PROTECTIVE EFFECTS OF PF-10040 IN EXPERIMENTAL NSAID-GASTRITIS - ROLEOF LEUKOCYTES, LEUKOTRIENES AND PAF

The effects and mechanism of action of PF-10040, a quinoline derivativ e, were examined in an experimental model of NSAID-gastritis. Oral pre treatment with PF-10040 dose-dependently reduced the severity of indom ethacin-induced gastric damage, with a significant protective effect b eing observed with doses of 10 mg/kg or greater. The protective effect s of this compound persisted for as long as 6 h after administration. PF-10040 also significantly reduced the severity of aspirin- or naprox en-induced gastric damage. At protective doses, PF-10040 did not signi ficantly affect gastric LTB4 synthesis, LTB4-induced granulocyte recru itment to intradermal injection sites, or LTD4-induced changes in gast ric blood flow. The free radical scavenging effects of PF-10040 were e xamined using an in vitro assay, in which it failed to exert significa nt effects at concentrations of up to 10 mM. PF-10040 had no significa nt effect on gastric acid secretion. In rat mesenteric venules, PF-100 40 inhibited PAF-, but not LTB4-induced leukocyte adherence and emigra tion. These results suggest that the protective effects of PF-10040 ar e not attributable to scavenging of free radicals, inhibition of leuko triene synthesis, blockade of LTB4 or LTD4 receptors or inhibition of LTB4-mediated leukocyte endothelial cell adhesion.