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.