Increased ability of tirofiban to maintain its inhibitory effects on the binding of fibrinogen to platelets in blood from patients with and without diabetes mellitus.
OBJECTIVE
Both tirofiban and eptifibatide release rapidly from glycoprotein IIb-IIIa but have different dissociation constants (KD of tirofiban=15 nmol/l, of eptifibatide=120 nmol/l). Binding of fibrinogen to glycoprotein IIb-IIIa is biphasic, forming an initial reversible complex (KD=155-180 nmol/l) and a second more stable complex (KD=20-70 nmol/l). Diabetes is known to alter platelet function. To determine the influence of affinity on inhibitory effects in blood from patients with (n=20) and without (n=20) diabetes mellitus, we characterized the extent of inhibition as a function of time.


METHODS
Blood was added to reaction tubes containing tirofiban 100 ng/ml or eptifibatide 1.7 microg/ml (concentrations previously defined to be optimal) plus a platelet agonist (1 micromol/l adenosine diphosphate or 25 micromol/l thrombin receptor agonist peptide), and fluorochrome-labeled fibrinogen before analysis by flow cytometry.


RESULTS
The extent of inhibition early on (30 s to 3 min) was similar (>85%) with either agent in blood from those with and without diabetes mellitus, whereas the extent of inhibition 10-15 min later was maintained more effectively with tirofiban than with eptifibatide (difference in slope P<0.01). After 15 min, the extent of inhibition in response to adenosine diphosphate in those with diabetes mellitus was 95+/-6% for tirofiban and 70+/-15% for eptifibatide (P<0.001); in those without diabetes mellitus, it was 91+/-9% for tirofiban and 73+/-19% for eptifibatide (P<0.001).


CONCLUSIONS
For glycoprotein IIb-IIIa antagonists with a rapid rate of release, the biphasic binding of fibrinogen influences to a similar extent their ability to maintain inhibitory effects in blood from patients with and without diabetes mellitus.
Schneider
David J
DJ
Cardiology Unit, Department of Medicine, University of Vermont, Burlington, Vermont 05446, USA. david.schneider@uvm.edu
Keating
Friederike K
FK
Baumann
Patricia Q
PQ
Whitaker
Deborah A
DA
Sobel
Burton E
BE
D000368:Aged; D003920:Diabetes Mellitus / Q000097:blood* / Q000188:drug therapy; D005260:Female; D005340:Fibrinogen / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D005340:Fibrinogen; D000077466:Tirofiban