title: Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors.
abstract: Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity. We compared the anti-inflammatory effects of roflumilast with those of PDE4 inhibitors rolipram, piclamilast, and cilomilast in ovalbumin (OVA)-sensitized and challenged Brown-Norway rats. Animals were treated orally 1h before OVA challenge with roflumilast (0.3, 1.0, and 3.0mg/kg), rolipram (0.8, 2.8, and 8.3mg/kg), piclamilast (10.0, 20.0, and 30.0mg/kg), or cilomilast (10.3, 34.3, and 103.0mg/kg). Airway hyperresponsiveness (AHR) against adenosine was investigated by measuring airway resistance 200min after OVA challenge. Subsequently, neutrophil influx and tumor necrosis factor-alpha (TNF-alpha) release in the lungs were determined by bronchoalveolar lavage. Direct bronchodilation at the time point of AHR assessment by PDE4 inhibitors was examined in serotonin-challenged animals. Evaluation of neutropenic animals or treatment with anti-TNF-alpha antibody revealed that AHR was independent of neutrophil accumulation or TNF-alpha release. Roflumilast (50% inhibitory dose [ID(50)]=1.5mg/kg) inhibited AHR 3-, 16-, and 27-fold more potently than rolipram, piclamilast, and cilomilast, respectively. Likewise, roflumilast was a more potent inhibitor of neutrophil influx (ID(50)=0.9mg/kg) than rolipram (ID(50)=6.9mg/kg), piclamilast (ID(50)=28.1mg/kg), or cilomilast (ID(50)=37.7mg/kg). Roflumilast, rolipram, and piclamilast-but not cilomilast-suppressed OVA-induced TNF-alpha release in a dose-dependent manner. Roflumilast (ID(50)=0.9mg/kg) exhibited 9- and 23-fold more potent inhibition of TNF-alpha release than rolipram and piclamilast, respectively. Roflumilast did not inhibit serotonin-induced bronchoconstriction 4.5h after administration, suggesting that inhibition of AHR by roflumilast results from anti-inflammatory, not bronchodilatory, effects. This study suggests that roflumilast has anti-inflammatory action and provides rationale for the investigation of roflumilast in asthmatic patients.
authors.affiliation: ALTANA Pharma, Byk-Gulden-Strasse 2, 78467 Konstanz, Germany. stefan-lutz.wollin@altanapharma.com
authors.forename: L
authors.initials: L
authors.lastname: Wollin
authors.forename: D S
authors.initials: DS
authors.lastname: Bundschuh
authors.forename: A
authors.initials: A
authors.lastname: Wohlsen
authors.forename: D
authors.initials: D
authors.lastname: Marx
authors.forename: R
authors.initials: R
authors.lastname: Beume
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000627:therapeutic use*; D001986:Bronchial Spasm / Q000139:chemically induced / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D007114:Immunization / Q000379:methods; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use; D010047:Ovalbumin / Q000008:administration & dosage; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D020889:Rolipram / Q000008:administration & dosage / Q000627:therapeutic use; D012701:Serotonin / Q000008:administration & dosage; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C424423:Roflumilast; D012701:Serotonin; C433247:Cilomilast; D010047:Ovalbumin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; C087566:piclamilast