Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients.

Abstract

The effect of a single oral dose (800 mg) of zileuton (A-64077), a specific 5-lipoxygenase inhibitor, on the early and late airway responses to inhaled allergen was studied in a randomised, double blind, placebo controlled, and crossover trial in nine subjects with atopic asthma. Leukotriene generation was also assessed in vivo by measuring urinary leukotriene (LT) E4 excretion, and ex vivo by measuring calcium ionophore stimulated whole blood LTB4 production. Zileuton almost completely inhibited ex vivo LTB4 production but reduced urinary excretion of LTE4 by only about half. There was a trend for the early asthmatic response to be less on the day of zileuton treatment, but this did not reach statistical significance (p = 0 08). The zileuton induced reduction in maximum fall in FEVy in the early asthmatic response was, however, significantly related to the reduction in urinary LTE4 excretion (r = 0 8), but not to the reduction in LTB4 generation ex vivo. There was no significant change in the allergen induced late asthmatic response, or in the increase in airway responsiveness to methacholine following antigen. The results provide some support for the hypothesis that the cysteinyl leukotrienes have a role in the allergen induced early asthmatic response. More complete in vivo inhibition of 5-lipoxygenase may be needed to produce a significant reduction in airway response to allergen challenge.

Effects of single-dose zileuton on bronchial hyperresponsiveness in asthmatic patients treated with inhaled corticosteroids

“…within 1 h) increased FEV1 by ~0.35 L in patients with an FEV1 of ~57-60% pred [12]. Such improvement was not observed in other studies [7,8] or in the present patients, presumably because the FEV1 was close to its predicted value in these studies. Thus, an increase in airway calibre is unlikely to be the explanation for the reduced responses to histamine and UNDW challenge after zileuton found in the present study.…”

“…One of these drugs, zileuton (N-1-(benzo(b)thien-2-ylethyl)-N-hydroxyurea), an inhibitor of the 5-lipoxygenase pathway, has been shown to be efficacious in patients with asthma [3][4][5][6]. Single-dose studies have shown an attenuation of the asthmatic response to cold dry air [7], but not after allergen challenge [8]. In aspirin-sensitive asthmatics, 2.4 mg zileuton daily for 1 week prevented the fall in forced expiratory volume in one second (FEV1) in response to ingestion of aspirin [9].…”

Zileuton, a 5‐lipoxygenase inhibitor, increases production of thromboxane A2 and platelet aggregation in patients with asthma

“…Leukotriene antagonists, including 5-lipoxygenase inhibitors such as Zileuton, have been proven effective as anti-asthmatic agents and are widely used in clinical practice [11][12][13][14]. Zileuton is considered a relatively safe agent.…”

Direct Injection Method for Quantitation of Endogenous Leukotriene E4 in Human Urine by Liquid Chromatography/Electrospray Ionization Tandem Mass Spectrometry with a Column-switching Technique

“…[3][4][5][6][7] A number of anti-leukotriene drugs, which act as biosynthesis inhibitors or receptor antagonists of the LTs, have proved to be of benefit to treat asthmatic reactions. 8,9 Peptide leukotriene metabolites are excreted into urine as LTE4 in humans, 10 and urinary LTE4 may therefore reflect the status of LTs in the whole body. Quantitative determination of LTE4 in urine may thus be useful for evaluation of the effects of anti-leukotriene drugs in various diseases, and there is a need for an accurate and reproducible analytical method for determination of LTE4 in urine.…”