DIFFERING EFFECTS OF TICLOPIDINE AND 2 PROSTAGLANDIN SYNTHETASE INHIBITORS ON MAXIMUM RATE OF ADP-INDUCED AGGREGATION

Many platelet inhibitors are known which block the secondary (2°) phase of ADP-induced aggregation. These agents normally inhibit platelet cyclooxygenase (CO). Agents which are able to inhibit primary (1°) ADP-induced aggregation usually cause elevation of platelet cAMP. Ticlopidine hydrochloride (T), a drug which does net stimulate platelet adenylate cyclase or inhibit platelet cAMP phosphodiesterase, or platelet CO, inhibits 1° ADP-induced aggregation. Healthy human volunteers were dosed orally from 3-8 days with doses of T from 125 to 500 mg/day. When the maximum rate of ADP-induced aggregation on the day following cessation of dosing was compared with that obtained predosing, statistically significant inhibition of maximum rate was obtained at each dose. Similar studies were done with naproxen (N) a CO inhibitor. Healthy human volunteers were given 125 to 1000 mg/day of N. When the rates of ADP-induced aggregation at 3 and 8 hours postdosing were compared to predose rates, there were no statistically significant differences at any dose. At these times collagen and arachidonic acid-induced aggregation were essentially totally inhibited. An experimental agent, 5-benzoyl-l, 2-dihydro-3H-pyrrolo [l,2-a]-pyrrole- 1.carboxylic acid, with potent platelet CO inhibiting activity, given orally to human volunteers at 2.5 to 200 mg/day showed the same results at 3 and 24 hours post dosing as did N.We conclude that T is an inhibitor of 1°phase of ADP- induced aggregation, and that agents with CO-inhibiting action alone are incapable of inhibiting 1° phase of ADP- induced aggregation despite occasional reports to the contrary.