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Relationship between phosphodiesterase type 4 inhibition and anti‐inflammatory activity of CI‐1044 in rat airways
Author(s) -
Pruniaux MariePierre,
Lagente Vincent,
Ouaged Malika,
Bertin Bernadette,
Moreau François,
JulienLarose Christine,
Rocher MarieNoelle,
Leportier Christelle,
Martin Brigitte,
Bouget Anita,
Dubuit JeanPierre,
Burnouf Catherine,
Doherty Annette M.,
Bertrand Claude P.
Publication year - 2010
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2009.00725.x
Subject(s) - rolipram , ex vivo , in vivo , eosinophilia , pharmacology , medicine , tumor necrosis factor alpha , phosphodiesterase , lipopolysaccharide , chemistry , endocrinology , biology , enzyme , biochemistry , microbiology and biotechnology
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 α (TNFα) production in whole blood and antigen‐induced lung eosinophilia. In vitro, CI‐1044 inhibited TNFα production with an IC 50 of 0.31 μ m being equipotent to Cilomilast (IC 50 = 0.26 μ m ) and rolipram (IC 50 = 0.11 μ m ). Given orally, CI‐1044 inhibited ex vivo TNFα production with an ED 50 value of 0.4 mg/kg after single administration, whereas rolipram (ED 50 = 1.4 mg/kg) and cilomilast (ED 50 = 1.6 mg/kg) were less potent. In the same ex vivo setting, but given repeatedly, CI‐1044 led to an ED 50 of 0.5 mg/kg corresponding to a plasma concentration of 82.6 ng/mL (0.22 μ m ). In vivo, CI‐1044 prevented TNFα release with an ED 50 of 1 mg/kg p.o. and inhibited ovalbumin‐induced lung eosinophilia following single or repeated oral administration with an ED 50 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.