Relationship between phosphodiesterase type 4 inhibition and anti-inflammatory activity of CI-1044 in rat airways

The anti-inflammatory effects of CI-1044 and of the other selective PDE4 inhibitors rolipram and cilomilast were investigated in Brown-Norway (BN) rats, against lipopolysaccharide-induced tumor necrosis factor alpha (TNF alpha) production in whole blood and antigen-induced lung eosinophilia. In vitro, CI-1044 inhibited TNF alpha production with an IC50 of 0.31 mu m being equipotent to Cilomilast (IC50 = 0.26 mu m) and rolipram (IC50 = 0.11 mu m). Given orally, CI-1044 inhibited ex vivo TNF alpha production with an ED50 value of 0.4 mg/kg after single administration, whereas rolipram (ED50 = 1.4 mg/kg) and cilomilast (ED50 = 1.6 mg/kg) were less potent. In the same ex vivo setting, but given repeatedly, CI-1044 led to an ED50 of 0.5 mg/kg corresponding to a plasma concentration of 82.6 ng/mL (0.22 mu m). In vivo, CI-1044 prevented TNF alpha release with an ED50 of 1 mg/kg p.o. and inhibited ovalbumin-induced lung eosinophilia following single or repeated oral administration with an ED50 of 3.25 and 4.8 mg/kg p.o., respectively, suggesting the absence of pharmacological tolerance. CI-1044 in this model was equipotent to rolipram (81% inhibition at 10 mg/kg) but better than cilomilast (25% inhibition at 10 mg/kg). Finally, CI-1044 (10 mg/kg) inhibited inflammatory cell recruitment with a long duration of action (up to 8 h) and was still active when given post-challenge. Our data show that CI-1044 is an orally active PDE4 inhibitor that may be used as an anti-inflammatory therapy in lung inflammatory diseases.