Detrol
Comparison of the effects of novel antimuscarinic drugs on human detrusor smooth muscle.

Yono M, Yoshida M, Takahashi W, Inadome A, Ueda S.

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

OBJECTIVE: To evaluate the effects of tolterodine, vamicamide and temiverine, novel antimuscarinic drugs developed for the treatment of frequency and urinary incontinence, on human detrusor smooth muscle. Materials and methods Specimens of human urinary bladder were obtained from 20 patients who underwent total cystectomy for malignant bladder tumour. Using an organ-bath technique, the effects of various drugs on the contractions induced by carbachol, KCl, CaCl2 and electrical field stimulation in the detrusor strips were investigated. RESULTS: Carbachol (0.001-10000 micromol/L) caused concentration-dependent contractions in human detrusor smooth muscles. Tolterodine (0.01-10 micromol/L), vamicamide (0.01-10 micromol/L), temiverine (0.01-1 micromol/L) and atropine (0.001-1 micromol/L) caused parallel shifts to the right of the concentration-response curves to carbachol. All slopes for the regression line of Schild plots were close to unity, and the rank order of pA2 values was atropine = tolterodine > vamicamide > temiverine. Tolterodine, vamicamide and atropine did not inhibit the maximum contractile responses to carbachol, while temiverine (10 micromol/L) significantly inhibited the maximum contractions. Tolterodine (0.001-1 micromol/L) and vamicamide (0.01-10 micromol/L) did not inhibit the KCl- (80 mmol/L) and CaCl2-induced (5 mmol/L) contractions, while temiverine (0.01-10 micromol/L) significantly inhibited the contractions. Electrical field stimulation (2-60 Hz) caused frequency-dependent contractions in human detrusor smooth muscles, which were significantly inhibited by various drugs. In the presence of 1 micromol/L atropine, tolterodine and vamicamide did not inhibit the contractions induced by electrical field stimulation at all frequencies, while temiverine (10 micromol/L) significantly inhibited the contractions. CONCLUSION: Tolterodine and vamicamide inhibited contractions of human detrusor smooth muscles only through their antimuscarinic action, while temiverine had both antimuscarinic and calcium-antagonist actions. Furthermore, these novel drugs have different efficacies and potencies for inhibiting human detrusor smooth muscle.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11069384&dopt=Abstract tolterodine Detrol



Detrol
Gender specificity of tolterodine on micturition and the diurnal variation of urine production of the conscious rat.

Yoshimura Y, Schmidt F, Constantinou CE.

Department of Urology, Fukushima Medical College, Fukushima, Japan.

OBJECTIVE: To evaluate the effect of the oral administration of tolterodine on the diurnal micturition characteristics of the male and female conscious rat, and to examine the relative effect of tolterodine in influencing water consumption and urine production. MATERIALS AND METHODS: Baseline micturition volume and frequency characteristics of nine male and 10 female Sprague-Dawley age-matched adult rats (body weight 399 +/- 15 and 249 +/- 3 g, respectively) were evaluated over 24-h. Initial hydration conditions were standardized with an oral dose (5 mL) of water. Rats were subsequently placed in a metabolic cage and had free access to water. Micturition volume/frequency characteristics were derived from the measurements of voided volume (measured using a digital balance below the metabolic cage and connected to a computer). The total volume of water consumed over the 24 h was also measured. Two separate baseline studies were conducted, followed by the administration of a single oral dose of 1 mg/mL of tolterodine dissolved in 5 mL of water. The mean frequency of micturition and mean volume voided per micturition were computed in 3-h periods and plotted over the 24-h period. In addition, the mean values of the number of micturitions and voided volumes during the day/dark cycle were evaluated. RESULTS: Baseline data showed that females (when corrected for body weight) consistently imbibed significantly more water (83%) than did male rats. Tolterodine did not significantly affect water consumption in the males but significantly reduced water consumption in females by 42%. Tolterodine did not significantly affect the amount of urine produced by male rats but significantly reduced the total amount of urine production in females by 26%. Tolterodine significantly increased the number of voids in male rats compared with baseline during the day but not during the night. More importantly tolterodine produce no significant effect on the volume voided per micturition in male rats either during the day or night cycle, but significantly decreased the volume voided per micturition in females. CONCLUSIONS: These results suggest that the effect of tolterodine on micturition is gender-specific, suppressing water consumption and urine production in female but not male rats, and decreasing bladder volume. There is a possibility that the reported clinical effects of tolterodine arise through the suppression of fluid consumption.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11069417&dopt=Abstract tolterodine Detrol



