PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease.
Inflammation is a hallmark of inflammatory bowel disease (IBD), and elevation of cAMP levels can inhibit the pro-inflammatory and tissue-destructive properties of leukocytes. Phosphodiesterase 4 (PDE4) is the predominant enzyme that metabolizes cAMP in inflammatory cells, and the anti-inflammatory and immunomodulatory potential of PDE4 inhibitors in human leukocytes, endothelium and epithelium is well documented. Although PDE4 inhibitors have been investigated as treatments for several inflammatory diseases, this has focused mainly on asthma and chronic obstructive disease (COPD). Historically, their clinical utility has been limited by nausea and emesis. However, the PDE4 inhibitors cilomilast and roflumilast have recently shown efficacy in asthma and COPD, with a reduced propensity to cause nausea and emesis. In this review, we summarize for the first time the evidence that PDE4 inhibitors might have therapeutic benefit in IBD, and discuss mechanisms of action beyond the inhibition of inflammatory cells.
Banner
Katharine H
KH
Pfizer Global Research and Development, Discovery Biology, Allergy and Respiratory Group, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. kathy_banner@sandwich.pfizer.com
Trevethick
Michael A
MA
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D002264:Carboxylic Acids; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology; D009570:Nitriles
D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D001993:Bronchodilator Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D009570:Nitriles; C424423:Roflumilast; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4