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Platelet antiaggregant activity of plafibride ex vivo in rat, dog and rabbit
Abstract:
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.
Insights
Plafride, a novel compound, effectively reduces triglycerides and prevents platelet aggregation in animal models. Its antiplatelet activity is comparable to aspirin but with a delayed onset, showing therapeutic potential.
Area of Science:
- Pharmacology
- Biochemistry
- Cardiovascular Research
Background:
- N-2-(p-Chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride) is an acyl derivative of morpholinomethylurea (MMU).
- Plafibride exhibits hypotriglyceridemic activity, increasing serum alpha-lipoproteins and reducing serum turbidity.
- This study investigates the ex vivo antiaggregating activity of plafibride in experimental animals.
Purpose of the Study:
- To evaluate the antiplatelet aggregation effects of plafibride in various animal models.
- To compare the efficacy of plafibride with established antiplatelet agents like acetylsalicylic acid (ASA).
- To explore the mechanism of action and therapeutic potential of plafibride.
Main Methods:
- Platelet aggregation assays were performed in rats, rabbits, and dogs using various inducers (ADP, collagen, adrenaline, arachidonic acid).
- Plafibride was administered orally (p.o.) and intravenously (i.v.) in different dosages.
- Inhibition kinetics and comparison with ASA, dipyridamole, and clofibrate were analyzed.
Main Results:
- Plafibride demonstrated significant antiplatelet activity in rats, rabbits, and dogs, comparable in intensity to ASA but with a more delayed effect.
- Inhibition of arachidonic acid-induced aggregation by plafibride was competitive, unlike the unspecific inhibition by ASA.
- Plafibride effectively inhibited spontaneously formed circulating platelet aggregates in rats.
Conclusions:
- Plafibride is a potent ex vivo antiplatelet agent with both hypolipemic and antiaggregant properties.
- Its antiplatelet activity is comparable to ASA, suggesting potential therapeutic applications.
- The competitive inhibition mechanism and sustained activity warrant further investigation for clinical relevance.