title: The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.
abstract: OBJECTIVE
  The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model.
  
  
  METHODS
  The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression.
  
  
  RESULTS
  Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo.
  
  
  CONCLUSIONS
  These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.
authors.affiliation: Division of Clinical Pharmacology and Section of Gastroenterology, University of Munich, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Rieder
authors.forename: Britta
authors.initials: B
authors.lastname: Siegmund
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Bundschuh
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Andreas
authors.initials: A
authors.lastname: Eigler
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology*; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099192:CD69 Antigens
chemical_list: D000631:Aminopyridines; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001549:Benzamides; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003521:Cyclopropanes; D016264:Dextran Sulfate; D007371:Interferon-gamma; D037181:Lectins, C-Type; D009287:Naphthyridines; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens; C528394:pumafentrine; C424423:Roflumilast