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Article Dans Une Revue Fundamental & Clinical Pharmacology Année : 2010

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

Marie-Pierre Pruniaux
  • Fonction : Auteur
Malika Ouaged
  • Fonction : Auteur
Bernadette Bertin
  • Fonction : Auteur
François Moreau
  • Fonction : Auteur
Christine Julien-Larose
  • Fonction : Auteur
Marie-Noelle Rocher
  • Fonction : Auteur
Christelle Leportier
  • Fonction : Auteur
Brigitte Martin
  • Fonction : Auteur
Anita Bouget
  • Fonction : Auteur
Jean-Pierre Dubuit
  • Fonction : Auteur
Catherine Burnouf
  • Fonction : Auteur
Annette M. Doherty
  • Fonction : Auteur
Claude P. Bertrand
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-00742372 , version 1 (16-10-2012)

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Citer

Marie-Pierre Pruniaux, Vincent Lagente, Malika Ouaged, Bernadette Bertin, François Moreau, et al.. Relationship between phosphodiesterase type 4 inhibition and anti-inflammatory activity of CI-1044 in rat airways.. Fundamental & Clinical Pharmacology, 2010, 24 (1), pp.73-82. ⟨10.1111/j.1472-8206.2009.00725.x⟩. ⟨hal-00742372⟩
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