Document Detail


Effect of fiduxosin, an antagonist selective for alpha(1A)- and alpha(1D)-adrenoceptors, on intraurethral and arterial pressure responses in conscious dogs.
MedLine Citation:
PMID:  11805208     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Fiduxosin is an alpha(1)-adrenoceptor antagonist with higher affinity for alpha(1A)-adrenoceptors and for alpha(1D)-adrenoceptors than for alpha(1B)-adrenoceptors. Our hypothesis is that such a compound with higher affinity for subtypes implicated in the control of lower urinary tract function and lower affinity for a subtype implicated in the control of arterial pressure could result in a superior clinical profile for the treatment of lower urinary tract symptoms suggestive of benign prostatic obstruction. The purpose of this study was to evaluate the potency and selectivity of fiduxosin for effects on prostatic intraurethral pressure (IUP) versus mean arterial pressure (MAP) relative to current clinical standards, terazosin and tamsulosin, in conscious dogs. Phenylephrine (PE)-induced increases in IUP and MAP were determined before and at various time points after an oral dose of each antagonist. Hypotensive potency was also determined. All three antagonists caused dose- and time-dependent blockade of the IUP and MAP pressor effects of PE. The IUP ED(50) values of fiduxosin, tamsulosin, and terazosin were 0.24, 0.004, and 0.23 mg/kg p.o., respectively. The corresponding MAP ED(50) values were 1.79, 0.006, and 0.09 mg/kg p.o. The rank order of IUP selectivity (ratio) was fiduxosin (7.5-fold), tamsulosin (1.5-fold), and terazosin (0.4 = 2.5-fold MAP-selective). Tamsulosin and terazosin caused dose-dependent hypotension, whereas no change in arterial pressure was seen after fiduxosin. These data, illustrating a superior selectivity profile of fiduxosin, are consistent with our hypothesis.
Authors:
Michael E Brune; Sweta P Katwala; Ivan Milicic; David G Witte; James F Kerwin; Michael D Meyer; Arthur A Hancock; Michael Williams
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  300     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2002 Feb 
Date Detail:
Created Date:  2002-01-25     Completed Date:  2002-02-25     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  487-94     Citation Subset:  IM    
Affiliation:
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-6118, USA. michael.e.brune@abbott.com
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MeSH Terms
Descriptor/Qualifier:
Adrenergic alpha-Agonists / pharmacology
Adrenergic alpha-Antagonists / pharmacology*
Animals
Blood Pressure / drug effects*
Dogs
Dose-Response Relationship, Drug
Heterocyclic Compounds, 3-Ring / pharmacology
Male
Phenylephrine / antagonists & inhibitors,  pharmacology
Prazosin / analogs & derivatives*,  pharmacology
Prostate / blood supply,  drug effects
Pyrimidinones / pharmacology
Receptors, Adrenergic, alpha-1 / antagonists & inhibitors*
Regional Blood Flow / drug effects
Sulfonamides / pharmacology
Urethra / blood supply,  drug effects*
Chemical
Reg. No./Substance:
0/3-(4-(9-methoxy-1,2,3,3a,4,9b-hexahydro(1)benzopyran(3,4-c)pyrrol-2-yl)butyl)-8-phenylpyrazino(2',3'-4,5)thieno(3,2-d)pyrimidine-2,4(1H,3H)-dione; 0/Adrenergic alpha-Agonists; 0/Adrenergic alpha-Antagonists; 0/Heterocyclic Compounds, 3-Ring; 0/Pyrimidinones; 0/Receptors, Adrenergic, alpha-1; 0/Sulfonamides; 0/adrenergic receptor alpha(1a); 0/adrenergic receptor alpha(1d); 106133-20-4/tamsulosin; 19216-56-9/Prazosin; 59-42-7/Phenylephrine; 63590-64-7/Terazosin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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