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.
Han
G
G
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis 38163.
Bond
S E
SE
Lawrence
W H
WH
Dillingham
E O
EO
Zheng
X
X
Gollamudi
R
R
D000328:Adult; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004837:Epinephrine; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009557:Nipecotic Acids / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013924:Thrombophlebitis / Q000139:chemically induced / Q000517:prevention & control
D009557:Nipecotic Acids; D010975:Platelet Aggregation Inhibitors; C043099:alpha, alpha'-bis(3-(N,N-diethylcarbamoyl)piperidino)-4-xylene; D003094:Collagen; D001241:Aspirin; D004837:Epinephrine