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Effect of tiplaxtinin (PAI‐039), an orally bioavailable PAI‐1 antagonist, in a rat model of thrombosis
Author(s) -
HENNAN J. K.,
MORGAN G. A.,
SWILLO R. E.,
ANTRILLI T. M.,
MUGFORD C.,
VLASUK G. P.,
GARDELL S. J.,
CRANDALL D. L.
Publication year - 2008
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2008.03063.x
Subject(s) - thrombosis , thrombus , medicine , antithrombotic , venous thrombosis , pharmacology , antagonist , anesthesia , receptor
Summary. Objective: To assess the antithrombotic and profibrinolytic effects of tiplaxtinin (PAI‐039), an orally bioavailable antagonist of PAI‐1, in rat models of thrombosis. Methods and results: Carotid artery and vena cava vascular injury was produced by application of FeCl 3 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.