Search

The possible utility of DuP 654, a potent 5-lipoxygenase inhibitor, for treating human inflammatory skin disease was investigated in murine skin treated with 1.0 mg arachidonic acid (AA). When DuP 654 was applied to murine skin treated with AA, it inhibited the resulting inflammation and influx of cells. High performance liquid chromatography and radioimmunoassay analysis of lipid extracts from AA-treated ears indicated that the influx of polymorphonuclear leukocytes (PMN) was temporally preceded by an appearance of significant amounts of 5-HETE (6.7 ± 1.4 ng/ear) and Leukotriene B4 LTB4 0.92 ± 0.2 ng/ear) when compared with extracts of untreated ears (5-HETE, 02 ± 0.3 ng/ear; LTB4, < 0.1 ng/ear). The levels of the 5-lipoxygenase products were reduced by treatment with 10 µg/ear DuP 654. Lipid extracts from AA-treated ears contain chemotactic activity for human PMN and this chemotactic activity in the AA-treated ears could be reduced but not eliminated by immunosorption with anti-LTB4 antibodies coupled to protein A-agarose. The appearance of the chemotactic activity was inhibited by DuP 654. Taken together, these data suggest that DuP 654 may have utility in human inflammatory skin disease.

Azapropazone at concentrations of 0.1 to 1 mM inhibited by 30–70% rat neutrophil migration, aggregation, and degranulation in response to the synthetic chemotactic peptide fMet-Leu-Phe. Binding studies using fNle-Leu-[ 3 H]Phe, a radiolabeled analog of fMet-Leu-Phe, showed that azapropazone did not inhibit these responses by interfering with fMet-Leu-Phe binding. Azapropazone also decreased both the apparent rate of production and maximal levels of Superoxide anion (O 2 − ) generated by cells stimulated with 100 ng/ml phorbol-12-myristate-13-acetate (PMA). The concentrations of azapropazone that inhibit these neutrophil responses in vitro approximate those previously found in vivo after administration of therapeutic doses of drug to rats or humans. Taken together, the data suggest that the efficacy of azapropazone in gouty arthritis may be partly due to its ability to inhibit key neutrophil functional responses in vivo .