DRUGS FOR THE PREVENTION OF CORONARY-THROMBOSIS - FROM AN ANIMAL-MODEL TO CLINICAL-TRIALS

Platelets contribute to the progression of atherosclerotic disease and also to partial or complete thrombotic occlusion of stenosed human coronary or cerebral arteries. Thus, there is considerable interest in being able to measure in vivo or ex vivo platelet function or level of activity. Currently, platelet activity and the platelet inhibitory effect of drugs can be assessed ex vivo or in vitro by platelet aggregometry. There is also an experimental animal model (the cyclic flow, or Felts, model) for studying the interactions of platelets with damaged and stenosed arterial walls. This model was first used to show that aspirin can prevent coronary thrombosis in stenosed canine coronary arteries and is fairly predictive in determining which drugs are likely to inhibit platelet activity in vivo. It is also useful in identifying which drugs may be beneficial in ameliorating unstable angina and preventing coronary thrombosis. Studies with this model predict that aspirin, sulfinpyrazone, the monoclonal antibody 7E3 to the platelet glycoprotein GpIIb-IIIa fibrinogen receptor, arginine-glycine-aspartic acid peptide mimetics, or clopidogrel (an analogue of ticlopidine) would inhibit platelet-mediated thrombosis in patients with coronary or cerebral artery stenosis. The model also predicts that heparin or dipyridamole alone would not prevent platelet-mediated arterial thrombosis. Finally, studies with the cyclic model suggest that while serotonin receptor blockers, alpha-adrenergic blockade, or infusions of prostacyclin (or its analogue, Iloprost) would inhibit platelet activity, the resulting hypotension would severely limit the clinical usefulness of these compounds.