Platelet antiaggregant activity of plafibride ex vivo in rat, dog and rabbit

N-2-(p-Chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104) is an acyl derivative of morpholinomethylurea (MMU) with clofibric acid that was found to be active as a hypotriglyceridemic increasing the serum alpha-lipoproteins and decreasing drastically the serum turbidity after olive oil ingestion. This paper reports the antiaggregating activity ex vivo of plafibride in experimental Animals. In ADP-induced platelet aggregation in the rat, plafibride at double dose was as active as acetylsalicylic acid (ASA), dipyridamole was less active and clofibrate practically inactive. In the rabbit, plafibride either administered p.o. or i.v. was as active as ASA. In ADP-, collagen- or adrenaline-induced aggregation in the dog, plafibride showed marked platelet antiaggregant activity after a single dose of 100 mg/kg p.o. In all the experiments, the antiaggregating activity of plafibride was similar in intensity to that of ASA but more retarded. Inhibition by plafibride of arachidonic acid-induced platelet aggregation was of a competitive type whereas the inhibition by ASA was unspecific. In the rat, plafibride inhibited significantly the spontaneously formed circulating platelet aggregates. In vitro plafibride appeared as an effective antiaggregant agent although less powerful than morpholinomethylurea, one of its presumed metabolites. The ex vivo activity of MMU was nevertheless too short-lasting to be of any therapeutic interest. The kinetics of platelet antiaggregant activity and the correlation between hypolipemic and platelet antiaggregant activity of plafibride is discussed in this paper. It is evident that plafibride at above dose is active as an antiaggregant and hypolipemic agent.