Abstract
Background: CHF6001 is a novel selective phosphodiesterase type 4 (PDE4) inhibitor designed for inhaled administration and in development for the treatment of chronic obstructive pulmonary disease (COPD). We compared the anti-inflammatory effects of CHD6001 with the oral PDE4 inhibitor roflumilast using COPD alveolar macrophages (AM) and lung tissue explants as ex-vivo models.
Methods: AM from 11 COPD patients and 9 smoking controls and lung tissue from 7 COPD patients were stimulated with LPS (1µg/ml) following preincubation with roflumilast (0.001-10000nM), CHF6001 (0.001-100nM), or vehicle. After 24h, the supernatants were analysed for TNFa by ELISA.
Results: Roflumilast and CHF6001 significantly (p<0.05) reduced TNFa production in AM from COPD patients and controls and lung tissue from COPD patients with maximum inhibitions of 53% (1000nM), 43% (100nM) and 79% (1000nM) for roflumilast and 49% (1nM), 40% (1nM) and 70% (10nM) for CHF6001 in respective samples. CHF6001 was more potent than roflumilast with lower EC50s of 0.02, 0.01 and 0.31nM compared to 0.87, 0.47 and 10.8nM in respective samples and maximal inhibition reached at lower concentrations.
Conclusion
This is the first demonstration that PDE4 inhibitors can elicit a robust anti-inflammatory effect in AM from COPD patients. CHF6001 caused more potent inhibition of TNFa production from COPD AM and lung tissue when compared to roflumilast.
- © 2014 ERS