Detrol
Different responses to drugs against overactive bladder in detrusor muscle of pig, guinea pig and mouse.

Wust M, Averbeck B, Reif S, Brater M, Ravens U.

Institute of Pharmacology and Toxicology, Faculty of Medicine, Dresden University of Technology, Fetscherstrasse 74, Dresden D-01307, Germany.

Direct comparison of experimental data for drugs commonly used in the treatment of overactive bladder is difficult because of possible species differences. In this study, we compare the effects of atropine, propiverine, oxybutynin and tolterodine in strips of pig, guinea pig and mouse detrusor muscle. In the three species, we observed slight differences in potency of carbachol-induced biphasic contractile responses between the species (guinea pig>pig>mouse). Cumulative concentration-response curves for carbachol were shifted to the right by atropine, propiverine, oxybutynin and tolterodine. However, at higher concentrations of the latter three antagonists, the maximum response to carbachol was also reduced. Therefore, propiverine, oxybutynin and tolterodine must have additional pharmacological actions beyond competitive antagonism at muscarinic receptors. Electric field stimulation (30 Hz) of detrusor strips led to contraction amplitudes, which remained constant over time (210 min) in pig, decreased by 17+/-5% in guinea pig, and increased by 28+/-9% in mouse detrusor muscle. Electric field stimulation-evoked contractions were suppressed to 18% of pre-drug control by high concentrations of atropine (10 microM) in pig, but to a much lesser extent in guinea pig and mouse (to 46% and 70%, respectively). In all three species, a myogenic component of contraction was observed in the presence of tetrodotoxin (1 microM). Compared to atropine, the bladder spasmolytic agents propiverine, oxybutynin and tolterodine also reduced electrically evoked contractions in the three species, though higher concentrations were required. The differences in the reported effects of the spasmolytic agents commonly used for treating overactive bladder suggest that drug action is strongly dependent on the species. Thus, a comparison of drug effects is only feasible in the same animal model and the results cannot easily be transferred to humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12409006&dopt=Abstract tolterodine Detrol



Detrol
Effects of ATP-sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction.

Fey TA, Gopalakrishnan M, Strake JG, King LL, Brioni JD, Sullivan JP, Coghlan MJ, Brune ME.

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6118, USA. tom.a.fey abbott.com

AIMS: To compare in vivo the efficacy, potency, and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs), YM934 and (-)-cromakalim to a muscarinic antagonist, tolterodine in a novel partial outlet obstructed pig model. METHODS: Partially obstructed female Landrace pigs were implanted with telemetry transmitters to allow the continuous measurement of intravesical, abdominal and arterial pressures. A subcutaneous port catheter was used to adjust bladder volume. Bladder and arterial pressure were simultaneously monitored under isoflurane anesthesia before and after increasing i.v. doses of test compounds. RESULTS: Under anesthesia, voiding was completely inhibited, but spontaneous, nonvoiding bladder contractions were observed with mean amplitude of 16 +/- 1 cm H(2)O, duration of 35 +/- 2 seconds, and intercontraction interval of 43 +/- 4 seconds (n = 25). YM934 and (-)-cromakalim both caused dose-dependent decreases in bladder contraction area under the curve (AUC) with effective doses to inhibit AUC by 35% of 3.6 and 14.9 nmol/kg, i.v., respectively. However, concomitant reductions in mean arterial pressure of 12 and 13% were also observed. Tolterodine did not inhibit spontaneous bladder contractions at doses up to 100 nmol/kg, i.v. corresponding to plasma concentrations up to 41 ng/mL. CONCLUSIONS: The superior efficacy of KCOs to inhibit spontaneous bladder contractions relative to tolterodine support the hypothesis that KCOs may provide an alternate therapeutic mechanism to treat symptoms of overactive bladder if bladder-vascular selectivity can be sufficiently improved. The minimally invasive model described herein appears useful in the preclinical evaluation of potential therapeutics targeted to treat the overactive bladder. Copyright 2003 Wiley-Liss, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12579633&dopt=Abstract tolterodine Detrol



Detrol
The use of tolterodine in children after oxybutynin failure.

Bolduc S, Upadhyay J, Payton J, Bagli DJ, McLorie GA, Khoury AE, Farhat W.

