Document Detail

Restenosis following angioplasty in the swine coronary artery is inhibited by an orally active PDGF-receptor tyrosine kinase inhibitor, RPR101511A.
MedLine Citation:
PMID:  10385505     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Platelet-derived growth factor (PDGF), a purported mediator of arterial response to injury, stimulates proliferation, chemotaxis, and matrix production by activation of its membrane receptor tyrosine kinase. Because these activities underlie restenosis, inhibition of the PDGF-receptor tyrosine kinase (PDGFr-TK) is postulated to decrease restenosis. METHODS AND RESULTS: RPR101511A is a novel compound which selectively and potently inhibits the cell-free and in situ PDGFr-TK and PDGFr-dependent proliferation and chemotaxis in vascular smooth muscle cells (VSMC). To evaluate the effect of RPR101511A (30 mg. kg-1. d-1 BID for 28 days following PTCA) on coronary restenosis, PTCA was performed in hypercholesterolemic minipigs whose left anterior descending (LAD) coronary artery had been injured by overdilation and denudation, yielding a previously existing lesion. Angiographically determined prePTCA minimal lumen diameters (MLD) were similar in vehicle and RPR101511A-treated pigs (1.98+/-0.09 versus 2.01+/-0.08 mm) and increased to the same extent in the 2 groups following successful PTCA (2.30+/-0.06 versus 2.52+/-0.13). At termination, there was an average 50% loss of gain in the vehicle-treated group but no loss of gain with RPR101511A (2.16+/-0. 05 versus 2.59+/-0.11, P<0.001). Morphometric analysis of the LAD showed that RPR101511A caused a significant decrease in total intimal/medial ratio (0.96+/-0.58 versus 0.67+/-0.09, P<0.05). CONCLUSIONS: RPR101511A, which acts by inhibition of the PDGFr-TK, completely prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia.
G Bilder; T Wentz; R Leadley; D Amin; L Byan; B O'Conner; S Needle; H Galczenski; J Bostwick; C Kasiewski; M Myers; A Spada; L Merkel; C Ly; P Persons; K Page; M Perrone; C Dunwiddie
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Circulation     Volume:  99     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  1999 Jun 
Date Detail:
Created Date:  1999-07-16     Completed Date:  1999-07-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3292-9     Citation Subset:  AIM; IM    
Department of Cardiovascular Biology, Medicinal Chemistry, Rhone-Poulenc Rorer, Collegeville, PA, USA.
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MeSH Terms
Administration, Oral
Angioplasty, Transluminal, Percutaneous Coronary*
Coronary Disease / prevention & control*,  therapy
Enzyme Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Quinoxalines / pharmacology*
Receptors, Platelet-Derived Growth Factor / metabolism*
Thiophenes / pharmacology*
Time Factors
Tunica Intima / metabolism
Tunica Media / metabolism
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Quinoxalines; 0/RPR 101511A; 0/Thiophenes; EC Kinases; EC, Platelet-Derived Growth Factor

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