PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression

Phosphodiesterase 4 (PDE4) is a major cyclic AMP-hydrolyzing enzyme in inflammatory and immunomodulatory cells. The wide range of inflammatory mechanisms under control by PDE4 points to this isoenzyme as an attractive target for new anti-inflammatory drugs. Selective inhibitors of PDE4 have demonstr...

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Bibliographic Details
Published in:Pharmacology & therapeutics (Oxford) 2005-06, Vol.106 (3), p.269-297
Main Authors: Sanz, María Jesús, Cortijo, Julio, Morcillo, Esteban J
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
Aminopyridines - pharmacology
Aminopyridines - therapeutic use
Anti-Inflammatory Agents - pharmacology
Anti-Inflammatory Agents - therapeutic use
Benzamides - pharmacology
Benzamides - therapeutic use
Carboxylic Acids - pharmacology
Carboxylic Acids - therapeutic use
Cell Adhesion Molecules - biosynthesis
Cell Movement - drug effects
Cyclic Nucleotide Phosphodiesterases, Type 4
Cyclohexanecarboxylic Acids
Cyclopropanes - pharmacology
Cyclopropanes - therapeutic use
Humans
Nitriles - pharmacology
Nitriles - therapeutic use
Phosphodiesterase Inhibitors - pharmacology
Phosphodiesterase Inhibitors - therapeutic use
Pulmonary Disease, Chronic Obstructive - drug therapy
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Summary:Phosphodiesterase 4 (PDE4) is a major cyclic AMP-hydrolyzing enzyme in inflammatory and immunomodulatory cells. The wide range of inflammatory mechanisms under control by PDE4 points to this isoenzyme as an attractive target for new anti-inflammatory drugs. Selective inhibitors of PDE4 have demonstrated a broad spectrum of anti-inflammatory activities including the inhibition of cellular trafficking and microvascular leakage, cytokine and chemokine release from inflammatory cells, reactive oxygen species production, and cell adhesion molecule expression in a variety of in vitro and in vivo experimental models. The initially detected side effects, mainly nausea and emesis, appear at least partially overcome by the 'second generation' PDE4 inhibitors, some of which like roflumilast and cilomilast are in the later stages of clinical development for treatment of chronic obstructive pulmonary disease. These new drugs may also offer opportunities for treatment of other inflammatory diseases.
ISSN:0163-7258
1879-016X
DOI:10.1016/j.pharmthera.2004.12.001