Synergistic antiplatelet effects of a nipecotamide A-1C and low dose aspirin

1. The effects of an antithrombotic nipecotamide, A-1, and aspirin were examined separately and in combination, on human platelet aggregation in vitro and on collagen+epinephrine-induced thromboembolic death of mice in vivo. 2. Concurrent addition of the two agents to a platelet suspension resulted in a supraadditive inhibition. Racemic A-1 and its meso diastereomer A-1C behaved similarly in this respect. The IC50 value of rac. A-1 declined from 46.25 to 18.4 microM in the presence of aspirin. 3. In vivo, concurrent administration of A-1C and aspirin produced significant potentiation of antithrombotic activity. A 2-fold reduction in the ED50 of A-1C occurred when it was coadministered with aspirin to mice; also, the toxicity reduced slightly, increasing the therapeutic index by a factor of 2.2. 4. The design and synthesis of new compounds possessing the structural features of the two molecules appears to provide superior antithrombotic agents.