title: 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.
abstract: 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.
authors.affiliation: Cardiology Unit, Department of Medicine, University of Vermont, Burlington, Vermont 05446, USA. david.schneider@uvm.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Schneider
authors.forename: Friederike K
authors.initials: FK
authors.lastname: Keating
authors.forename: Patricia Q
authors.initials: PQ
authors.lastname: Baumann
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Whitaker
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
mesh_terms: 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
chemical_list: D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D005340:Fibrinogen; D000077466:Tirofiban