Effect of BW B70C, a novel inhibitor of arachidonic acid 5-lipoxygenase, on allergen-induced bronchoconstriction and late-phase lung eosinophil accumulation in sensitised guinea-pigs.
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.
Yeadon
M
M
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, UK.
Dougan
F L
FL
Petrovic
A
A
Beesley
J E
JE
Payne
A N
AN
D000284:Administration, Oral; D000485:Allergens / Q000009:adverse effects*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000276:immunology*; D006168:Guinea Pigs; D006898:Hydroxylamines / Q000494:pharmacology*; D006918:Hydroxyurea / Q000031:analogs & derivatives*; D007114:Immunization; D007958:Leukocyte Count / Q000187:drug effects; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D008297:Male; D008782:Methylurea Compounds / Q000494:pharmacology*; D010544:Peroxidases / Q000378:metabolism; D011738:Pyrilamine / Q000494:pharmacology; D011897:Random Allocation
D000485:Allergens; D006898:Hydroxylamines; D016859:Lipoxygenase Inhibitors; D008782:Methylurea Compounds; C080871:BW B70C; D010544:Peroxidases; D011738:Pyrilamine; D006918:Hydroxyurea