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 LTE4 levels which increase further upon aspirin ingestion, and that sulphidopeptide leukotriene receptor antagonists attenuate aspirin-induced airflow obstruction. If the cysteinyl leukotrienes cause aspirin-induced asthmatic reactions, inhibition of the 5-lipoxygenase pathway should prevent aspirin-induced bronchospasm. This hypothesis has been tested with ZD2138, a specific non-redox 5-lipoxygenase inhibitor.


METHODS
Seven subjects (four men) with aspirin-sensitive asthma with baseline FEV1 values > 67% were studied. ZD2138 (350 mg) or placebo was given on two separate occasions two weeks apart in a randomised double blind fashion. A single dose of aspirin was administered four hours after dosing and FEV1 was measured for six hours. Inhibition of the 5-lipoxygenase pathway by ZD2138 was assessed by measurements of urinary LTE4 levels and ex vivo calcium ionophore stimulated LTB4 generation in whole blood, before administration of drug or placebo and at regular time intervals after dosing and aspirin administration.


RESULTS
ZD2138 protected against the aspirin-induced reduction in FEV1 with a 20.3 (4.9)% fall in FEV1 following placebo compared with 4.9 (2.9)% following ZD2138. This was associated with 72% inhibition of ex vivo LTB4 generation in whole blood at 12 hours and a 74% inhibition of the rise in urinary LTE4 excretion at six hours after aspirin ingestion.


CONCLUSIONS
In aspirin-sensitive asthma the 5-lipoxygenase inhibitor ZD2138 inhibits the fall in FEV1 induced by aspirin and this is associated with substantial inhibition of 5-lipoxygenase.
Nasser
S M
SM
Department of Allergy and Allied Respiratory Disorders, UMDS, Guy's Hospital, London.
Bell
G S
GS
Foster
S
S
Spruce
K E
KE
MacMillan
R
R
Williams
A J
AJ
Lee
T H
TH
Arm
J P
JP
D000328:Adult; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D000001:Calcimycin; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D017999:Leukotriene E4 / Q000097:blood / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011714:Pyrans / Q000627:therapeutic use*; D015363:Quinolones / Q000627:therapeutic use*
D016859:Lipoxygenase Inhibitors; D011714:Pyrans; D015363:Quinolones; C075799:ICI D2138; D000001:Calcimycin; D017999:Leukotriene E4; D001241:Aspirin