Lack of effect of the 5-lipoxygenase inhibitor zileuton in blocking oral aspirin challenges in aspirin-sensitive asthmatics.
BACKGROUND
Leukotrienes (LTs) have been implicated as major mediators of aspirin-(ASA)-induced respiratory reactions. It was therefore logical to assume that an inhibitor of 5-lipoxygenase (5-LO), such as zileuton, given before and during oral challenges with ASA, might prevent ASA-induced respiratory reactions. Indeed, in prior studies, pretreatment of ASA-sensitive respiratory disease patients with leukotriene modifiers eliminated or attenuated respiratory reactions upon re-challenge with the previously established provoking dose of ASA. However, doses higher than the provoking doses were not administered during these reported studies.


OBJECTIVE
We wished to determine whether zileuton pretreatment could prevent ASA-induced respiratory reactions in our six volunteers with aspirin-sensitive respiratory disease when ASA challenge doses were started below the usual provoking dose of 60 mg and then increased until a respiratory reaction occurred.


METHODS
Aspirin sensitivity was established previously in all six patients during a prior ASA oral challenge. In this study, pretreatment with zileuton 600 mg qid was initiated 7 days prior to, and continued during oral ASA challenges. Patients underwent single-blind oral ASA challenges with escalating doses of ASA, every 3 hours, according to our standard protocol.


RESULTS
All six patients reacted to doses of ASA between 45 and 325 mg. Four patients experienced bronchospasm (FEV1 declined 19% to 53%) while receiving zileuton. All six had naso-ocular reactions. Concentrations of urine LTE4 also increased significantly (mean 334 pg/mg Cr at baseline, increasing to 1024 pg/mg Cr at respiratory reactions).


CONCLUSIONS
During ASA challenges, zileuton, in standard doses of 600 mg qid was associated with increased synthesis of LTs in five of six patients and naso-ocular reactions in all six patients, as well as bronchospasm in four patients.
Pauls
J D
JD
Allergy Associates Medical Group, San Diego, California, USA.
Simon
R A
RA
Daffern
P J
PJ
Stevenson
D D
DD
D000284:Administration, Oral; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D001249:Asthma / Q000139:chemically induced / Q000517:prevention & control; D003888:Desensitization, Immunologic; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D015289:Leukotrienes / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*
D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D001241:Aspirin; C063449:zileuton; D006918:Hydroxyurea