Inhibition of neointima formation by a nonpeptide alpha(v)beta(3) integrin receptor antagonist in a rabbit cuff model.
This study was performed to determine whether a highly selective nonpeptide alpha(v)beta(3) antagonist (SH306) would prove effective in inhibiting neointima formation in a rabbit cuff model. The animals were dosed with SH306, 5 mg/kg i.v., followed by 10 mg/kg s. c., 3 times daily for 3 days, or with vehicle (10% DMAC). Rabbits were sacrificed and perfused on days 1, 3, and 21; the vessels were paraffin embedded. A reduction in the intima/media (I/M) of the SH306-treated rabbits, as compared with the vehicle-treated control group, was noted (0.20 vs 0.36 [n = 4]). A significant increase in the area of the media was observed in the SH306-treated group versus the control group (0.20 vs 0.13). No difference was observed in cell proliferation between SH306 and vehicle after 1-day and 3-day dosing. Thrombi were found in 43% of the control vessels and in only 14% of the drug-treated vessels. No anticoagulant was used during the surgical procedure. No increase in inhibition of GPIIb/IIIa was observed in SH306-treated animals, as compared with the vehicle control group. We conclude that selective inhibition of alpha(v)beta(3) reduced neointima formation in a rabbit model at 3 weeks.
Racanelli
A L
AL
Cardiovascular Department of the DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400, USA. adrienne.l.racanelli@dupontpharma.com
Gibbs
S K
SK
Schlingmann
K L
KL
Corjay
M H
MH
Jadhav
P K
PK
Reilly
T M
TM
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005263:Femoral Artery / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011725:Pyridines; D019030:Receptors, Vitronectin; C408289:SH 306