In vitro effect of the potent poly(ADP-ribose) polymerase (PARP) inhibitor INO-1001 alone and in combination with aspirin, eptifibatide, tirofiban, enoxaparin or alteplase on haemostatic parameters.
It has been shown that PARP inhibition is protective in several models of ischemia-reperfusion injury including cardiac, cerebral and renal ones. Due to their ability to reduce myocardial necrosis and to improve myocardial function PARP inhibitors emerged as candidates for treating various cardiovascular diseases including acute myocardial ischemia. Since the pathophysiology of acute ischemic cardiac diseases involves haemostatic impairment and the therapeutic regimen includes antithrombotic drugs, we investigated the effect of the potent poly(ADP-ribose) polymerase (PARP) inhibitor INO-1001 alone and in combination with platelet aggregation inhibitors (aspirin, eptifibatide and tirofiban), unfractionated heparin, low molecular weight heparin (enoxaparin) or the recombinant fibrinolytic drug (alteplase), on various haemostatic parameters in vitro. ADP- and epinephrine-induced platelet aggregation was evaluated by optical aggregometry in the presence or absence of different concentrations of INO-1001, in combination with aspirin, tirofiban, eptifibatide or saline on ten healthy volunteers' platelet rich plasma (PRP). Activated partial thromboplastin time, Anti-Xa activity and euglobulin lysis time were determined in the presence or absence of different concentrations of INO-1001, in combination with sodium heparin, enoxaparin or alteplase, respectively. INO-1001, on its own does not affect the measured platelet, and haemostatic functions, i.e. does not reduce the respective anti-platelet, anti-coagulant and thrombolytic activity of therapeutically relevant concentrations of aspirin, tirofiban, eptifibatide, enoxaparin and alteplase in vitro. INO-1001 enhanced the effects of heparins above therapeutic ranges; the magnitude of this effect was negligible. Consequently, the PARP inhibitor INO-1001 can be safely applied together with the drugs tested.
1st Department of Medicine, University of Pécs, Hungary, 13. Ifjúság út, Pécs, 7624 Hungary. orsolya.toth@aok.pte.hu
Orsolya
O
Tóth
Csaba
C
Szabó
Marianna
M
Kecskés
László
L
Pótó
Agnes
A
Nagy
Hajna
H
Losonczy
D001241:Aspirin / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000077542:Eptifibatide; D065427:Factor Xa Inhibitors; D005260:Female; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010314:Partial Thromboplastin Time; D010455:Peptides / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000077466:Tirofiban; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; C491685:INO 1001; D007211:Indoles; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014443:Tyrosine; D006493:Heparin; D010959:Tissue Plasminogen Activator; D000077466:Tirofiban; D000077542:Eptifibatide; D001241:Aspirin