Division of Urology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

OBJECTIVE: To assess the safety and efficacy of tolterodine tartrate prescribed to children who previously failed to tolerate oxybutynin chloride. PATIENTS AND METHODS: We reviewed 34 children, followed for>1 year, who were prospectively crossed-over from oxybutynin to tolterodine because of side-effects. The initial diagnosis was dysfunctional voiding in 31 patients. All patients were placed on a behavioural modification protocol. When their symptoms did not improve after 6 months, treatment with an anticholinergic agent was considered. Urodynamic studies were conducted in 20 patients, confirming uninhibited contractions in 19. The remaining 14 patients were empirically started on antimuscarinic or anticholinergic agents. The 34 patients were treated with oxybutynin for a median (range) of 6 (2-84) months. When significant side-effects were reported, they were crossed over to tolterodine. The efficacy of tolterodine was assessed as defined by the International Children's Continence Society, with tolerability assessed and side-effects documented using a questionnaire. RESULTS: The mean age at the first dose of tolterodine was 8.9 years; the dose was 1 mg twice daily for 12 patients and 2 mg twice daily for 22. The median treatment with tolterodine was 11.5 months, with 20 (59%) patients reporting no side-effects; six described the same but tolerable side-effects as with oxybutynin. Eight patients discontinued tolterodine because of side-effects after a median (range) of 5 (1-11) months. The efficacy of tolterodine was comparable with that of oxybutynin, as reported by the questionnaire and voiding diaries. The reduction in wetting episodes at 1 year was> 90% in 23 (68%), more than half in five and less than half (or failure) in six patients. CONCLUSION: Tolterodine is tolerated well in children. In this subgroup of patients who could not tolerate oxybutynin, 77% were able to continue tolterodine treatment with no significant side-effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12603422&dopt=Abstract tolterodine Detrol



Detrol
Implementation of a nursing home urinary incontinence management program with and without tolterodine.

Ouslander JG, Maloney C, Grasela TH, Rogers L, Walawander CA.

Wesley Woods Center of Emory University and the Atlanta Veterans Administration Rehabilitation Research and Development Center, Atlanta, GA 30329-5102, USA.

OBJECTIVE: To evaluate the implementation of a nursing home urinary incontinence management program. DESIGN: A prospective field trial of the program incorporating practice guidelines and principles of continuous quality improvement. SETTING: Five nursing homes in New York, Virginia, and Georgia PARTICIPANTS: One hundred fifty-one residents identified as being incontinent of urine and who met inclusion criteria for ongoing participation in the program. INTERVENTION: Key multidisciplinary staff from the five nursing homes were trained in the program and assumed responsibility for implementing it in their facilities. The program consisted of a clinical assessment, toileting protocols, and the addition of the antimuscarinic drug tolterodine in selected residents who did not respond well to toileting alone. Data on dryness rates during the 60-day toileting protocols, collected by nursing home staff, were analyzed on a weekly basis by an overall project coordinator who sent data back to the nursing homes in an easy-to-read graphical format. MEASURES: (1) The dryness rate, defined as the number of times the resident was dry divided by the number of times the resident was checked (every 2 hours from 7 a.m. to 7 p.m.); and (2) adverse events (eg, dry mouth, increased confusion, need for dosage reduction). RESULTS: Of 645 residents in the 5 nursing homes, 377 (58%) were identified as incontinent of urine, of whom 151 (40%) were placed on an ongoing toileting program. Of these 151 residents, 48 (32%) were prescribed tolterodine, and 117 (78%) completed the 60-day trial. The initial dryness rate was 57%, and for the group as a whole remained essentially unchanged (increase in dryness 1%, P = 0.50). Among 50 clinically stable residents on a toileting program alone, the increase in the dryness rate was 16% (P = 0.001), and for 31 clinically stable residents prescribed tolterodine, the increase in the dryness rate was 29% (P = 0.012). Two residents had their dosage of tolterodine reduced because of dry mouth and nausea,one resident was taken off the drug because of increased pain in the back and legs and increased confusion. CONCLUSIONS: Overall, this program resulted in significant increases in dryness rates for clinically stable incontinent nursing home residents. These residents represented 22% of the total number of residents identified as incontinent in the five participating nursing homes. Tolterodine was prescribed for approximately one-third of incontinent residents as a supplement to a toileting program, and was well tolerated. Nursing homes should be encouraged to implement similar urinary incontinence programs, target toileting protocols to the most responsive residents, and maintain the program using principles of continuous quality improvement.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12812542&dopt=Abstract tolterodine Detrol