914-68 SDZ GPI 562, an Oral Peptidomimetic Inhibitor of the Platelet GpIIbIIIaAbolishes Epinephrine and Shear Induced Cyclic Flow Reductions in Stenosed Monkey Carotid Arteries

Abstract

Aspirin (ASA) is the only oral agent approved as an anti platelet agent (AA) to prevent platelet mediated thrombosis (PMT) myocardial infarction, strokes and reocclusion after thrombolysis or angioplasty. However, animal and human platelets inhibited with ASA can be reactivated to produce PMT with elevated plasma epinephrine levels or increased shear stress. In 7 anesthetized monkeys (M), mechanical carotid artery stenosis (MCAS) 70% diameter reduction with intimal damage was produced and blood flow measured (EMF probe). Cyclic flow reductions (CFR's) occurred due to acute PMT followed by embolization to the brain, ASA, 5 mg/kg IV, abolished the CFR's in all M but they returned with Epinephrine (E), 0,2 μ/kg given IV, or increase in MCAS to 85%, due to shear induced aggregation. In 8 M with 70% MCAS, after 30 minutes of CFR's, 1–2 mg/kg of the drug SDZ GPl562 was given by stomach tube. Eighty-five ± 22 min after SDZ GPI 562, the CFR's were abolished in all 8 M. Template bleeding time increased from a control of 2.3 ± 1.0 min to 4.1 ± 1.2 min (p < 0.05) Ex vivo whole blood platelet aggregation (collagen stimulus) decreased by 76 ± 8% (p < 0,0001) and by 83 ± 10% (p < 0.0001) to ADP after SDZ GPI 562, The CFR's due to periodic acute PMT were not renewed by E, 0.2 μ/kg/min given IV for 20 minutes and/or by increased stenosis from 70% to 85% diameter reduction which increases shear from 144 ± 15 Pa to 266 ± 22 Pa (p < 0.005). CFR's due to acute PMT have been observed in patient coronary arteries at the time of angioplasty inspire of pretreatment with aspirin and heparin but could be abolished with c7E3, a monoclonal antibody inhibitor of the platelet Gpllbilia which is available only for IV use. SDZ GPI 562 is likely to be a superior AA because it is available in oral or IV form, it blocks the final step in platelet activation by blocking the platelet GpII b III a , thus protecting against platelet activation by elevated E and shear stress produced by very severe stenosis. It is also likely to be more effective than ASA for reducing the platelet contribution to atherosclerosis preventing coronary thrombosis and fatal or non fatal myocardial infarction and early and late PMT after angioplasty or atherectomy procedures.