Detrol
Effect of muscarinic antagonists on micturition pressure measured by cystometry in normal, conscious rats.

Modiri AR, Alberts P, Gillberg PG.

Department of Pharmacology, Biovitrum, Uppsala, Sweden.

OBJECTIVES: To establish an in vivo model to screen new muscarinic antagonists for the treatment of overactive urinary bladder and to calculate the respective ID(50) values. METHODS: The conscious rat cystometry model was modified to determine a complete dose-response curve in each animal. Spontaneous micturition was induced by infusion of room-temperature saline into rat bladders at a constant rate of 12 mL/hr. Cumulative doses of muscarinic antagonists administered in the femoral vein caused dose-dependent inhibition of the urinary bladder contraction measured as the micturition pressure. In addition, the in vitro pK(B) values for atropine, PNU-200577 (DD01), tolterodine, oxybutynin, and terodiline were determined in carbachol-contracted rat bladder strips. RESULTS: The rank order of the in vivo ID(50) values were atropine (14 +/- 4 nmol/kg), PNU-200577 (22 +/- 12 nmol/kg), tolterodine (94 +/- 20 nmol/kg), oxybutynin (175 +/- 89 nmol/kg), darifenacin (236 +/- 144 nmol/kg), desethyloxybutynin (313 +/- 209 nmol/kg), propiverine (4561 +/- 2079 nmol/kg), and terodiline (18,339 +/- 5348 nmol/kg). Tolterodine and PNU-200577 caused a parallel shift of the in vitro concentration-response curve to the right and did not alter the maximal contraction. The ID(50) values correlated significantly with the in vitro rat pK(B) and human bladder pA(2) values. CONCLUSIONS: The present results suggest that the rat cystometry model can be used in in vivo screening for new muscarinic antagonists.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12031395&dopt=Abstract tolterodine Detrol



Detrol
Tolterodine and its active 5-hydroxymethyl metabolite: pure muscarinic receptor antagonists.

Nilvebrant L.

Nilvebrant Pharma Consulting AB, Bromma, Sweden. lisbeth.nilvebrant telia.com

Tolterodine and its major active 5-hydroxymethyl metabolite (5-HM) are potent muscarinic receptor antagonists that show selectivity for the urinary bladder over salivary glands in vivo. This tissue selectivity cannot be attributed to muscarinic receptor subtype selectivity, since both compounds are non-selective with respect to the M1-M5 receptor subtypes. The aim of the present in vitro study was to determine the specificity of tolterodine and 5-HM for muscarinic receptors compared to other potential cellular targets. Carbachol-induced contractions of isolated guinea pig bladder were effectively inhibited by tolterodine (IC50 14 nM) and 5-HM (IC50 5.7 nM). Tolterodine and 5-HM were weak inhibitors of effects mediated by alpha-adrenergic receptors (rat portal vein), histamine receptors (guinea pig ileum) and calcium channels (guinea pig potassium-depolarised urinary bladder, spontaneously beating right atria and electrically-driven right papillary muscle). The IC50 values were in the microM range and the antimuscarinic potency of tolterodine was 27, 200 and 370-485 times higher, respectively, than its potency in blocking histamine receptors, alpha-adrenoceptors and calcium channels. The active metabolite, 5-HM, was >900 times less potent at these sites than at bladder muscarinic receptors. Radioligand binding data on 54 different receptors and binding sites showed that tolterodine and 5-HM bind with significant affinity only at muscarinic receptors. In conclusion, the results of the present study indicate that both tolterodine and 5-HM are specific muscarinic receptor antagonists. The tissue selectivity of these agents in vivo cannot therefore be explained by secondary pharmacological actions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12076307&dopt=Abstract tolterodine Detrol



Detrol
Does gender or age affect the efficacy and safety of tolterodine?

Michel MC, Schneider T, Krege S, Goepel M.

Department of Medicine, University of Essen, Essen, Germany.

PURPOSE: We compared the importance of patient age and gender relative to the intensity of baseline symptoms of overactive bladder in the therapeutic response to the muscarinic receptor antagonist tolterodine. MATERIALS AND METHODS: Data from an open label, observational study of 2,250 patients with overactive bladder treated for 12 weeks with tolterodine were analyzed for alterations in frequency, urgency and urge incontinence, and for global efficacy and tolerability using logistic regression analysis, stratifying for gender, age, baseline symptom intensity and tolterodine dose. RESULTS: Gender or tolterodine dose were not consistently associated with altered treatment efficacy. Greater age was associated with a slight but statistically significant decrease in treatment efficacy. Patients with great baseline symptom intensity had greater treatment associated improvement but a lesser chance to become symptom-free. Even with a large number of patients no statistically significant gender or age associated alterations in the tolerability of tolterodine treatment were detected. CONCLUSIONS: The extent of the therapeutic response to tolterodine is largely determined by the extent of baseline symptoms. While gender does not affect the efficacy or tolerability of tolterodine in a clinically relevant manner, advanced age is associated with a slight decrease in efficacy but not in tolerability.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12187215&dopt=Abstract tolterodine Detrol



Detrol
The subtypes of muscarinic receptors for neurogenic bladder contraction in rats.

Hirose H, Aoki I, Kimura T, Fujikawa T, Numazawa T, Sasaki K, Nishikibe M, Noguchi K.

Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Okubo 3, Ibaraki, Tsukuba 300-2611, Japan.

We evaluated in vivo functional selectivity profiles for muscarinic M(2) and M(3) subtypes of four muscarinic antagonists: Compound A (a novel muscarinic receptor antagonist with M(2)-sparing antagonistic activity), darifenacin, (a muscarinic M(3) receptor antagonist); methoctramine (a muscarinic M(2) receptor antagonist) and tolterodine (a nonselective muscarinic receptor antagonist), and compared the inhibition potency on distention-induced bladder contraction in rats. In an in vivo functional study, Compound A (0.03-10 mg/kg, i.v.) showed antimuscarinic activity with high selectivity for M(3) (salivation) over M(2) (bradycardia) (>100-fold). Darifenacin (0.01-0.3 mg/kg, i.v.) showed only slight selectivity for M(3) over M(2) (3.7-fold). Methoctramine (0.003-1 mg/kg, i.v.) showed the reverse selectivity profile (0.077-fold). Tolterodine (0.003-0.3 mg/kg, i.v.) showed less selectivity (1.2-fold). Compound A at M(3) inhibitory doses (0.1 and 0.3 mg/kg, i.v.) showed inhibition in a distention-induced neurogenic bladder contraction model, and its maximal inhibitory effects were about 60% at an even higher dose (3 mg/kg). Methoctramine at M(2) inhibitory doses (0.03 and 0.1 mg/kg, i.v.) did not significantly affect distention-induced bladder contraction. When tolterodine and darifenacin caused inhibition of distention-induced bladder contraction, its maximal inhibitory effects were similar to that of Compound A. Therefore, these findings suggest that Compound A would be an excellent pharmacological tool to give a better understanding of which subtypes of muscarinic receptors act in bladder function so far, and muscarinic M(3), but not M(2), receptors mainly mediate the cholinergic component of distention-induced bladder contraction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12354576&dopt=Abstract tolterodine Detrol