In Vivo Efficacy in Airway Disease Models of Roflumilast, a Novel Orally Active PDE4 Inhibitor
- Daniela S. Bundschuh1,
- Manfrid Eltze1,
- Johannes Barsig1,
- Lutz Wollin1,
- Armin Hatzelmann2 and
- Rolf Beume1
- Departments of 1Pharmacology (D.S.B., M.E., J.B., L.W., R.B.) and2Biochemistry (A.H.), Byk Gulden, Konstanz, Germany
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
