EVALUATION OF THE CUTANEOUS ANTIINFLAMMATORY ACTIVITY OF AZASPIRANES

Objective and Design: The ability of azaspiranes to modulate and acute inflammatory response in models of skin inflammation was examined. Ma terial: The in vivo experiments involved the use of 5-6 age-matched ma le Balb/c inbred mice (22-25 g) per treatment group and a control grou p of 8-10 animals. In vitro mechanistic studies used RBL-1 and U937 ce lls lines and freshly isolated human monocytes. Treatment: Arachidonic acid (AA) (2 mg/20 ul in acetone) or PMA (phorbol myristate acetate) (4 ug/20 ul) were applied topically. SK&F 106615 and SK&F 106610 were administered topically either dissolved in acetone or dimethylacetamid e just after the application of the irritant. Isolated cells were trea ted with the compounds dissolved in DMSO. Methods: The thickness and i nflux of neutrophils into the treated ears was measured as was the eff ects of the azaspiranes on 5-lipoxygenase activity, cyclooxygenase act ivity, prostaglandin and leukotriene synthesis, and the activation of the transcription factor NF-kappa B. Results: SK&F 106615 and SK&F 106 610 significantly reduced inflammation in the AA- and PMA-induced infl ammation models (p < 0.05) with ED50's of 179 and 120 mg/ear for edema and myeloperoxidase, respectively. The compounds did not inhibit eico sanoid biosynthesis, have a direct effect on 5-lipoxygenase or cycloox ygenase enzymes, or inhibit NF-kappa B. Conclusions: The potent anti-i nflammatory and immunomodulatory activities of the azaspiranes observe d in these and other studies appear to be mediated by a novel mechanis m.