PB, thanks for looking up the abstracts (posted below). A couple of interesting things jump out, at least to this NB (Non Biologist).
1 - first abstract compares Tolterodine with oxybutynin. In this pre-clinical model, both appear to have similar efficacy.
2 - second abstract provides minimal information ... from a clinical trial
3 - third abstract talks about a PNU pipeline product, their own "ICE", cf from the abstract: "A major active metabolite, (PNU-200577) the 5-hydroxymethyl
derivative of tolterodine, has a similar pharmacological profile. Based
on pharmacological and pharmacokinetic data, it has been concluded that
this metabolite contributes significantly to the therapeutic effect of
tolterodine."
Peter
.
ncbi.nlm.nih.gov
Eur J Pharmacol 1997 May 30;327(2-3):195-207
Tolterodine--a new bladder-selective antimuscarinic agent.
Nilvebrant L, Andersson KE, Gillberg PG, Stahl M, Sparf B
Medical Department Urology, Pharmacia & Upjohn AB, Uppsala, Sweden.
Tolterodine is a new muscarinic receptor antagonist intended for the
treatment of urinary urge incontinence and other symptoms related to an
overactive bladder. The aim of the present study was to compare the
antimuscarinic properties of tolterodine with those of oxybutynin, in
vitro and in vivo. Tolterodine effectively inhibited carbachol-induced
contractions of isolated strips of urinary bladder from guinea pigs
(K(B) 3.0 nM; pA2 8.6; Schild slope 0.97) and humans (K(B) 4.0 nM; pA2
8.4; Schild slope 1.04) in a concentration-dependent, competitive
manner. The affinity of tolterodine was similar to that derived for
oxybutynin (K(B) 4.4 nM; pA2 8.5; Schild slope 0.89) in the guinea-pig
bladder. Tolterodine (21-2103 nmol/kg (0.01-1 mg/kg); intravenous
infusion) was significantly more potent in inhibiting
acetylcholine-induced urinary bladder contraction than
electrically-induced salivation in the anaesthetised cat. In contrast,
oxybutynin displayed the opposite tissue selectivity. Radioligand
binding data showed that tolterodine bound with high affinity to
muscarinic receptors in urinary bladder (K(i) 2.7 nM), heart (K(i) 1.6
nM), cerebral cortex (K(i) 0.75 nM) and parotid gland (K(i) 4.8 nM) from
guinea pigs and in urinary bladder from humans (K(i) 3.3 nM). Tolterod
ine and oxybutynin were equipotent, except in the parotid gland, where
oxybutynin bound with 8-times higher affinity (K(i) 0.62 nM). Binding
data on human muscarinic m1-m5 receptors expressed in Chinese hamster
ovary cells showed that oxybutynin, in contrast to tolterodine, exhibits
selectivity (10-fold) for muscarinic m3 over m2 receptors. The K(B)
value determined for oxybutynin (4.4 nM) in functional studies on
guinea-pig bladder correlated better with the binding affinity at
muscarinic M2/m2 receptors (K(i) 2.8 and 6.7 nM) than at muscarinic
M3/m3 receptors (K(i) 0.62 and 0.67 nM). The tissue selectivity
demonstrated for tolterodine in vivo cannot be attributed to selectivity
for a single muscarinic receptor subtype. However, the combined in vitro
and in vivo data on tolterodine and oxybutynin may indicate either that
muscarinic M3/m3 receptors in glands are more sensitive to blockade than
those in bladder smooth muscle, or that muscarinic M2/m2 receptors
contribute to bladder contraction.
PMID: 9200560, UI: 97344033
ncbi.nlm.nih.gov
World J Urol 1997;15(2):144-151
Efficacy and safety of two doses of tolterodine versus placebo in
patients with detrusor overactivity and symptoms of frequency, urge
incontinence, and urgency: urodynamic evaluation. The International
Study Group.
Jonas U, Hofner K, Madersbacher H, Holmdahl TH
Department of Urology, Hannover Medical School, Germany.
Tolterodine is a new competitive muscarinic receptor antagonist
developed for the treatment of the unstable bladder. A total of 242
patients were enrolled in a multicenter, multinational, randomized,
double-blind, placebo-controlled study conducted over a period of 4
weeks in patients with detrusor overactivity and symptoms of frequency,
urgency, and urge incontinence. The objective of the study was to
compare the efficacy and safety of tolterodine given at 1 or 2 mg b.i.d.
versus placebo. At week 4 a statistically significant increase in the
volume at first contraction (p = 0.030) and maximal cystometric capacity
(p = 0.034) was only in the tolterodine 2 mg b.i.d. group. Tolterodine
was safe and generally well tolerated. The incidence of dry mouth, as
the most commonly reported adverse event, was only 9% and of mild to
moderate intensity.
Publication Types:
_Clinical trial
_Multicenter study
_Randomized controlled trial
Published erratum appears in World J Urol 1997;15(3):210
PMID: 9144906, UI: 97290150
ncbi.nlm.nih.gov
Life Sci 1997;60(13-14):1129-1136
Tolterodine--a new bladder selective muscarinic receptor antagonist:
preclinical pharmacological and clinical data.
Nilvebrant L, Hallen B, Larsson G
Medical Dept. Urology, Pharmacia & Upjohn, Uppsala, Sweden.
Tolterodine is a new, potent and competitive muscarinic receptor
antagonist in clinical development for the treatment of urge
incontinence and other symptoms of unstable bladder. Tolterodine has a
high affinity and specificity for muscarinic receptors in vitro and it
exhibits a selectivity for the urinary bladder over salivary glands in
vivo. A major active metabolite, (PNU-200577) the 5-hydroxymethyl
derivative of tolterodine, has a similar pharmacological profile. Based
on pharmacological and pharmacokinetic data, it has been concluded that
this metabolite contributes significantly to the therapeutic effect of
tolterodine. The bladder selectivity demonstrated by tolterodine and
PNU-200577 in vivo cannot be attributed to selectivity for a single
muscarinic receptor subtype. Moreover, this favourable
tissue-selectivity seems to occur also in humans. Tolterodine is well
tolerated and it exerts a marked effect on bladder function in healthy
volunteers. Phase II data indicate that tolterodine is an efficacious
and safe treatment for patients with idiopathic detrusor instability or
detrusor hyperreflexia. An optimal efficacy/side-effect profile is
obtained with tolterodine, at a dosage of 1 or 2 mg twice daily, which
seems to have less propensity to cause dry mouth than the currently
available antimuscarinic drugs.
Publication Types:
_Review
_Review, tutorial
PMID: 9121357, UI: 97236692 |
