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Vol. 297, Issue 1, 280-290, April 2001
Departments of Pharmacology (D.S.B., M.E., J.B., L.W., R.B.) and
Biochemistry (A.H.), Byk Gulden, Konstanz, Germany
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 its
N-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 TNF
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 TNF 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.
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