Pharmacodynamic characterization of the interaction between the glycoprotein IIb/IIIa inhibitor YM337 and unfractionated heparin and aspirin in humans.
OBJECTIVE
To investigate the pharmacodynamic interaction of unfractionated heparin (UFH) and acetylic salicylic acid (ASA) on YM337, a monoclonal humanized antibody of the platelet GPIIb/IIIa receptor.


METHODS
In a randomized, placebo-controlled study three treatment groups each with six healthy volunteers received the following medication: group 1, ASA (3 days) + UFH + YM337 (placebo); group 2, ASA (placebo) + UFH (placebo) + YM337; group 3, ASA + UFH + YM337. Assessments were made over 24 h and included bleeding time (BT), ADP (20 microm)- and collagen (5 microg ml-1)-induced platelet aggregation and PAC1 and CD62 expression measured by flow cytometry.


RESULTS
In group 3 BT was prolonged to 35 [median, 16-45 min (1,3 quartile)] after UFH administration, increasing to 45 [median, 42-45 min (1,3 quartile)] after YM infusion (6 h). BT remained elevated to 26 [median, 14-45 min (1,3 quartile)] at 24 h, while groups 1 and 2 returned to normal values. Collagen-induced aggregation was 73% [median, 70-80% (1,3 quartile)] under YM337 alone, 79% [median, 72-80% (1,3 quartile)] under ASA + UFH and reduced only in group 3 to 24% [median, 18-29% (1,3 quartile)]. In both groups receiving active YM337, PAC1 expression showed a reduction to < 20% after 6 h of infusion. CD62 expression was not significantly affected by any treatment.


CONCLUSIONS
UFH and YM337 have strong synergistic effects on BT, while coadministration of ASA strongly augments inhibitory effects of YM337 on collagen-induced platelet aggregation.
Graff
Jochen
J
Institute of Clinical Pharmacology, University Hospital Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. graff@em.uni-frankfurt.de
Klinkhardt
Ute
U
Westrup
Dagmar
D
Kirchmaier
Carl M
CM
Breddin
Hans Klaus
HK
Harder
Sebastian
S
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D001760:Bleeding Time; D004347:Drug Interactions; D054641:Dual Specificity Phosphatase 2; D019040:E-Selectin / Q000378:metabolism; D005260:Female; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D019040:E-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D006493:Heparin; D054648:Protein Phosphatase 2; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2; D017027:Protein Tyrosine Phosphatases; D001241:Aspirin