Diuretic effect of ITA 529.

The diuretic and saluretic activity of ITA 529 (Ethyl-beta-[(5-tert-butyl-3-chloro-2-hydroxy)benzylamino]crotonate++ +) in rat, rabbit and monkey is described in this study. In rat, the diuretic ED50 of ITA 529 was 1.23 mg/kg p.o. and its ED100 1.69 mg/kg p.o. The diuretic ED50 of furosemide was 18.48 mg/kg p.o. and its ED100 22.38 mg/kg p.o. Their effect lasted approximately 3 hours. In monkey, the diuretic ED50 of ITA 529 was 2.29 mg/kg p.o. and its ED100 6.54 mg/kg p.o. while for furosemide its ED50 was 2.44 mg/kg p.o. and its ED100 5.72 mg/kg p.o. In rabbit the ED50 of ITA 529 was 1.83 mg/kg p.o. and its ED100 3.37 mg/kg p.o. For furosemide, its ED50 was 2.25 mg/kg p.o. and its ED100 7.13 mg/kg p.o. The natriuretic activity of ITA 529 was reduced by indomethacin.

Activity of plafibride on erythrocyte deformability.

N-2-(p-Chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, Idonor, Perifunal, Plafibrinol) is an acid derivative of morpholinomethylurea and clofibric acid. In these studies the effects of plafibride on haemorheological properties have been observed. The studies have been carried out in different animal species (rat, rabbit and dog), and in human volunteers. Under these circumstances, plafibride has shown itself to be highly active in all the animal species and in humans, as well as with the two laboratory methods used for determination of erythrocyte deformability, these being Teitel's method, which evaluates the deformative capacity of erythrocytes when forming compact groups, and the method of Schmid-Schoenbein in which the deformability of individual erythrocytes is measured by passage through fine capillaries. In trials in volunteers, the increase in erythrocyte deformability is notable even 5 days after the last administration. In addition to its microhaemorheological activity, plafibride has been shown to have effects on platelet aggregation and hyperlipaemia.

Microhaemorheological properties of binifibrate. Part I: Experimental studies.

The microhaemorheological properties of 3-pyridine carboxylic acid 2-[2-(4-chlorophenoxy)-2-methyl-1-oxopropoxy]-1,3-propanediyl ester (binifibrate, Biniwas), a hypolipidaemic and anti-arteriosclerotic drug composed of two nicotinic radicals and one clofibric radical united by glycerol, were studied. Binifibrate increased passage of a suspension of red blood cells at 80% haematocrit value through filters of 30-40 micron (Teitel's method), and erythrocyte deformability detectable by increase of flow rate through filters of pore size lesser than erythrocyte diameter (Schmid-Schönbein's method). After treatment, resistance to lysis in hypotonic solution is also augmented, indicating that microhaemorheological activity is due to modification of the elastic properties of the erythrocyte membrane.

Microhaemorheological properties of binifibrate. Part II: Preliminary open studies in patients with peripheral arteriopathies.

3-Pyridinecarboxylic acid 2-[2-(4-chlorophenoxy)-2-methyl-1-oxo-propoxy]-1,3-propanediyl ester (binifibrate, Biniwas) an anti-arteriosclerotic and hypolipidaemic agent which showed an effect on microhaemorheological properties during studies in experimental animals (rat and rabbit), was administered to six hyperlipidaemic patients who suffered from circulatory disturbances in the lower limbs. The treatment with binifibrate was applied at a dosage of 3 X 600 mg/day during one month. Both subjective symptoms such as paraesthesia, dysthaesia, coldness at rest and functional weakness of movements were improved, as well as objective symptoms measured by oscillometry. The microhaemorheological analyses demonstrated a positive variation in relative parameters. The correlation between microhaemorheological parameters and clinical symptoms is discussed.

Influence of plafibride, an antiplatelet and hypolipemic agent, on prostacyclin and thromboxane synthesis, 3',5'-cyclic AMP phosphodiesterase activity and serum clearance of a lipid emulsion.

The activity of N-2-(p-chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104) on arachidonic acid metabolism, the 3',5'-cyclic AMP-phosphodiesterase and the serum clearance of a lipid emulsion is reported in order to clarify its mechanism of action on platelet aggregation and lipid metabolism. Plafibride did not act on the arachidonic acid metabolism as far as platelet aggregation was concerned, since it did not modify the generation of prostaglandin endoperoxides nor prostacyclin. Neither did it act on the generation of thromboxane A2. Plafibride inhibited the activity of 3',5'-cyclic AMP-phosphodiesterase, which is one of the principal mechanisms of inhibition of platelet aggregation. The serum c clearance of a commercial lipid emfy the generation of prostaglandin endoperoxides nor prostacyclin. Neither did it act on the generation of thromboxane A2. Plafibride inhibited the activity of 3',5'-cyclic AMP-phosphodiesterase, which is one of the principal mechanisms of inhibition of platelet aggregation. The serum clearance of a commercial lipid emulsion was increased by plafibride which also possessed a strong hypotriglyceride activity. The correlation between platelet antiaggregant and hypolipemic activity of plafibride is discussed in this paper.

Synthesis and pharmacological evaluation of N'-morpholinomethylurea derivatives with platelet antiaggregant activity.

In the attempt to prolong and stabilize the known antiaggregant activity of morpholinomethylurea (MMU) derivatives were prepared with carboxylic acids possessing antiaggregant, anti-inflammatory or hypolipemic activity. The results of the experiments showed the important anti-aggregant and hypolipemic activity of N-2-(p-chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104). The results obtained seem to indicate that the activity of these new N-acyl-N'-MMU is due initially to the molecule per se although it cannot be totally ruled out that part of the pharmacodynamic effect of the MMU may depend on a prodrug-like behaviour.

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.