Correlation between the in vivo efficacy of GPIIb/IIIa receptor antagonists (m7E3, MK-383 and DMP-728) and ex vivo platelet inhibition.

In vivo antithrombotic efficacy of GPIIb/IIIa receptor antagonists (m7E3, MK-383 and DMP-728) was studied with respect to their ex vivo platelet inhibition in heparinized platelet-rich plasma (hPRP) and citrated platelet-rich plasma (cPRP) using a canine model of carotid artery thrombosis. For each drug group (n = 6), the right carotid artery was used as control vessel and resulting occlusive thrombus was kept in situ to examine the direct thrombolytic efficacy of the antagonists. Thirty minutes after occlusion of control vessel, a low or high dose of each antagonist was administered and the left carotid artery was used as test vessel. All control vessels occluded within 86-96 min in response to electrolytic injury. The incidence of occlusion with lower doses of m7E3, DMP-728, and MK-383 was 100, 33 and 100%, respectively; corresponding times to occlusion were 174, 220 and 118 min. Lower doses inhibited ADP- or AA-induced platelet aggregation in cPRP (>80%). Incidence of occlusion with high doses of m7E3, DMP-728 and MK-383 was 33, 0 and 0%, respectively; corresponding times to occlusion were 209, >240 and >240 min. Higher doses inhibited aggregation in cPRP (>80%), but only partially in hPRP (45-66%). Dose-dependent prolongation of bleeding time occurred with all antagonists. None of the antagonists lyzed preformed thrombi in control vessels. The results indicate that ex vivo platelet aggregation conducted in hPRP, as opposed to conventional cPRP, provides a better assessment of the in vivo efficacy of GPIIb/IIIa receptor antagonists.
AuthorsJ Huang, S S Rebello, J D Faul, B R Lucchesi
JournalPharmacology (Pharmacology) Vol. 58 Issue 5 Pg. 252-64 (May 1999) ISSN: 0031-7012 [Print] SWITZERLAND
PMID10087466 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • Citrates
  • Immunoglobulin Fab Fragments
  • Mesylates
  • Peptides, Cyclic
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • DMP 728
  • Arachidonic Acid
  • Tyrosine
  • Adenosine Diphosphate
  • Heparin
  • tirofiban
  • Adenosine Diphosphate (pharmacology)
  • Animals
  • Antibodies, Monoclonal (pharmacology)
  • Arachidonic Acid (pharmacology)
  • Bleeding Time
  • Blood Flow Velocity (drug effects)
  • Blood Platelets (drug effects, physiology)
  • Carotid Arteries (drug effects, pathology, physiopathology)
  • Carotid Artery Thrombosis (blood, physiopathology, prevention & control)
  • Citrates (pharmacology)
  • Dogs
  • Dose-Response Relationship, Drug
  • Female
  • Heparin (pharmacology)
  • Immunoglobulin Fab Fragments (pharmacology)
  • Male
  • Mesylates (pharmacology)
  • Mice
  • Peptides, Cyclic (pharmacology)
  • Platelet Aggregation (drug effects)
  • Platelet Aggregation Inhibitors (pharmacology)
  • Platelet Count (drug effects)
  • Platelet Glycoprotein GPIIb-IIIa Complex (antagonists & inhibitors)
  • Treatment Outcome
  • Tyrosine (analogs & derivatives, pharmacology)

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