Effect of topically applied cyclooxygenase-2-selective inhibitors on arachidonic acid- and tetradecanoylphorbol acetate-induced dermal inflammation in the mouse.
The topical effects of cyclooxygenase-2 (COX-2)-selective inhibitors, flosulide (CGP 28238), L-745,337 and SC-57,666 were examined in AA- and TPA-induced ear dermal inflammation in the mouse. The doses that caused 50% inhibition in AA edema (ED50) were 2.4, 0.45 and 0.35 mg/ear for flosulide, L-745,337 and SC-57,666, respectively. The respective ED50s in TPA-edema were 1, 0.45 and 0.14. Indomethacin and zileuton showed higher activity than the COX-2-selective inhibitors in both models. Flosulide and L-745,337 inhibited the AA-induced increase in 6-keto-PGF1 alpha, while SC-57,666 was inactive, 80% inhibition was seen with indomethacin while zileuton had no effect. COX-2-selective inhibitors and indomethacin had no effect on LTB4 levels, while zileuton produced a 50% inhibition. The TPA-induced increase in 6-keto-PGF1 alpha was greatly inhibited by all COX-2 inhibitors while LTB4 was potentiated by both flosulide and L-745,337. Indomethacin inhibited 6-keto-PGF1 alpha and zileuton reduced 6-keto-PGF alpha and strongly reduced LTB4. The neutrophil influx induced by AA was lower than that of TPA. Myeloperoxidase (MPO) levels were lowered by flosulide and L-745,337 but not by SC-57,666. TPA-induced MPO increase was decreased by all COX-2 inhibitors. Indomethacin and zileuton had similar effect on AA and TPA-induced increase in MPO. The results indicate that COX-2-selective inhibitors showed lower topical anti-inflammatory activity than indomethacin or zileuton.
Puigneró
V
V
Unitat de Fisiologia, Facultat de Farmàcia Universitat de Barcelona, Spain.
Queralt
J
J
D000118:Acetylglucosaminidase / Q000378:metabolism; D000287:Administration, Topical; D000818:Animals; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003875:Drug Eruptions / Q000378:metabolism / Q000473:pathology*; D015777:Eicosanoids / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D007527:Isoenzymes; D016718:Arachidonic Acid; D009195:Peroxidase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000118:Acetylglucosaminidase; D013755:Tetradecanoylphorbol Acetate