Effects of a new platelet glycoprotein IIb/IIIa antagonist, SR121566, on platelet activation, platelet-leukocyte interaction and thrombin generation.
The effects of SR121566, a new inhibitor of the glycoprotein (GP) IIb/IIIa complex on platelet activation and platelet-leukocyte interactions, as well as on thrombin generation were investigated. SR121566 dose-dependently inhibited adenosine diphosphate (ADP)-induced platelet fibrinogen binding determined either by flow cytometry analysis (IC50=50 nmol/l) or by measuring the binding of 125I-fibrinogen to activated human gel-filtered platelets (IC50=20 nmol/l). Consistent with its inhibitory effects on platelet fibrinogen binding, SR121566 demonstrated a dose-dependent inhibition of collagen-, ADP- or thrombin-induced platelet aggregation with IC50 values ranging between 20 and 60 nmol/l. SR121566, even tested at high concentrations, did not significantly affect ADP-induced platelet-leukocyte aggregate formation. The GPIIb/IIIa antagonist strongly inhibited thrombin generation in both native clotting blood and recalcified whole blood, suggesting that SR121566, by interfering with the platelet-activation events involved in facilitating thrombin generation, may also function as an anticoagulant, an effect which may contribute to its antithrombotic properties in humans.
Li
N
N
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden. nali@mb.ks.se
Wallén
N H
NH
Savi
P
P
Hérault
J P
JP
Herbert
J M
JM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001596:Benzylamines; D001792:Blood Platelets / Q000502:physiology*; D002449:Cell Aggregation / Q000187:drug effects; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007457:Iodine Radioisotopes; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013844:Thiazoles; D013917:Thrombin / Q000096:biosynthesis* / Q000494:pharmacology
D001596:Benzylamines; D007457:Iodine Radioisotopes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C106774:SR 121566; D013844:Thiazoles; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D013917:Thrombin