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

Chronic obstructive pulmonary disease (COPD) is a common. progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor alpha (TNF-alpha) plays a central role as a pro-inflammatory cytokine in COPD. TNF-alpha 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-alpha 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-alpha release with IC50 values of 1.3 +/- 0.7, 2.8 +/- 0.9 u-N-4. higher to 10 mum and lesser than 0.03 muM for Cl-1044, rolipram, cilomilast and dexamethasone, respectively. We observed a sirnilar inhibition in the whole blood from healthy volunteers with, however, higher IC50 values. These results indicate that CI-1044 inhibits in vitro LPS-induced TNF-alpha 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. (C) 2004 Elsevier Ltd. All rights reserved.