The novel phosphodiesterase 4 inhibitor, CI-1044, inhibits LPS-induced TNF-α production in whole blood from COPD patients

• Published in: Pulmonary pharmacology & therapeutics Vol. 18; no. 1; pp. 49 - 54
• Main Authors: Ouagued, M., Martin-Chouly, C.A.E., Brinchault, G., Leportier-Comoy, C., Depincé, A., Bertrand, C., Lagente, V., Belleguic, C., Pruniaux, M.P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-01-2005
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - pharmacology; 3',5'-Cyclic-AMP Phosphodiesterases - therapeutic use; Adult; Azepines - pharmacology; Azepines - therapeutic use; Carboxylic Acids - pharmacology; Carboxylic Acids - therapeutic use; COPD; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Dose-Response Relationship, Drug; Female; France; Human whole blood; Humans; Inflammation; Male; Middle Aged; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Niacinamide - therapeutic use; Nitriles - pharmacology; Nitriles - therapeutic use; PDE4 inhibitors; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - therapeutic use; Polysaccharides, Bacterial - drug effects; Polysaccharides, Bacterial - pharmacology; Pulmonary Disease, Chronic Obstructive - blood; Pulmonary Disease, Chronic Obstructive - drug therapy; Rolipram - pharmacology; Rolipram - therapeutic use; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - metabolism; Inflammation; PDE4 inhibitors; Human whole blood; COPD
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2004.09.031

Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor α (TNF-α) plays a central role as a pro-inflammatory cytokine in COPD. TNF-α release is markedly inhibited by phosphodiesterase type 4 (PDE4) inhibitors that have proven efficacious in COPD clinical trials. The aim of this study was to compare the in vitro activities of the novel selective PDE4 inhibitors CI-1044 compared to well-known PDE4 inhibitors, rolipram and cilomilast, and to the glucocorticoid dexamethasone at reducing lipopolysaccharide (LPS)-induced TNF-α release in whole blood from COPD patients and healthy subjects. In the whole blood from COPD patients pre-incubation with PDE4 inhibitors or dexamethasone resulted in a dose-dependent inhibition of LPS-induced TNF-α release with IC
50 values of 1.3±0.7, 2.8±0.9
μM, higher to 10
μM and lesser than 0.03
μM for CI-1044, rolipram, cilomilast and dexamethasone, respectively. We observed a similar inhibition in the whole blood from healthy volunteers with, however, higher IC
50 values. These results indicate that CI-1044 inhibits in vitro LPS-induced TNF-α release in whole blood from COPD patients better than rolipram and cilomilast and suggested that it could be a useful anti-inflammatory therapy in COPD.