Anti-inflammatory effect of FR140423, a novel selective cyclo-oxygenase-2 inhibitor, in rat adjuvant arthritis without gastrointestinal side effects.
We investigated the effect of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulphinyl)phen yl]pyrazole), a novel and selective cyclo-oxygenase (COX)-2 inhibitor, in rat adjuvant arthritis. The results were compared with that of indomethacin. We tested the inhibitory effects of FR140423 on paw oedema and the formation of the arachidonic acid metabolites prostaglandin (PG) E2 and leukotriene (LT) B4 in inflamed paws immunized with heat-killed and dried Mycobacterium tuberculosis. Oral administration of FR140423 showed a dose-dependent anti-inflammatory effect. This effect was two- to threefold more potent than that of indomethacin. The increase of PGE2 and LTB4 in inflamed paws was associated with the development of paw swelling. FR140423 and indomethacin dose-dependently suppressed the level of PGE2 but not LTB4 in arthritic paws. Unlike indomethacin, FR140423 did not induce gastric lesions even at doses up to 10 mgkg(-1) in arthritic rats. FR140423 has a potent anti-inflammatory effect mediated by inhibition of PGE2 produced by COX-2 in inflamed tissues. The safety profile of FR140423 appears to be an improvement on the safety profile of indomethacin.
Ochi
T
T
Department of Immunology and Inflammation, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, Osaka, Japan.
Goto
T
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D051546:Cyclooxygenase 2; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005753:Gastric Mucosa / Q000187:drug effects; D006614:Hindlimb / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use; D007527:Isoenzymes / Q000494:pharmacology*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D013454:Sulfoxides
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D011720:Pyrazoles; D013454:Sulfoxides; C108904:3-(difluoromethyl)-1-(4-methoxyphenyl)-5-(4-(methylsulfinyl)phenyl)pyrazole; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin