SYNERGISTIC ANTIPLATELET EFFECTS OF A NIPECOTAMIDE A-1C AND LOW-DOSE ASPIRIN

1. The effects of an antithrombotic nipecotamide, A-1, and aspirin wer e examined separately and in combination, on human platelet aggregatio n in vitro and on collagen + epinephrine-induced thromboembolic death of mice in vivo. 2. Concurrent addition of the two agents to a platele t suspension resulted in a supraadditive inhibition. Racemic A-1 and i ts meso diastereomer A-1C behaved similarly in this respect. The IC50 value of rac. A-1 declined from 46.25 to 18.4 mu M in the presence of aspirin. 3. In vivo, concurrent administration of A-1C and aspirin pro duced significant potentiation of antithrombotic activity. A 2-fold re duction in the ED(50) 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 n ew compounds possessing the structural features of the two molecules a ppears to provide superior antithrombotic agents.