Evaluation of the cutaneous anti-inflammatory activity of azaspiranes.
OBJECTIVE
The ability of azaspiranes to modulate the acute inflammatory response in models of skin inflammation was examined.


METHODS
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.


METHODS
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.
Griswold
D E
DE
Department of Immunopharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA. Don_E_Griswold@SBPHRD.com
Martin
L D
LD
Badger
A M
AM
Breton
J
J
Chabot-Fletcher
M
M
D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid; D002460:Cell Line / Q000187:drug effects; D051545:Cyclooxygenase 1; D003877:Dermatitis, Contact / Q000188:drug therapy* / Q000209:etiology; D015232:Dinoprostone / Q000096:biosynthesis; D004423:Ear; D004487:Edema / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007527:Isoenzymes / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013755:Tetradecanoylphorbol Acetate
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D010880:Piperidines; D013141:Spiro Compounds; C099015:azaspirane; C080395:SK&F 106610; D007975:Leukotriene B4; D016718:Arachidonic Acid; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate