In vitro inhibitory effect of SR 27417, a potent platelet-activating factor (PAF) receptor antagonist, on the PAF-induced bovine platelet aggregation.

The in vitro inhibitory effect of SR 27417, an antagonist of the platelet-activating factor (PAF) receptor, on PAF-induced platelet aggregation was studied in blood collected from seven healthy Friesien calves. Inhibitory effects of SR 27417 were determined at thirteen different concentrations (0.1-400 nM) by using the dose-response curves of PAF on calf platelet aggregation. In the presence of SR 27417, the maximal slopes of aggregation (%/min) induced by low and high concentrations of PAF were significantly different from the control values obtained without an antagonist at p < or = 0.05 and p < or = 0.01 respectively. In vitro PAF-induced calf platelet aggregation was dose-dependently inhibited by SR 27417. The drug inhibited PAF-induced platelet aggregation in a competitive reversible manner (pA2 = 10.46 +/- 2.36 mol x L(-1)). In conclusion, the results of our study showed that addition of SR 27417 to bovine platelet in vitro inhibits PAF-induced platelet aggregation.

The effect of intravenous administration of WEB 2086 on PAF-induced platelet aggregation in healthy Friesian calves.

The in vivo ability of the specific PAF-antagonist WEB 2086, a thienotriazolodiazepine, to inhibit platelet-activating factor (PAF) in cattle was investigated by in vitro determination of platelet aggregation curves. WEB 2086 was infused intravenously into a group of 5 healthy male Friesian calves in a dose of 3 mg/kg over 1 min. The resultant inhibition peaked between 30 min and 1 h after administration of WEB 2086. The inhibition was significantly reduced after 3 h and became non-significant after 6 h, but maximal pre-treatment aggregation had not been restored by 24 h after the injection of WEB 2086. These results confirm previous results obtained in vitro and suggest that WEB 2086 is a potent antagonist of PAF activity in calves. They also suggest that further clinical studies with WEB 2086 in cattle are desirable.

Morphological alterations of blood platelets induced by platelet activating factor (PAF) and partial inhibition by ketoprofen in calves.

The influence of platelet activating factor (PAF) was investigated in vivo on the ultrastructure of bovine platelets, and on the platelet count. The effect of an intravenous administration of ketoprofen (a non-steroidal anti-inflammatory drug) pretreatment followed by PAF infusion was also observed in a group of six healthy male Friesian calves. PAF infusion alone caused a moderate thrombocytopenia, which peaked one minute post challenge and returned to levels not significantly different from control after 30 min. Electron microscopy revealed that after PAF infusion, platelets lost their lentiform shape and became irregular, with many pseudopods. Their microtubules became impossible to distinguish. The numbers of alpha granules and dense bodies were significantly decreased. Glycogen particles became rare or even disappeared. Giant platelets occasionally appeared. The Golgi apparatus was more often visible and the number of mitochondria was significantly increased. Ketoprofen pretreatment lowered PAF-induced thrombocytopenia and decrease in the number of dense bodies. Under these conditions, the Golgi apparatus was rarely visible and giant platelets were not observed. These results showed that the morphological ultrastructure of blood platelets in bovines were modified following PAF infusion and that ketoprofen pretreatment before PAF infusion provided partial protection, limiting the extent of the morphological alterations and maintaining a normal platelet count.

Combined effect of Web 2086 (Paf antagonist) and ketoprofen (Nsaid) on Paf-induced ex vivo platelet aggregation in bovine.

The effect of the specific PAF-antagonist WEB 2086, a thieno-triazolo-diazepine, and ketoprofen, a NSAID, was investigated on PAF-induced bovine platelet aggregation measured ex vivo in platelet-rich plasma (PRP). WEB 2086 was infused intravenously over 1 min followed immediately by ketoprofen administration over 1 s (both drugs = 3 mg/kg), in a group of six healthy male Friesian calves. Depending on the PAF concentration, a reversible (10(-8)-10(-9) mol/l) and irreversible (10(-5)-10(-7) mol/l) platelet aggregation was observed. The reversible aggregation was completely blocked by pretreatment of the animal with WEB 2086 and ketoprofen. The inhibitory effects observed during the irreversible aggregation were 47.22%, 54.00% and 88.00% at 10(-5), 10(-6) and 10(-7) mol/l PAF, respectively. Moreover, the aggregation obtained in these condition became reversible. Maximal inhibitory effect of WEB 2086 and ketoprofen on PAF-induced platelet aggregation in calves was observed within 30 min after administration of both drugs. This inhibition persisted even after 24 h and was significantly different from control with P < 0.05. The combined effect of both drugs exceeded the sum of the individual effects (synergism). It was concluded that WEB 2086 and ketoprofen very effectively blocked PAF-induced bovine platelet aggregation in platelet-rich plasma. The study also suggested a synergism between both substances.