EFFECT OF THE 5-LIPOXYGENASE INHIBITOR ZD2138 ON ALLERGEN-INDUCED EARLY AND LATE ASTHMATIC RESPONSES

Background - Leukotrienes are lipid mediators generated from arachidon ic acid by the 5-lipoxygenase pathway which may play an important part in the pathophysiology of asthma. Previous studies have demonstrated attenuation of the allergen-induced early and late asthmatic responses by leukotriene receptor antagonists. The effect of the 5-lipoxygenase inhibitor ZD2138, a non-redox lipoxygenase inhibitor which inhibits l eukotriene synthesis for 24 hours after single doses of 350 mg, on all ergen-induced early and late asthmatic responses has been assessed. Me thods - Eight asthmatic subjects with baseline FEV(1) >70% were studie d. On screening, all subjects developed an allergen-induced biphasic a sthmatic response to grass pollen, cat dander, or house dust mite. ZD2 138 (350mg) or placebo was given on two occasions separated by two wee ks in a randomised double blind fashion. Allergen inhalation challenge was performed four hours after dosing and FEV(1) was measured for eig ht hours. The inhibitory activity of ZD2138 on the 5-lipoxygenase path way was assessed by measurements of calcium ionophore-stimulated gener ation of LTB(4) in whole blood ex vivo and by analysis of urinary LTE( 4) levels before administration of drug or placebo and at regular inte rvals after oral drug dosing and allergen challenge. Results - ZD2138 produced no significant bronchodilatation or attenuation of the early or late asthmatic response, although there was 82% inhibition of whole blood generation of LTB(4) in response to calcium ionophore stimulati on and 52% reduction in urinary excretion of LTE(4). Conclusions - In asthmatic subjects the 5-lipoxygenase inhibitor ZD2138 did not protect against allergen-induced asthmatic responses, despite substantial inh ibition of 5-lipoxygenase.