[The mode of anti-inflammatory action of a topical non-steroidal anti-inflammatory drug, etofenamate].
In order to ascertain the mode of anti-inflammatory action of a topical non-steroidal anti-inflammatory drug, etofenamate which is a diethylene glycol ester of flufenamic acid, the in vitro test for the mechanism of the action were carried out. Etofenamate (3 microM) was hydrolysed to flufenamic acid at a rate of 39.5% and 57.0% of the dose during 30 and 60 min incubation, respectively, when incubated with rat peritoneal macrophages stimulated with starch and bacto peptone in phosphate-buffered saline. PGE2 generation by these cells in MEM medium was dose-relatedly inhibited with etofenamate as well as flufenamic acid at the dosage range of 1 to 30 microM. This suggests that unchanged etofenamate is active, since the highest conversion rate of etofenamate to flufenamic acid was 15% of the dose during the incubation. Etofenamate produced a dose-related inhibition against lipoxygenase prepared from peritoneal polymorphonuclear leucocytes of guinea pigs, and its activity (IC50 = 5.3 X 10(-5) M) was stronger than that of caffeic acid; flufenamic acid was inactive. Inhibitory activity of etofenamate was one-third or less that of flufenamic acid against the hypotonic-hyperthermic lysis of rat erythrocytes and heat-denaturation of bovine serum albumin. From these results, it was suggested that topically applied etofenamate produces its anti-inflammatory action through prostaglandin synthesis inhibition by flufenamic acid produced in the inflammatory tissue and inhibition of prostaglandin synthesis by macrophages and lipoxygenase inhibition by unchanged etofenamate.
D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015232:Dinoprostone; D004910:Erythrocyte Membrane / Q000187:drug effects; D005439:Flufenamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D010529:Peritoneal Cavity / Q000166:cytology; D011458:Prostaglandins E / Q000096:biosynthesis; D011489:Protein Denaturation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006634:Histamine H1 Antagonists; D016859:Lipoxygenase Inhibitors; D011458:Prostaglandins E; D005439:Flufenamic Acid; D015232:Dinoprostone; C015207:etofenamate