3% difference. First-line OAB direct drug costs account for 19% and 15% of total costs for extended-release tolterodine and controlled-release oxybutynin, respectively. Sensitivity analysis showed these results to be relatively stable. CONCLUSION: The results from this analysis suggest that for patients with OAB and initiating long-acting pharmacologic therapy in the primary care setting, the treatment with extended-release tolterodine is slightly less costly than treatment with controlled-release oxybutynin. Studies directly comparing these treatment alternatives are needed, however, to determine which approach or combination of approaches is the most cost-effective.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14613400&dopt=Abstract tolterodine Detrol



Detrol
Comparison of in vitro selectivity profiles of solifenacin succinate (YM905) and current antimuscarinic drugs in bladder and salivary glands: a Ca2+ mobilization study in monkey cells.

Kobayashi S, Ikeda K, Miyata K.

Pharmacology Laboratories Applied Pharmacology Research, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba-city, Ibaraki 305-8585, Japan. kobayashi.seiji yamanouchi.co.jp

We investigated the effects of the new muscarinic receptor antagonist solifenacin succinate [YM905; (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate] and the current antimuscarinic drugs for the treatment of overactive bladder (oxybutynin, tolterodine and darifenacin) on intracellular Ca(2+) mobilization in response to M(3) muscarinic receptor activation in bladder smooth muscle and submandibular gland cells isolated from Cynomolgus monkeys. Solifenacin concentration-dependently inhibited carbachol-induced Ca(2+) mobilization, with affinity constant values (pKi) of 8.5 +/- 0.053 in bladder smooth muscle cells and 8.2 +/- 0.051 in submandibular gland cells (n = 5). The pKi value of solifenacin was almost equivalent to the values of oxybutynin, tolterodine and darifenacin in bladder smooth muscle cells (8.7, 8.5 and 8.4, respectively), while being lower than those in submandibular gland cells (9.0, 8.7 and 8.8, respectively). The bladder-selectivity index (Ki ratio: submandibular gland/bladder) for solifenacin (2.1) was statistically higher, moreover, than those for oxybutynin, tolterodine and darifenacin (0.51, 0.65 and 0.46, respectively). These findings consequently indicate solifenacin's unique profile in terms of its selectivity for bladder smooth muscle cells over salivary gland cells in non-human primates, relative to oxybutynin, tolterodine and darifenacin. Solifenacin may, therefore, confer a promising therapeutic advantage for reducing adverse effects, such as dry mouth, exhibited by current antimuscarinic therapy for overactive bladder.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14659973&dopt=Abstract tolterodine Detrol



Detrol
Cardiac ion channel effects of tolterodine.

Kang J, Chen XL, Wang H, Ji J, Reynolds W, Lim S, Hendrix J, Rampe D.

Department of Drug Safety Evaluation, Bridgewater, NJ, USA.

Tolterodine is a muscarinic antagonist widely used in the treatment of urinary incontinence. Although tolterodine has not been reported to alter cardiac repolarization, it is chemically related to other muscarinic antagonists known to prolong cardiac repolarization. For this reason, we studied the effects of tolterodine on cardiac ion channels and action potential recordings. Using patch-clamp electrophysiology, we found that tolterodine was a potent antagonist of the human ether-a-go-go-related gene (HERG) K(+) channel, displaying an IC(50) value of 17 nM. This potency was similar to that observed for the antiarrhythmic drug dofetilide (IC(50) of 11 nM). Tolterodine block of HERG displayed a positive voltage dependence, suggesting an interaction with an activated state. Tolterodine had little effect on the human cardiac Na(+) channel at concentrations of up to 1 microM. Inhibition of L-type Ca(2+) currents by tolterodine was frequency-dependent with IC(50) values measuring 143 and 1084 nM at 1 and 0.1 Hz, respectively. Both tolterodine and dofetilide prolonged action potential duration in single guinea pig myocytes over the concentration range of 3 to 100 nM. However, prolongation was significantly larger for dofetilide compared with tolterodine. Tolterodine seems to be an unusual drug in that it blocks HERG with high affinity, but produces little QT prolongation clinically. Low plasma levels after therapeutic doses combined with mixed ion channel effects, most notably Ca(2+) channel blockade, may serve to attenuate the QT prolonging effects of this potent HERG channel antagonist.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14711935&dopt=Abstract tolterodine Detrol



Detrol
Retrospective analysis of efficacy and tolerability of tolterodine in children with overactive bladder.

Raes A, Hoebeke P, Segaert I, Van Laecke E, Dehoorne J, Vande Walle J.

Department of Paediatrics, Paediatric Uro-Nephrological Centre, Ghent University Hospital, De Pintelaan185, B-9000 Ghent, Belgium. ann.raes Ugent.be

OBJECTIVE: To evaluate the efficacy and tolerability of tolterodine in children with an overactive bladder, treated in a single incontinence centre. MATERIALS AND METHODS: A retrospective analysis of a database of a total of two hundred and fifty-six patients (175 boys and 81 girls, age range 3 years to 17 years, mean age 8.33 years) with urodynamically confirmed bladder overactivity was performed. All children received tolterodine tartrate (dose range of 0.5-4 mg orally). In group I (n=205) tolterodine tartrate replaced anticholinergic drugs (AC) (oxybutinin chloride or oxyphencyclimin hydrochloride). A subgroup of patients switched because of intolerance due to serious adverse events (60.4%) or because of lack of improvement in micturition variables (39.6%). In group II tolterodine was prescribed as initial therapy (n=51). Tolerability was assessed by a standardised questionnaire on adverse events at every outdoor clinic visit. Efficacy assessment was based on micturition diary variables, mean change of maximum bladder capacity and number of incontinence episodes/24 h. RESULTS: The mean treatment time was 9.32 months with a range from 1.5 months to 23.4 months. The final dose was 0.1mg/kg orally daily divided into two doses. In group I central nervous system disorders (81%) were the most common adverse events, 26.2% showed flushing, 12.2% accommodation problems and 25.2% had gastrointestinal complaints (constipation, encopresis, abdominal pain). Withdrawal of the non-selective antimuscarinic drug resulted in total recovery from adverse events.Introduction of tolterodine in group I and II caused no serious adverse events. Nine patients (3.5%) reported side-effects and only two discontinued treatment. There were no reports of flushing, troubles of visual accommodation, hyperpyrexia. In group I we observed a mean decrease in urgency by 38.7%, a mean increase in maximal bladder capacity by 33.6% and the number of incontinence episodes decreased by 64.8%. In group II we observed equivalent values with a significant (p<0.001) change in maximal bladder capacity (49.7%), incontinence episodes (64.8%) and micturition episodes/24 h. CONCLUSIONS: The results of this retrospective analysis suggest that tolterodine is well tolerated in children and offers an effective treatment for urinary symptoms due to overactive bladder. Tolterodine is superior to non-selective antimuscarinic drugs, with respect to adverse events, allowing more compliance and more effective treatment in children.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14734013&dopt=Abstract tolterodine Detrol