Restenosis following angioplasty in the swine coronary artery is inhibited by an orally active PDGF-receptor tyrosine kinase inhibitor, RPR101511A

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 kinas...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 1999-06, Vol.99 (25), p.3292-3299
Main Authors: BILDER, G, WENTZ, T, MYERS, M, SPADA, A, MERKEL, L, CUONG LY, PERSONS, P, PAGE, K, PERRONE, M, DUNWIDDIE, C, LEADLEY, R, AMIN, D, BYAN, L, O'CONNER, B, NEEDLE, S, GALCZENSKI, H, BOSTWICK, J, KASIEWSKI, C
Format: Article
Language:English
Subjects:
Administration, Oral
Angioplasty, Balloon, Coronary
Animals
Biological and medical sciences
Cardiovascular system
Coronary Disease - prevention & control
Coronary Disease - therapy
Enzyme Inhibitors - pharmacology
Medical sciences
Pharmacology. Drug treatments
Protein-Tyrosine Kinases - antagonists & inhibitors
Quinoxalines - pharmacology
Receptors, Platelet-Derived Growth Factor - metabolism
Recurrence
Swine
Thiophenes - pharmacology
Time Factors
Tunica Intima - metabolism
Tunica Media - metabolism
Vascular wall
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Summary: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. 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
ISSN:0009-7322
1524-4539
DOI:10.1161/01.cir.99.25.3292