title: The novel phosphodiesterase 4 inhibitor, CI-1044, inhibits LPS-induced TNF-alpha production in whole blood from COPD patients.
abstract: Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor alpha (TNF-alpha) plays a central role as a pro-inflammatory cytokine in COPD. TNF-alpha release is markedly inhibited by phosphodiesterase type 4 (PDE4) inhibitors that have proven efficacious in COPD clinical trials. The aim of this study was to compare the in vitro activities of the novel selective PDE4 inhibitors CI-1044 compared to well-known PDE4 inhibitors, rolipram and cilomilast, and to the glucocorticoid dexamethasone at reducing lipopolysaccharide (LPS)-induced TNF-alpha release in whole blood from COPD patients and healthy subjects. In the whole blood from COPD patients pre-incubation with PDE4 inhibitors or dexamethasone resulted in a dose-dependent inhibition of LPS-induced TNF-alpha release with IC(50) values of 1.3+/-0.7, 2.8+/-0.9 microM, higher to 10 microM and lesser than 0.03 microM for CI-1044, rolipram, cilomilast and dexamethasone, respectively. We observed a similar inhibition in the whole blood from healthy volunteers with, however, higher IC(50) values. These results indicate that CI-1044 inhibits in vitro LPS-induced TNF-alpha release in whole blood from COPD patients better than rolipram and cilomilast and suggested that it could be a useful anti-inflammatory therapy in COPD.
authors.affiliation: PFIZER Global Research and Development, Fresnes Laboratories, Fresnes, France.
authors.forename: M
authors.initials: M
authors.lastname: Ouagued
authors.forename: C A E
authors.initials: CA
authors.lastname: Martin-Chouly
authors.forename: G
authors.initials: G
authors.lastname: Brinchault
authors.forename: C
authors.initials: C
authors.lastname: Leportier-Comoy
authors.forename: A
authors.initials: A
authors.lastname: Depincé
authors.forename: C
authors.initials: C
authors.lastname: Bertrand
authors.forename: V
authors.initials: V
authors.lastname: Lagente
authors.forename: C
authors.initials: C
authors.lastname: Belleguic
authors.forename: M P
authors.initials: MP
authors.lastname: Pruniaux
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use; D002264:Carboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011135:Polysaccharides, Bacterial / Q000187:drug effects / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000188:drug therapy; D020889:Rolipram / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism
chemical_list: D001381:Azepines; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D011135:Polysaccharides, Bacterial; D014409:Tumor Necrosis Factor-alpha; D009536:Niacinamide; D003907:Dexamethasone; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; C418118:CI 1044