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. Method: 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.