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The Effect of Inhibition of 5-Lipoxygenase by Zileuton in Mild-to-Moderate Asthma

Elliot Israel, MD; Paul Rubin, MD; James P. Kemp, MD; Jay Grossman, MD; William Pierson, MD; Sheldon C. Siegel, MD; David Tinkelman, MD; John J. Murray, MD, PhD; William Busse, MD; Allen T. Segal, MD; James Fish, MD; Harold B. Kaiser, MD; Dennis Ledford, MD; Sally Wenzel, MD; Richard Rosenthal, MD; Judith Cohn, MD, PhD; Carmine Lanni, PhD; Helene Pearlman, MS; Peter Karahalios, MS; and Jeffrey M. Drazen, MD
[+] Article and Author Information

Request for Reprints: Elliot Israel, MD, Pulmonary and Critical Care Division, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215. Acknowledgments: The authors thank Vivian Simonelli and Carmen Hall for assistance with manuscript preparation. Grant Support: In part by a grant from Abbott Laboratories. The study was designed by the investigators, and data collection and entry were done by the investigators. Data coding and initial analysis were done by Abbott Laboratories.


Copyright 2004 by the American College of Physicians


Ann Intern Med. 1993;119(11):1059-1066. doi:10.7326/0003-4819-119-11-199312010-00001
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Objective: To evaluate the effectiveness of inhibiting the formation of the 5-lipoxygenase products of arachidonic acid by the 5-lipoxygenase inhibitor zileuton in the treatment of mild-to-moderate asthma.

Design: Randomized, double-blind, placebo-controlled study.

Setting: University hospitals and private allergy and pulmonary practices.

Patients: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV1) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids.

Intervention: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks.

Measurements: Airway function, -agonist use, and symptoms; inhibition of 5-lipoxygenase assessed by measurement of urinary leukotriene E4 (LTE4).

Results: Zileuton produced a 0.35-L (95% CI, 0.25 to 0.45 L) increase in the FEV1 within 1 hour of administration (P < 0.001 compared with placebo), equivalent to a 14.6% increase from baseline. After 4 weeks of zileuton therapy, airway function and symptoms improved, with the greatest improvements occurring in the 2.4 g/d group: This group's FEV1 increased by 0.32 L (CI, 0.16 to 0.48 L), a 13.4% increase, compared with a 0.05-L (CI, 0.10 to 0.20 L) increase in patients taking placebo (P = 0.02). Symptoms and frequency of -agonist use also decreased with zileuton, 2.4 g/d. The mean urinary LTE4 level decreased by 39.2 pg/mg creatinine (CI, 18.1 to 60.4 pg/mg creatinine) and 26.5 pg/mg creatinine (CI, 6.6 to 46.5 pg/mg creatinine) in the 2.4 g/d and 1.6 g/d groups, respectively, compared with a slight increase in the placebo group (P = 0.007 and P = 0.05). No difference was noted in the number of adverse events among treatment groups.

Conclusions: Inhibition of 5-lipoxygenase can improve airway function and decrease symptoms and medication use in patients with asthma, suggesting that this inhibition can be useful therapy for asthma. Also, 5-lipoxygenase products may mediate part of the baseline airway obstruction in patients with mild-to-moderate asthma.

Figures

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Figure 1.
Change in the forced expiratory volume during the 2 hours after administration of zileuton or placebo.1PPP

Zileuton (600 mg) produced an increase in forced expiratory volume in 1 second (FEV ) at all time points ( < 0.005) compared with preadministration values. This increase was significant compared with placebo at 60 minutes and 120 minutes (** < 0.001; * = 0.01). Values represent mean SE.

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Figure 2.
Change in forced expiratory volume after 4 weeks of administration of zileuton or placebo.1P

Values represent the mean change in weekly forced expiratory volume in 1 second (FEV ) ( SE) compared with values at the end of the dummy lead-in. At 4 weeks, patients receiving 2.4 g/d of zileuton were improved compared with placebo recipients (* = 0.02).

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Figure 3.
Change in peak expiratory flow during 4 weeks of treatment with zileuton.Left.Right.

Morning peak expiratory flow (PEF). Evening PEF. Bars represent the mean change for the previous week SE. Brackets refer to the comparison between 2.4 g/d of zileuton and placebo.

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Figure 4.
Change in frequency of daily -agonist use during 4 weeks of treatment with zileuton and placebo.P

Points represent the mean change in daily use of -agonist for the previous week SE. At the end of 4 weeks of therapy, patients receiving 2.4 g/d of zileuton had a 24% decrease in use of agonist (0.76 occasions) compared with a 7% decrease (0.23 occasions) in the placebo group (* = 0.03).

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Figure 5.
Mean urinary leukotriene E4 before and after 4 weeks of zileuton administration.4444PP

Bars represent the mean + SE; open bars = dummy lead-in urinary leukotriene E (LTE ); black bars = urinary LTE after 4 weeks of treatment. Patients receiving zileuton at 1.6 g/d and 2.4 g/d had decreased urinary LTE levels of 26% and 39%, respectively, compared with dummy lead-in (* < 0.05; ** = 0.007).

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