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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

In Vivo Efficacy in Airway Disease Models of Roflumilast, a Novel Orally Active PDE4 Inhibitor

Daniela S. Bundschuh, Manfrid Eltze, Johannes Barsig, Lutz Wollin, Armin Hatzelmann and Rolf Beume
Journal of Pharmacology and Experimental Therapeutics April 2001, 297 (1) 280-290;
Daniela S. Bundschuh
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Manfrid Eltze
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Johannes Barsig
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Lutz Wollin
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Armin Hatzelmann
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Rolf Beume
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Abstract

We have investigated the bronchodilator and anti-inflammatory properties of roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyrid-4-yl]-benzamide), a novel, highly potent, and selective phosphodiesterase 4 (PDE4) inhibitor. Additionally, we compared the effects of roflumilast and itsN-oxide, the primary metabolite in vivo, with those of the PDE4 inhibitors piclamilast, rolipram, and cilomilast. Roflumilast inhibited the ovalbumin-evoked contractions of tracheal chains prepared from sensitized guinea pigs (EC50 = 2 × 10−7 M) but showed no relaxant effect on tissues contracted spontaneously. In spasmogen-challenged rats and guinea pigs, intravenously administered roflumilast displayed bronchodilatory activity (ED50 = 4.4 and 7.1 μmol/kg, respectively). Furthermore, roflumilast dose dependently attenuated allergen-induced bronchoconstriction in guinea pigs (ED50 = 0.1 μmol/kg i.v.). Roflumilast given orally (ED50 = 1.5 μmol/kg) showed equal potency to its N-oxide (ED50 = 1.0 μmol/kg) but was superior to piclamilast (ED50 = 8.3 μmol/kg), rolipram (ED50 = 32.5 μmol/kg), and cilomilast (ED50 = 52.2 μmol/kg) in suppressing allergen-induced early airway reactions. To assess the anti-inflammatory potential of orally administered roflumilast, antigen-induced cell infiltration, total protein, and TNFα concentration in bronchoalveolar lavage fluid of Brown Norway rats were determined. Roflumilast and its N-oxide equally inhibited eosinophilia (ED50 = 2.7 and 2.5 μmol/kg, respectively), whereas the reference inhibitors displayed lower potency (ED50 = 17–106 μmol/kg). Besides, orally administered roflumilast abrogated LPS-induced circulating TNFα in the rat (ED50 = 0.3 μmol/kg), an effect shared by its N-oxide, with both molecules exhibiting 8-, 25-, and 310-fold superiority to piclamilast, rolipram, and cilomilast, respectively. These results, coupled with the in vitro effects of roflumilast on inflammatory cells, suggest that roflumilast represents a potential new drug for the treatment of asthma and chronic obstructive pulmonary disease.

Footnotes

  • Send reprint requests to: Dr. Daniela S. Bundschuh, Department of Pharmacology, Byk Gulden, P.O. Box 10 03 10, 78403 Konstanz, Germany. E-mail: daniela.bundschuh{at}byk.de

  • This work is dedicated to the inventor of roflumilast, Dr. Hermann Amschler, who deceased in 1999 to our deepest regret.

  • Abbreviations:
    COPD
    chronic obstructive pulmonary disease
    PDE4
    phosphodiesterase type 4
    roflumilast
    3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyrid-4-yl]-benzamide
    cilomilast
    Ariflo, SB 207499
    N-oxide
    roflumilastN-oxide
    piclamilast
    RP 73401
    BN
    Brown Norway
    OVA
    ovalbumin
    LPS
    lipopolysaccharide, endotoxin
    PEG400
    polyethylene glycol 400
    AHG
    Al(OH)3
    F
    flow
    PIP
    inflation pressure
    TV
    tidal volume
    RAW
    airway resistance
    CON
    conductance
    AUC
    area under the curve
    BAL
    bronchoalveolar lavage
    TNFα
    tumor necrosis factor-α
    BALF
    bronchoalveolar lavage fluid
    ELISA
    enzyme-linked immunosorbent assay
    • Received September 15, 2000.
    • Accepted December 4, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 1
1 Apr 2001
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

In Vivo Efficacy in Airway Disease Models of Roflumilast, a Novel Orally Active PDE4 Inhibitor

Daniela S. Bundschuh, Manfrid Eltze, Johannes Barsig, Lutz Wollin, Armin Hatzelmann and Rolf Beume
Journal of Pharmacology and Experimental Therapeutics April 1, 2001, 297 (1) 280-290;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

In Vivo Efficacy in Airway Disease Models of Roflumilast, a Novel Orally Active PDE4 Inhibitor

Daniela S. Bundschuh, Manfrid Eltze, Johannes Barsig, Lutz Wollin, Armin Hatzelmann and Rolf Beume
Journal of Pharmacology and Experimental Therapeutics April 1, 2001, 297 (1) 280-290;
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