BACKGROUND: The principal inhibitor of fibrinolysis in vivo is plasminogen activator inhibitor-1 (PAI-1). PAI-749 is a small molecule inhibitor of PAI-1 with proven antithrombotic efficacy in several preclinical models. OBJECTIVE: To assess the effect of PAI-749, by using an established ex vivo clinical model of thrombosis and a range of complementary in vitro human plasma-based and whole blood-based models of fibrinolysis. METHODS: In a double-blind, randomized, crossover study, ex vivo thrombus formation was assessed using the Badimon chamber in 12 healthy volunteers during extracorporeal administration of tissue-type plasminogen activator (t-PA) in the presence of PAI-749 or control. t-PA-mediated lysis of plasma clots and of whole blood model thrombi were assessed in vitro. The role of vitronectin was examined by assessing lysis of fibrin clots generated from purified plasma proteins. RESULTS: There was a dose-dependent reduction in ex vivo thrombus formation by t-PA (P < 0.0001). PAI-749 had no effect on in vitro or ex vivo thrombus formation or fibrinolysis in the presence or absence of t-PA. Inhibition of PAI-1 with a blocking antibody enhanced fibrinolysis in vitro (P < 0.05). CONCLUSIONS: Despite its efficacy in a purified human system and in preclinical models of thrombosis, the current study suggests that PAI-749 does not affect thrombus formation or fibrinolysis in a range of established human plasma and whole blood-based systems.
RCT Entities:
BACKGROUND: The principal inhibitor of fibrinolysis in vivo is plasminogen activator inhibitor-1 (PAI-1). PAI-749 is a small molecule inhibitor of PAI-1 with proven antithrombotic efficacy in several preclinical models. OBJECTIVE: To assess the effect of PAI-749, by using an established ex vivo clinical model of thrombosis and a range of complementary in vitro human plasma-based and whole blood-based models of fibrinolysis. METHODS: In a double-blind, randomized, crossover study, ex vivo thrombus formation was assessed using the Badimon chamber in 12 healthy volunteers during extracorporeal administration of tissue-type plasminogen activator (t-PA) in the presence of PAI-749 or control. t-PA-mediated lysis of plasma clots and of whole blood model thrombi were assessed in vitro. The role of vitronectin was examined by assessing lysis of fibrin clots generated from purified plasma proteins. RESULTS: There was a dose-dependent reduction in ex vivo thrombus formation by t-PA (P < 0.0001). PAI-749 had no effect on in vitro or ex vivo thrombus formation or fibrinolysis in the presence or absence of t-PA. Inhibition of PAI-1 with a blocking antibody enhanced fibrinolysis in vitro (P < 0.05). CONCLUSIONS: Despite its efficacy in a purified human system and in preclinical models of thrombosis, the current study suggests that PAI-749 does not affect thrombus formation or fibrinolysis in a range of established human plasma and whole blood-based systems.
Authors: Ashley A Reinke; Shih-Hon Li; Mark Warnock; Maxim E Shaydakov; Naga Sandhya Guntaka; Enming J Su; Jose A Diaz; Cory D Emal; Daniel A Lawrence Journal: J Biol Chem Date: 2018-12-03 Impact factor: 5.157
Authors: Mohammed N Meah; Jennifer Raftis; Simon J Wilson; Vidya Perera; Samira M Garonzik; Bindu Murthy; J Gerry Everlof; Ronald Aronson; Joseph Luettgen; David E Newby Journal: Arterioscler Thromb Vasc Biol Date: 2020-09-10 Impact factor: 8.311
Authors: Amanda L Hunter; Jon Unosson; Jenny A Bosson; Jeremy P Langrish; Jamshid Pourazar; Jennifer B Raftis; Mark R Miller; Andrew J Lucking; Christoffer Boman; Robin Nyström; Kenneth Donaldson; Andrew D Flapan; Anoop S V Shah; Louis Pung; Ioannis Sadiktsis; Silvia Masala; Roger Westerholm; Thomas Sandström; Anders Blomberg; David E Newby; Nicholas L Mills Journal: Part Fibre Toxicol Date: 2014-12-09 Impact factor: 9.400
Authors: Simon J Wilson; Thomas M Connolly; Gary Peters; Atalanta Ghosh; Maureen Johnson; David E Newby Journal: Cardiovasc Res Date: 2019-03-01 Impact factor: 10.787
Authors: Claire S Whyte; Hadj Ahmed Mostefai; Kim M Baeten; Andrew J Lucking; David E Newby; Nuala A Booth; Nicola J Mutch Journal: Int J Mol Sci Date: 2021-02-20 Impact factor: 6.208