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.