Effect of tiplaxtinin (PAI-039), an orally bioavailable PAI-1 antagonist, in a rat model of thrombosis.
OBJECTIVE
To assess the antithrombotic and profibrinolytic effects of tiplaxtinin (PAI-039), an orally bioavailable antagonist of PAI-1, in rat models of thrombosis.


RESULTS
Carotid artery and vena cava vascular injury was produced by application of FeCl3 and blood flow was monitored using ultrasonic technology. To assess efficacy in a thrombosis prevention paradigm, PAI-039 was administered orally 90 min before injury (1-30 mg kg(-1)). To assess efficacy in a thrombosis treatment paradigm, vascular injury and stable thrombus formation were followed 4 h later by recovery and PAI-039 administration. PAI-039 prevented carotid artery occlusion in 20, 68 and 60% of animals pretreated with 0.3, 1.0 and 3.0 mg kg(-1), respectively. Time to occlusive thrombosis was increased from 18.2 +/- 4.6 min in controls to 32.5 +/- 8.7 (P = ns), 46.1 +/- 7.0 (P < 0.05), and 41.6 +/- 11.3 min (P < 0.05) in the respective PAI-039 treatment groups. In the vena cava protocol, PAI-039 pretreatment significantly reduced thrombus weight at PAI-039 doses of 3, 10 and 30 mg kg(-1). When PAI-039 was dosed in a treatment paradigm 4 h after stable arterial and venous thrombosis, a significant reduction in thrombus weight was observed 24 h later at PAI-039 doses of 3, 10 and 30 mg kg(-1). PAI-039 (10, 30 and 100 mg kg(-1)) had no effect on platelet aggregation in response to ADP or collagen and was not associated with increased bleeding or prolonged prothrombin time. In animals bearing no vascular injury, PAI-039 had no effect on circulating, low-levels of PAI-1 activity. In contrast, circulating PAI-1 activity increased 5-fold following the induction of vascular injury, which was completely neutralized by PAI-039.


CONCLUSIONS
PAI-039 exerts antithrombotic efficacy in rat models of arterial and venous vascular injury without effecting platelet aggregation.
Hennan
J K
JK
Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, PA 19426, USA. hennanj@wyeth.com
Morgan
G A
GA
Swillo
R E
RE
Antrilli
T M
TM
Mugford
C
C
Vlasuk
G P
GP
Gardell
S J
SJ
Crandall
D L
DL
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D007210:Indoleacetic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1; D010974:Platelet Aggregation / Q000187:drug effects; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000517:prevention & control*
D007210:Indoleacetic Acids; D017395:Plasminogen Activator Inhibitor 1; C488103:tiplaxtinin