Detrol
Use of tolterodine in children with dysfunctional voiding: an initial report.

Munding M, Wessells H, Thornberry B, Riden D.

Section of Urology, The University of Arizona College of Medicine, Tucson, Arizona, USA.

PURPOSE: Tolterodine was recently approved for the treatment of incontinence and overactive bladder in adults, and has fewer side effects than oxybutynin. We evaluated the safety and efficacy of tolterodine in children with dysfunctional voiding. MATERIALS AND METHODS: We retrospectively reviewed our experience with 30 pediatric patients treated with tolterodine for a primary diagnosis of dysfunctional voiding. Patients were treated with adult doses of tolterodine and behavioral modifications. Standard definitions determined by the International Children's Continence Society were adapted to designate final treatment outcomes on medication as cured-greater than 90% reduction in wetting episodes, improved-greater than 50% reduction or failed-less than 50% reduction. RESULTS: The children were 4 to 17 years old (mean age 8.7) and were treated with tolterodine for an average of 5.2 months. The final dose was 1 mg. twice daily in 1, 2 mg. twice daily in 27 and 4 mg. twice daily in 2 patients. Wetting episodes were cured in 10 (33%), improved in 12 (40%), and failed to show improvement in 8 (27%) cases. Four patients (13.3%) reported side effects and only 1 discontinued the medication due to diarrhea. There were no reports of hyperpyrexia, flushing or intolerance to sunshine and outdoor temperature. CONCLUSIONS: Our results demonstrate that tolterodine at adult doses without titration can be used safely to decrease wetting episodes in children with dysfunctional voiding. Controlled clinical trials should be completed to evaluate further efficacy and safety in children.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11176516&dopt=Abstract tolterodine Detrol



Detrol
M3 muscarinic receptors but not M2 mediate contraction of the porcine detrusor muscle in vitro.

Sellers DJ, Yamanishi T, Chapple CR, Couldwell C, Yasuda K, Chess-Williams R.

Department of Biomedical Science, University of Sheffield, UK.

1. The objective of the study was to determine the role of muscarinic receptor subtypes in mediating contraction of the porcine detrusor smooth muscle in vitro. 2. Strips of pig detrusor muscle were set up in physiological salt solution and the tensions developed by the tissues were recorded. Responses to carbachol were obtained in the absence and presence of a range of muscarinic antagonists (4-DAMP, methoctramine, darifenacin, oxybutynin, tolterodine and pirenzepine). Antagonist affinity values (pKB values) were calculated and compared with those quoted in the literature for these antagonists at each of the muscarinic receptor subtypes. 3. The M3-selective antagonists, 4-DAMP and darifenacin had high affinities (pKB values of 9.4 and 8.6, respectively). Oxybutynin, tolterodine and pirenzepine had affinities of 8.2, 8.1 and 6.8, respectively, whilst the M2-selective agent methoctramine had a relatively low affinity (pKB = 6.1). The rank order of affinities was, therefore, 4-DAMP > darifenacin > oxybutynin > tolterodine > pirenzepine > methoctramine for the pig detrusor. Correlation of the antagonist affinities obtained on the bladder with those published for these antagonists at the five muscarinic receptor subtypes identified the M3(m3)-receptor as the muscarinic subtype mediating detrusor contractile responses in vitro. 4. These data suggest that a small population of M3-muscarinic receptors must mediate direct contractile responses of the pig detrusor muscle to muscarinic receptor stimulation in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11193006&dopt=Abstract tolterodine Detrol