The actions of
BW B70C, an orally available, biologically persistent and selective inhibitor of
arachidonic acid 5-lipoxygenase, have been examined in two systems of
anaphylaxis in actively sensitised guinea-pigs in vivo. In anaesthetised, artificially ventilated animals pretreated with
mepyramine and
indomethacin to leave only the "peptidoleukotriene-dependent" component (
leukotrienes C4, D4 and E4) of the anaphylactic response, direct inhalation of nebulised
allergen resulted in a slowly developing bronchoconstriction which was prevented in a dose-dependent manner by
BW B70C (2-50 mg/kg p.o.) administered 1 or 6 h before challenge. In conscious animals fasted overnight and then pretreated with
mepyramine to prevent death due to acute bronchial
anaphylaxis, exposure to nebulised
allergen produced slight respiratory symptoms. When blood and lung samples were analysed 4-48 h after
allergen provocation a sustained
leukocytosis and pulmonary eosinophil accumulation were observed. In contrast, in food-replete conscious animals, the early respiratory symptoms were still observed upon
allergen inhalation, but no significant blood
leukocytosis or accumulation of eosinophils in the lungs occurred subsequently. The eosinophil influx induced by
allergen in fasted animals was assessed both by histological examination and determination of tissue
peroxidase content, two measures which demonstrated reasonable agreement. Administration of a single dose of
BW B70C (10 mg/kg p.o.) 1 h prior to
allergen challenge did not affect the subsequent eosinophil infiltration 24 h later, but 20 mg/kg given in divided doses (-1 and +12 h) produced 67% inhibition of cell accumulation. A single dose of 50 mg/kg (-1 h) had a similar effect (78% inhibition). The potent glucocorticosteroid
betamethasone was used as a reference compound, and 4 mg/kg given as a divided dose (-1 and +7) fully inhibited
lung inflammation assessed 24 h after provocation with
allergen.
BW B70C inhibited both acute and allergic bronchoconstriction and late-phase eosinophil accumulation subsequent to
allergen inhalation in guinea-pigs. In view of the apparent requirement for sustained plasma levels of
BW B70C in order to prevent late-phase eosinophil recruitment to the lung after a single challenge with
allergen, it is unclear whether inhibition of
5-lipoxygenase underlies the observed anti-eosinophil accumulation effects of the compound, but the anti-
bronchoconstrictor effects are consistent with the known inhibitory activity of
BW B70C against
5-lipoxygenase.