Comparative antiplatelet efficacy of a novel, nonpeptide GPIIb/IIIa antagonist (XV454) and abciximab (c7E3) in flow models of thrombosis.
Glycoprotein (GP) IIb/IIIa is pivotal in homotypic platelet aggregation and may also be involved in the heterotypic adhesion of leukocytes and tumor cells to platelets. This study was primarily undertaken to compare the antiplatelet efficacy of a novel, nonpeptide GPIIb/IIIa antagonist, XV454, to that of abciximab in 2 flow models of platelet thrombus formation: (1) direct shear-induced platelet aggregation imposed by a cone-and-plate rheometer and (2) platelet adhesion onto von Willebrand factor (vWF)/collagen I followed by aggregation in a perfusion system. XV454 inhibited platelet aggregation in a concentration-dependent manner in both experimental models. Maximal inhibition of aggregation was achieved by XV454 at approximately 70% receptor occupancy, which is lower than the >/=85% previously reported for abciximab. At similar levels of receptor blockade (approximately 45%), XV454 appeared to be relatively more effective than abciximab in suppressing platelet aggregation. Neither XV454 nor abciximab inhibited platelet adhesion to collagen. Pretreatment of surface-adherent platelets with either XV454 or abciximab inhibited the attachment of monocytic THP-1 cells under flow. In contrast, the rapidly reversible GPIIb/IIIa inhibitor orbofiban failed to suppress these heterotypic interactions. These findings demonstrate that XV454 is a potent GPIIb/IIIa antagonist with a long receptor-bound lifetime like abciximab and may be beneficial for the treatment/prevention of thrombotic complications.
Abulencia
J P
JP
Department of Chemical Engineering, Johns Hopkins University, Baltimore, Md, USA.
Tien
N
N
McCarty
O J
OJ
Plymire
D
D
Mousa
S A
SA
Konstantopoulos
K
K
D000077284:Abciximab; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D005434:Flow Cytometry; D018056:Hemorheology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D008954:Models, Biological; D010080:Oxazoles / Q000494:pharmacology*; D010477:Perfusion; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013314:Stress, Mechanical; D013927:Thrombosis / Q000097:blood*
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C116340:XV 454; D000409:Alanine; D000077284:Abciximab