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.