Platelet activating factor (PAF) is a naturally occurring phospholipid with a wide spectrum of biological activities. Although PAF has been ascribed a potential role in various conditions including inflammation, asthma, glomerulonephritis and thrombosis, its precise function in physiologic/pathophysiologic processes remains unclear. The introduction of selective PAF receptor antagonists could represent a useful tool to extend our knowledge of the role of this mediator in health and disease.We have investigated the efficacy and tolerability of (RS)-2-methoxy-3-(octadecylcarbomoyloxy)propy1 2-(3-thiazolio)-ethyIphosphate (CV-3988, Takeda Chem. Ind), a selective PAF antagonist with structural analogies with PAF, after intravenous infusion in man in a double-blind, placebo-controlled study. The compound, in doses from 750 to 2,000 pg/kg, significantly reduced platelet sensitivity to PAF. The threshold aggregating concentration (TAC) of PAF was defined as the minimal concentration causing an irreversible aggregation with a maximal amplitude of at least 50% of the difference in light transmission between platelet rich plasma and platelet poor plasma. It increased in a dose-dependent manner reaching 3.6 times the basal TAC (p<0.0005) at the end and 2.60 times the basal TAC (p<0.0005) 4 hours after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 hours after the end of the infusion.CV-3988 did not cause major side effects nor changes in blood pressure, pulse or respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and four hours after the end of the infusion, indicating a slight haemolysis probably by high local concentrations at the infusion site.Our results indicate that, when adequate infusion volumes and infusion rates are used, CV-3988 can be safely administered to man and should be useful in elucidating the role of PAF in health and disease.
Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute
