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Antimuscarinic Drugs (antimuscarinic + drug)

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Medical Sciences	100%

Selected Abstracts

Antimuscarinic drugs in detrusor overactivity and the overactive bladder syndrome: motor or sensory actions?

BJU INTERNATIONAL, Issue 3 2006
STEVEN M. FINNEY
Antimuscarinic drugs are generally thought to exert their therapeutic action on detrusor overactivity by reducing the ability of the detrusor muscle to contract. We review currently available published data to establish whether there is any evidence to support this contention. Using a PubMed data search, only 14 original articles (including two abstracts) were found that contained cystometric data for both filling and voiding phases and where the actions of antimuscarinic drugs have been reported in detail. These articles were separated into three groups dealing with neuropathic patients (three papers), patients with idiopathic overactive bladder (four papers) and a group whose aetiology was unclear (seven papers). Variables relating to bladder function during the filling phase (time of first desire to void, time to first unstable contraction, and bladder capacity) were identified. Similarly, variables relating to voiding were identified and compared (e.g. maximum detrusor pressure and detrusor pressure at maximum flow rate). The antimuscarinic drugs have a clearly significant effect on sensations of urge, time to first sensation to void, maximum bladder capacity, decrease in voiding frequency and reduction in incontinence episodes. However, only one article (studying neuropaths) reported a significant reduction of the variables associated with detrusor contraction. The remaining four studies (idiopaths/not stated), reported no change in bladder contractility with antimuscarinic drugs. Thus the available data do not support the conclusion that antimuscarinic drugs at doses used in current clinical practice exert their therapeutic action by inhibiting detrusor contractility, but they suggest effects on variables associated with sensation. [source]

Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivo

BJU INTERNATIONAL, Issue 8 2008
Peter Ney
OBJECTIVE To investigate the primary pharmacology of fesoterodine (a novel antimuscarinic drug developed for treating overactive bladder) and SPM 7605 (its active metabolite, considered to be the main pharmacologically active principle of fesoterodine in man) against human muscarinic receptor subtypes, and to investigate in vitro and in vivo functional activity of these agents on the rat bladder compared with existing standard agents. MATERIALS AND METHODS The displacement of radioligand binding by fesoterodine, SPM 7605 and standard agents in membrane preparations of Chinese hamster ovary (CHO) cells expressing the different human muscarinic receptors (M1,M5) was characterized. Agonistic and antagonistic activities were studied using different CHO cell lines stably expressing the human recombinant muscarinic receptor subtypes. The effects of fesoterodine and SPM 7605 on isolated bladder strips contracted by carbachol or electrical field stimulation (EFS) were investigated. In vivo the effects of fesoterodine and SPM 7605 on micturition variables were assessed using continuous cystometry in conscious female Sprague-Dawley rats, and compared to those of oxybutynin and atropine. RESULTS In vitro SPM 7605 potently inhibited radioligand binding at all five human muscarinic receptor subtypes with equal affinity across all five. Fesoterodine had a similar balanced selectivity profile but was less potent than SPM 7605. Both substances were competitive antagonists of cholinergic agonist-stimulated responses in human M1-M5 cell lines and had a similar potency and selectivity profile to the radioligand-binding studies. In rat bladder strips, fesoterodine and SPM 7605 caused a rightward shift of the concentration-response curve for carbachol with no depression of the maximum, and concentration-dependently reduced contractions induced by EFS. The potency of both drugs was similar to that of atropine and oxybutynin. In the presence of the esterase inhibitor neostigmine, the concentration-response curve of fesoterodine was shifted to the right, suggesting that part of the activity was caused by metabolism to SPM 7605 by tissue enzymes. In vivo, low doses (0.01 mg/kg) of fesoterodine and SPM 7605 reduced micturition pressure and increased intercontraction intervals and bladder capacity, but did not affect residual volume. CONCLUSIONS Fesoterodine and its active metabolite, SPM 7605, are nonsubtype selective, competitive antagonists of human muscarinic receptors, but SPM 7605 has greater potency than the parent compound. Pharmacodynamic studies in the rat bladder in vitro confirm the competitive muscarinic antagonist profile of these agents in a native tissue preparation, and in vivo studies in the rat showed effects on bladder function consistent with a muscarinic antagonist profile. [source]

New once-daily formulation for trospium in overactive bladder

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 11 2010
C. Chapple
Summary Aims:, We examined the relative efficacy and safety of trospium 20 mg bid and 60 mg extended release formulations and position this drug against other antimuscarinic agents. Methods:, Data were identified on the pharmacology and pharmacokinetics of trospium chloride. Key publications on trospium 20-mg and 60-mg clinical studies in patients with overactive bladder (OAB) were identified and efficacy and safety compared between these formulations as well as other antimuscarinic agents. Results:, Trospium offers the principal advantage over other antimuscarinic agents that, as it is a quaternary amine, it does not cross the blood,brain barrier and is therefore less likely to cause central nervous system effects observed with several other agents. Moreover, with its minimal liver metabolisation, independent of the main cytochrome pathways, trospium has a low risk of drug,drug interaction in patients taking multiple pharmacological agents. Trospium 60 mg ER is as effective as trospium 20 mg bid in improving the key outcome parameters associated with OAB, but with a lower rate of dry mouth, the most common side effect of these agents. Trospium has comparable efficacy and safety to the other antimuscarinic agents currently marketed. Discussion:, Good patient persistence with treatment has been reported with trospium. There are currently a large number of antimuscarinic drugs on the market without clear evidence to distinguish one agent from another in terms of efficacy, provided that an adequate dose is used in the clinical setting. Conclusion:, The new formulation of trospium is certainly worth considering as a pharmacological treatment of patients with OAB, particularly in the elderly, in whom one wants to avoid the potential for cognitive dysfunction. [source]

Detection of muscarinic receptor subtypes in human urinary bladder mucosa: Age and gender-dependent modifications,,§

NEUROUROLOGY AND URODYNAMICS, Issue 5 2008
Nicola Arrighi
Abstract Aims Muscarinic receptor subtypes expressed in the human urinary bladder mucosa were characterized, investigating whether there were gender-dependent differences and if aging could induce changes in their expression. Methods The study was carried out on 34 subjects, 22 men and 12 women, divided in four groups, based on gender and age. Gene expression was evaluated by quantitative RT-PCR. The Western blot was performed using the 4,12% NuPAGE Bis,Tris Gel System. Results The molecular expression of each subtype of the M1 receptor family was observed and it was not influenced either by gender or age. M2 receptor family transcripts revealed that both M2 and M4 were detected and that the M2 transcripts were modified by both gender and age. Indeed, M2 mRNA was lower in old rather than adult men (P,<,0.05), but higher in rather old than adult women (P,<,0.05). Further, adult men expressed more M2 mRNA than adult women (P,<,0.05), while the opposite was detected in old age (P,<,0.05). The Western blot followed by quantification confirmed that the mRNAs were translated into proteins, and that the M2 subtype showed similar modifications found at molecular level. Discussion The selective modification of M2 receptors observed at the urinary bladder mucosa levels indicates that this anatomical structure could play an active role in the pathophysiology of micturition and supports evidence suggesting an effect of antimuscarinic drugs at this level. Whether these results may influence the age-dependent development of micturition disorders remains to be determined. Neurourol. Urodynam. 27:421,428, 2008. © 2007 Wiley-Liss, Inc. [source]