Apremilast, a cAMP phosphodiesterase‐4 inhibitor, demonstrates anti‐inflammatory activity in vitro and in a model of psoriasis

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 ce...

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Bibliographic Details
Published in:British journal of pharmacology 2010-02, Vol.159 (4), p.842-855
Main Authors: Schafer, PH, Parton, A, Gandhi, AK, Capone, L, Adams, M, Wu, L, Bartlett, JB, Loveland, MA, Gilhar, A, Cheung, Y‐F, Baillie, GS, Houslay, MD, Man, H‐W, Muller, GW, Stirling, DI
Format: Article
Language:English
Subjects:
Administration, Oral
Adult
Animals
Anti-Inflammatory Agents - administration & dosage
Anti-Inflammatory Agents - pharmacology
anti‐inflammatory drugs
Biological and medical sciences
Cell Proliferation - drug effects
chemokines
Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism
Cytokines - genetics
Cytokines - metabolism
Dermatology
Disease Models, Animal
Dose-Response Relationship, Drug
Enterotoxins - immunology
Gene Expression Regulation - drug effects
Humans
immunopharmacology
inflammation
Inflammation Mediators - metabolism
Keratinocytes - drug effects
Keratinocytes - enzymology
Keratinocytes - immunology
Killer Cells, Natural - drug effects
Killer Cells, Natural - enzymology
Killer Cells, Natural - immunology
Leukocytes, Mononuclear - drug effects
Leukocytes, Mononuclear - enzymology
Leukocytes, Mononuclear - immunology
Lipopolysaccharides - pharmacology
Medical sciences
Mice
Mice, SCID
Middle Aged
PDE inhibitor
Pharmacology. Drug treatments
Phosphodiesterase 4 Inhibitors
Phosphodiesterase Inhibitors - administration & dosage
Phosphodiesterase Inhibitors - pharmacology
Psoriasis
Psoriasis - drug therapy
Psoriasis - enzymology
Psoriasis - genetics
Psoriasis - immunology
Psoriasis - pathology
Psoriasis. Parapsoriasis. Lichen
Research Papers
RNA, Messenger - metabolism
Rodents
Severity of Illness Index
Skin - drug effects
Skin - enzymology
Skin - immunology
Skin - pathology
Skin - radiation effects
skin pharmacology
Skin Transplantation
Skin, nail, hair, dermoskeleton
Thalidomide - administration & dosage
Thalidomide - analogs & derivatives
Thalidomide - pharmacology
Time Factors
Transplantation, Heterologous
Tumor necrosis factor-TNF
U937 Cells
Ultraviolet Rays
Zymosan - metabolism
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Summary: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:  Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon‐γ and tumour necrosis factor (TNF)‐α, and interleukins (IL)‐2, IL‐12 and IL‐23. Production of TNF‐α by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF‐α, human leukocyte antigen‐DR and intercellular adhesion molecule‐1 in the lesioned skin. 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‐α, 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.
ISSN:0007-1188
1476-5381
DOI:10.1111/j.1476-5381.2009.00559.x