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Evaluation of the cutaneous anti-inflammatory activity of azaspiranes
D E Griswold1, L D Martin, A M Badger
1Department of Immunopharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA. Don_E_Griswold@SBPHRD.com
Objective And Design:
The ability of azaspiranes to modulate the acute inflammatory response in models of skin inflammation was examined.
Material:
The in vivo experiments involved the use of 5-6 age-matched male Balb/c inbred mice (22-25 g) per treatment group and a control group of 8-10 animals. In vitro mechanistic studies used RBL-1 and U937 cells lines and freshly isolated human monocytes.
Treatment:
Arachidonic acid (AA) (2 mg/20 microl in acetone) or PMA (phorbol myristate acetate) (4 microg/20 microl) were applied topically. SK&F 106615 and SK&F 106610 were administered topically either dissolved in acetone or dimethylacetamide just after the application of the irritant. Isolated cells were treated with the compounds dissolved in DMSO.
Methods:
The thickness and influx of neutrophils into the treated ears was measured as was the effects of the azaspiranes on 5-lipoxygenase activity, cyclooxygenase activity, prostaglandin and leukotriene synthesis, and the activation of the transcription factor NF-kappaB.
Results:
SK&F 106615 and SK&F 106610 significantly reduced inflammation in the AA- and PMA-induced inflammation models (p < 0.05) with ED50's of 179 and 120 mg/ear for edema and myeloperoxidase, respectively. The compounds did not inhibit eicosanoid biosynthesis, have a direct effect on 5-lipoxygenase or cyclooxygenase enzymes, or inhibit NF-kappaB.
Conclusions:
The potent anti-inflammatory and immunomodulatory activities of the azaspiranes observed in these and other studies appear to be mediated by a novel mechanism.