THE PIVOTAL ROLE OF 5-LIPOXYGENASE PRODUCTS IN THE REACTION OF ASPIRIN-SENSITIVE ASTHMATICS TO ASPIRIN

A subset of persons with asthma develop bronchospasm, naso-ocular, gas trointestinal, and/or dermal reactions after ingesting aspirin (ASA) o r agents with the capacity to inhibit cyclooxygenase. The bronchopulmo nary reactions have been associated with a rise in urinary LTE(4). We examined the effects of an inhibitor of 5-lipoxygenase, zileuton, in a group of eight asthmatic patients with known sensitivity to ASA accom panied by LTE(4) hyperexcretion. We first confirmed ASA sensitivity an d an increase in urinary LTE(4) after ASA ingestion in these patients using a placebo-controlled ASA challenge. Subjects were then randomize d to a double-blind, crossover trial to examine the effects of zileuto n versus placebo on the response to ASA. Zileuton treatment decreased baseline urinary LTE(4) excretion from a mean of 469 +/- 141 pg/mg cre atinine to 137 +/- 69 pg/mg creatinine (p < 0.02) and blunted the maxi mum increase in urinary LTE(4) after ingestion of ASA(3,539 +/- 826 pg /mg creatinine versus 1,120 +/- 316 pg/mg creatinine p < 0.01). The pre-ASA challenge FEV(1) was unchanged by zileuton (3.41 +/- 0.15 L ve rsus 3.35 +/- 0.17 L, zileuton versus placebo). Zileuton prevented the fall in FEV(1) in response to ingestion of ASA; post-ASA ingestion th e mean of the minimal FEV(1) fell to 2.72 +/- 0.18 L on the placebo da y while there was no significant fall on the zileuton day(3.26 +/- 0.1 7 L; p < 0.014). Zileuton also prevented the development of the nasal, gastrointestinal (p < 0.006 and p < 0.025, respectively), and dermal symptoms which developed after ASA ingestion. Our data demonstrate tha t products of the 5-lipoxygenase pathway are critical mediators of the bronchospasm and associated end-organ events seen after ingestion of ASA in sensitive asthmatic patients.