Evaluation of the cutaneous anti-inflammatory activity of azaspiranes.

Abstract

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.

• Authors: D E Griswold, L D Martin, A M Badger, J Breton, M Chabot-Fletcher
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 47 Issue 2 Pg. 56-61 (Feb 1998) ISSN: 1023-3830 [Print] Switzerland
• PMID: 9535542 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Immunosuppressive Agents
• Isoenzymes
• Membrane Proteins
• NF-kappa B
• Piperidines
• Spiro Compounds
• azaspirane
• SK&F 106610
• Leukotriene B4
• Arachidonic Acid
• Peroxidase
• Arachidonate 5-Lipoxygenase
• Cyclooxygenase 1
• PTGS1 protein, human
• Prostaglandin-Endoperoxide Synthases
• Ptgs1 protein, mouse
• Dinoprostone
• Tetradecanoylphorbol Acetate

Topics

• Administration, Topical
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, pharmacology, therapeutic use)
• Arachidonate 5-Lipoxygenase (metabolism)
• Arachidonic Acid
• Cell Line (drug effects)
• Cyclooxygenase 1
• Dermatitis, Contact (drug therapy, etiology)
• Dinoprostone (biosynthesis)
• Ear
• Edema (drug therapy, etiology)
• Humans
• Immunosuppressive Agents (administration & dosage, pharmacology, therapeutic use)
• Isoenzymes (metabolism)
• Leukotriene B4 (biosynthesis)
• Male
• Membrane Proteins
• Mice
• Mice, Inbred BALB C
• Monocytes (drug effects)
• NF-kappa B (metabolism)
• Peroxidase (metabolism)
• Piperidines (administration & dosage, pharmacology, therapeutic use)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Spiro Compounds (administration & dosage, pharmacology, therapeutic use)
• Tetradecanoylphorbol Acetate