EFFECTS OF 6‐[p‐(4‐PHENYLACETYLPIPERAZIN‐1‐YL)PHENYL]‐4,5‐DIHYDRO‐3(2H)PYRIDAZINONE (CCI 17810) AND ASPIRIN ON PLATELET AGGREGATION AND ADHESIVENESS

Abstract

1 The effects of 6-[p-(4-phenylacetylpiperazin-1-yl)-phenyl]-4,5-dihydro-3(2H)pyridazinone (CCI 17810) on platelet aggregation and adhesiveness have been investigated and compared with those of aspirin. 2 In vitro, CCI 17810 was a potent inhibitor of the aggregation of human platelets induced by collagen, adenosine 5′-diphosphate (ADP) (primary response), thrombin and arachidonic acid, with EC₅₀ values in the range 0.5 to 10 μg/ml. The second phase of the response to adrenaline was blocked by concentrations in the range 15 to 25 μg/ml. Platelets from rats, rabbits and dogs were as sensitive as human platelets to the effects of CCI 17810. Aspirin was nearly as effective as CCI 17810 against collagen, and adrenaline but about 10 times less active against arachidonic acid; it did not inhibit the primary response to ADP and was only a weak inhibitor of thrombin-induced aggregation. 3 In mice, single oral doses of CCI 17810 in the range 12.5 to 100 mg/kg inhibited collagen-induced thrombocytopenia. Arachidonic acid-induced mortality was markedly reduced by 10 mg/kg and possibly slightly reduced by 1 mg/kg. Aspirin was considerably less active than CCI 17810 in inhibiting collagen-induced thrombocytopenia but was almost as active as CCI 17810 in reducing arachidonic acid-induced mortality. 4 In vitro, CCI 17810 reduced the adhesiveness of human platelets to glass beads (retention of platelets in glass bead columns). Single oral doses of CCI 17810 in the range 25 to 200 mg/kg reduced mouse platelet adhesiveness; rat platelet adhesiveness was reduced by doses in the range 12.5 to 100 mg/kg. Aspirin (20 or 200 mg/kg) slightly increased mouse platelet adhesiveness.