Effects of a selective PDE4 inhibitor, D-22888, on human airways and eosinophils in vitro and late phase allergic pulmonary eosinophilia in guinea pigs.
The actions of a novel selective inhibitor of type 4 cyclic nucleotide phosphodiesterase (PDE4), D-22888, on human airway smooth muscle tone and human eosinophil respiratory burst in vitro and bronchoalveolar eosinophilia in allergen-challenged sensitized guinea pigs in vivo were assessed. D-22888 was a selective inhibitor of PDE4, exhibiting an IC50 against human neutrophil PDE4 of 0.15 microM, compared to IC 50 values of 4.4 microM and 1.1 microM for human platelet PDE3 and PDE5, respectively. D-22888 relaxed inherent tone in human bronchial rings in a concentration-dependent manner with an IC50 of 5.0 microM (geometric mean, 95% ci 3.0-8.4 microM) and also caused a concentration-dependent inhibition of opsonized zymosan-induced superoxide anion generation by human eosinophils with an IC50 of 3.1 microM (1.0-9.2 microM). Treatment of actively sensitized guinea pigs with single oral doses of D-22888 2 h before or 4 h after challenge reduced bronchoalveolar lavage (BAL) eosinophil numbers, 24 h after aerosol allergen challenge, by 48% and 73% at 10 mg/kg and 30 mg/kg, respectively, 2 h pre-challenge and 68% at 30 mg/kg 4 h post-challenge. Chronic twice-daily oral dosing with D-22888 for three days caused inhibition of 24 h post-challenge BAL eosinophilia, amounting to 88% at 30 mg/kg. These in vivo actions were comparable with those achieved with other selective PDE4 inhibitors and with the corticosteroid, dexamethasone. We conclude that D-22888 exerts actions on airway smooth muscle and eosinophil recruitment and activation that suggest that D-22888 may be a promising new drug for use in the treatment of allergic obstructive airways>> diseases such as bronchial asthma.
Dent
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G
Krankenhaus Grosshansdorf, Zentrum für Pneumologie und Thoraxchirurgie, LVA Hamburg, D-22927 Grosshansdorf, Germany. g.dent@soton.ac.uk
Poppe
H
H
Egerland
J
J
Marx
D
D
Szelenyi
I
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Branscheid
D
D
Magnussen
H
H
Rabe
K F
KF
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004802:Eosinophilia / Q000201:enzymology*; D004804:Eosinophils / Q000187:drug effects* / Q000201:enzymology; D006168:Guinea Pigs; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology; D007093:Imidazoles / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology; D011719:Pyrazines / Q000494:pharmacology*
D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; C116972:D 22888; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4