PF-5901 inhibits gastrointestinal platelet-activating factor synthesis in vivo

PF-5901, a novel anti-inflammatory compound, has previously been shown to inhibit the synthesis of platelet-activating factor (PAF) by peritoneal mast cells in vitro. The purpose of the present study was to assess the effects of this compound on PAF synthesis in vivo using two animal models which are characterized by elevated levels of gastrointestinal PAF synthesis. In the first study, rats were infected with Nippostrongylus brasiliensis and killed 17 days later. Groups of infected rats were given PF-5901 at doses ranging from 0.1 to 100 mg/kg, and 12 h later the effects on jejunal PAF synthesis were determined. PF-5901 reduced PAF synthesis in a concentration-dependent manner, with inhibition reaching 95% at the highest dose tested. In the second study, groups of rats were orally pretreated with PF-5901 (100 mg/kg) or vehicle 3 or 12 h prior to induction of endotoxic shock by i.v. administration of lipopolysaccharide from Salmonella typhosa. PAF synthesis in various regions of the gastrointestinal tract was assessed 15 min later. PF-5901 significantly reduced the hemoconcentration, but not the hypotension associated with endotoxic shock. Moreover, this compound significantly inhibited PAF synthesis in all tissues studied when a 12 h pretreatment time was used, and in all tissues except the duodenum when a 3 h pretreatment time was used. These studies demonstrate that PF-5901 inhibits gastrointestinal PAF synthesis in two in vivo models. This compound may therefore be a useful pharmacological tool for future studies on the role of PAF in inflammatory processes, and the effects of PF-5901 on PAF synthesis may contribute to its anti-inflammatory properties.