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 (TNFalpha) production in whole blood and antigen-induced lung eosinophilia. In vitro, CI-1044 inhibited TNFalpha production with an IC(50) of 0.31 microm being equipotent to Cilomilast (IC(50) = 0.26 microm) and rolipram (IC(50) = 0.11 microm). Given orally, CI-1044 inhibited ex vivo TNFalpha 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 microm). In vivo, CI-1044 prevented TNFalpha 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.
Pruniaux
Marie-Pierre
MP
Pfizer Global Research and Development, Fresnes Laboratories, Fresnes, France.
Lagente
Vincent
V
Ouaged
Malika
M
Bertin
Bernadette
B
Moreau
François
F
Julien-Larose
Christine
C
Rocher
Marie-Noelle
MN
Leportier
Christelle
C
Martin
Brigitte
B
Bouget
Anita
A
Dubuit
Jean-Pierre
JP
Burnouf
Catherine
C
Doherty
Annette M
AM
Bertrand
Claude P
CP
D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011657:Pulmonary Eosinophilia / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D011914:Rats, Inbred BN; D020889:Rolipram / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D001381:Azepines; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D008070:Lipopolysaccharides; D009570:Nitriles; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009536:Niacinamide; C433247:Cilomilast; D020889:Rolipram; C418118:CI 1044