Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.
Abstract | BACKGROUND AND PURPOSE:
Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis. EXPERIMENTAL APPROACH:
Apremilast was tested in vitro against endotoxin- and superantigen-stimulated PBMC, bacterial peptide and zymosan-stimulated polymorphonuclear cells, immunonoglobulin and cytokine-stimulated NK cells, and ultraviolet B light-activated keratinocytes. Apremilast was orally administered to beige-severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed. KEY RESULTS: CONCLUSIONS AND IMPLICATIONS:
Apremilast displayed a broad pattern of anti-inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF-alpha, IL-12 and IL-23 production, as well as NK and keratinocyte responses by this phosphodiesterase-4 inhibitor suggests a novel approach to the treatment of psoriasis.
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Authors | P H Schafer, A Parton, A K Gandhi, L Capone, M Adams, L Wu, J B Bartlett, M A Loveland, A Gilhar, Y-F Cheung, G S Baillie, M D Houslay, H-W Man, G W Muller, D I Stirling |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 159
Issue 4
Pg. 842-55
(Feb 2010)
ISSN: 1476-5381 [Electronic] England |
PMID | 20050849
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Inflammatory Agents
- Cytokines
- Enterotoxins
- Inflammation Mediators
- Lipopolysaccharides
- Phosphodiesterase 4 Inhibitors
- Phosphodiesterase Inhibitors
- RNA, Messenger
- enterotoxin B, staphylococcal
- Thalidomide
- Zymosan
- Cyclic Nucleotide Phosphodiesterases, Type 4
- apremilast
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Topics |
- Administration, Oral
- Adult
- Animals
- Anti-Inflammatory Agents
(administration & dosage, pharmacology)
- Cell Proliferation
(drug effects)
- Cyclic Nucleotide Phosphodiesterases, Type 4
(metabolism)
- Cytokines
(genetics, metabolism)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Enterotoxins
(immunology)
- Gene Expression Regulation
(drug effects)
- Humans
- Inflammation Mediators
(metabolism)
- Keratinocytes
(drug effects, enzymology, immunology)
- Killer Cells, Natural
(drug effects, enzymology, immunology)
- Leukocytes, Mononuclear
(drug effects, enzymology, immunology)
- Lipopolysaccharides
(pharmacology)
- Mice
- Mice, SCID
- Middle Aged
- Phosphodiesterase 4 Inhibitors
- Phosphodiesterase Inhibitors
(administration & dosage, pharmacology)
- Psoriasis
(drug therapy, enzymology, genetics, immunology, pathology)
- RNA, Messenger
(metabolism)
- Severity of Illness Index
- Skin
(drug effects, enzymology, immunology, pathology, radiation effects)
- Skin Transplantation
- Thalidomide
(administration & dosage, analogs & derivatives, pharmacology)
- Time Factors
- Transplantation, Heterologous
- U937 Cells
- Ultraviolet Rays
- Zymosan
(metabolism)
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