EFFECT OF THE 5-LIPOXYGENASE INHIBITOR ZD2138 ON ASPIRIN-INDUCED ASTHMA

Background - The cysteinyl leukotrienes may play a central part in the mechanisms of aspirin-sensitive asthma. Previous work has shown that individuals with aspirin-sensitive asthma have high basal urinary LTE( 4) levels which increase further upon aspirin ingestion, and that sulp hidopeptide leukotriene receptor antagonists attenuate aspirin-induced airflow obstruction. If the cysteinyl leukotrienes cause aspirin-indu ced asthmatic reactions, inhibition of the 5-lipoxygenase pathway shou ld prevent aspirin-induced bronchospasm. This hypothesis has been test ed with ZD2138, a specific non-redox 5-lipoxygenase inhibitor. Methods - Seven subjects (four men) with aspirin-sensitive asthma with baseli ne FEV(1) values >67% were studied. ZD2138 (350 mg) or placebo was giv en on two separate occasions two weeks apart in a randomised double bl ind fashion. A single dose of aspirin was administered four hours afte r dosing and FEV(1) was measured for six hours. Inhibition of the 5-li poxygenase pathway by ZD2138 was assessed by measurements of urinary L TE(4) levels and ex vivo calcium ionophore stimulated LTB(4) generatio n in whole blood, before administration of drug or placebo and at regu lar time intervals after dosing and aspirin administration. Results - ZD2138 protected against the aspirin-induced reduction in FEV(1) with a 20.3 (4.9)% fall in FEV(1) following placebo compared with 4.9 (2.9) % following ZD2138. This was associated with 72% inhibition of ex vivo LTB(4) generation in whole blood at 12 hours and a 74% inhibition of the rise in urinary LTE(4) excretion at six hours after aspirin ingest ion. Conclusions - In aspirin-sensitive asthma the 5-lipoxygenase inhi bitor ZD2138 inhibits the fall in FEV(1) induced by aspirin and this i s associated with substantial inhibition of 5-lipoxygenase.