0
March 27, 1996, Vol 275, No. 12 >
ARTICLE | March 27, 1996

Effect of Treatment With Zileuton, a 5-Lipoxygenase Inhibitor, in Patients With Asthma: Title and subTitle BreakA Randomized Controlled Trial FREE

Elliot Israel, MD; Judith Cohn, MD, PhD; Louise Dubé, PhD; Jeffrey M. Drazen, MD; Paul Ratner, MD; Warren Pleskow, MD; Arthur DeGraff, Jr, MD; Paul Chervinsky, MD; Stephen Wasserman, MD; Harold Nelson, MD; Michael Yocum, MD; Robert J. Dockborn, MD; Sheldon C. Siegel, MD; Thomas Aldrich, MD; Jill Karpel, MD; William Busse, MD; Stephen Lazarus, MD; Roger Menendez, MD; Allen T. Segal, MD; Austin Thompson, MD; Allan Weinstein, MD; Robert Barbee, MD; Alan Leff, MD; Mary Strek, MD; Manuel Lopez, MD; B. Lauren Charous, MD; Douglas Hutt, MD; John J. Murray, MD, PhD; David Tinkelman, MD; Jonathan Ilowite, MD; Harold B. Kaiser, MD; Bruce T. Bowling, MD; Jay Grossman, MD; Thomas Edwards, MD; James Fish, MD; J. H. VanBavel, MD; Roger Fox, MD; Alan A. Wanderer, MD; John A. Winder, MD; Howard J. Zeitz, MD; Theodore Lee, MD; Lawrence Scharer, MD; John P. Hanrahan, MD; Jim Lancaster, PhD; Richard Manski, MS; Sandy Bialek-Smith, MT; Linda J. Swanson, PhD
[+] Author Affiliations

Drs Israel and Drazen have consulted for Abbott Laboratories and have received less than $5000 per year in consulting fees. Dr Dubé is an employee of Abbott Laboratories and owns stock in the company. Dr Cohn is a former employee of Abbott Laboratories and formerly held stock in the company.

A complete list of the members of the Zileuton Clinical Trial Group appears at the end of this article.

Reprint requests to Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (Dr Israel).


JAMA. 1996;275(12):931-936. doi:10.1001/jama.1996.03530360041036
Text Size: A A A
Published online
Article
References

Objective.  —To study the effect of 3 months of treatment with zileuton, an inhibitor of the enzymatic pathway (5-lipoxygenase) leading to leukotriene formation, on disease control in patients with mild to moderate asthma.

Design.  —Randomized, double-blind, parallel-group study in 401 patients. A 10-day placebo lead-in was followed by a double-blind treatment period of 13 weeks.

Setting.  —Asthma study clinics in university hospitals and private practices.

Patients or Other Participants.  —Patients with mild to moderate asthma (forced expiratory volume in the first second [FEV1], 40% to 80% of predicted) whose only treatment was inhaled β-agonists.

Interventions.  —Treatment with 600 mg or 400 mg of zileuton or placebo (each taken four times daily).

Main Outcome Measures.  —Frequency of asthma exacerbation requiring treatment with corticosteroids, use of inhaled β-agonists, pulmonary function tests, asthma symptom assessment, and quality-of-life evaluation. Safety was evaluated by monitoring adverse events.

Results.  —Only eight (6.1%) of 132 patients receiving 600 mg of zileuton four times a day required corticosteroid treatment for asthma vs 21 (15.6%) of 135 patients receiving placebo (P=.02), giving a relative risk of 2.6. At the time of expected peak drug concentration, the average FEV1 improved 15.7% in the 600-mg zileuton group vs 7.7% in the placebo group (P=.006). Quality-of-life assessments significantly improved in the 600-mg zileuton group and not in the placebo group (P=.007 for the overall score). Elevations in liver function tests (more than three times normal), all of which reversed with drug withdrawal, occurred in five patients (P=.03 vs placebo), three patients (P=.12 vs placebo), and no patients treated with 600 mg of zileuton, 400 mg of zileuton, or placebo, respectively.

Conclusions.  —Three months of 5-lipoxygenase inhibition produced a significant improvement in asthma control. These data indicate that 5-lipoxygenase products of arachidonic acid metabolism are mediators of inflammation with an important role in the biology of asthma.(JAMA. 1996;275:931-936)

REFERENCES

1 +
Lewis RA, Austen KF, Drazen JM, Clark DA, Marfat A, Corey EJ.  Slow reacting substances of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources. Proc Natl Acad Sci U S A . 1980;;77:3710-3714.
2 +
Owen WF Jr, Soberman RJ, Yoshimoto T, Sheffer AL, Lewis RA, Austen KF.  Synthesis and release of leukotriene C4 by human eosinophils. J Immunol . 1987;;138:532-538.
3 +
Brown GP, Monick MM, Hunninghake GW.  Human alveolar macrophage arachidonic acid metabolism. Am J Physiol . 1988;;254:C809-C815.
4 +
Drazen JM.  Inhalation challenge with sulfido-peptide leukotrienes in human subjects. Chest . 1986;; 89:414-419.
5 +
Adelroth E, Morris MM, Hargreave FE, O'Byrne PM.  Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls. N Engl J Med . 1986;;315:480-484.
6 +
Smith LJ, Greenberger PA, Patterson R, Krell RD, Bernstein PR.  The effect of inhaled leukotriene D4 in humans. Am Rev Respir Dis . 1985;; 131:368-372.
7 +
Dahlen SE, Bjork J, Hedqvist P.  Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci U S A . 1981;;78:3887-3891.
8 +
Marom Z, Shelhamer JH, Bach MK, Morton DR, Kaliner M.  Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro. Am Rev Respir Dis . 1982;; 126:449-451.
9 +
Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur BW, Lee TH.  Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet . 1993;;341:989-990.
10 +
Fuller RW, Black PN, Dollery CT.  Effect of the oral leukotriene D4 antagonist LY171883 on inhaled and intradermal challenge with antigen and leukotriene D4 in atopic subjects. J Allergy Clin Immunol . 1989;;83:939-944.
11 +
Taylor IK, O'Shaughnessy KM, Fuller RW, Dollery CT.  Effect of cysteinyl-leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet . 1991;;337:690-694.
12 +
Hui KP, Taylor IK, Taylor GW, et al.  Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax . 1991;;46:184-189.
13 +
Findlay SR, Barden JM, Easley CB, Glass M.  Effect of the oral leukotriene antagonist, ICI 204, 219, on antigen-induced bronchoconstriction in subjects with asthma. J Allergy Clin Immunol . 1992;; 89:1040-1045.
14 +
Friedman BS, Bel EH, Buntinx A, et al. Oral  leukotriene inhibitor (MK-886) blocks allergen-induced airway responses. Am Rev Respir Dis . 1993;; 147:839-844.
15 +
Israel E, Juniper EF, Callaghan JT, et al.  Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics. Am Rev Respir Dis . 1989;;140:1348-1353.
16 +
Israel E, Dermarkarian R, Rosenberg M, et al.  The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med . 1990;;323: 1740-1744.
17 +
Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O'Byrne PM.  Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med . 1990;;323:1736-1739.
18 +
Robuschi M, Riva E, Fuccella LM, et al.  Prevention of exercise-induced bronchoconstriction by a new leukotriene antagonist (SK&F 104353): a double-blind study versus disodium cromoglycate and placebo. Am Rev Respir Dis . 1992;;145:1285-1288.
19 +
Makker HK, Lau LC, Thomson HW, Binks SM, Holgate ST.  The protective effect of inhaled leukotriene receptor D4 receptor antagonist ICI 204,219 against exercise-induced asthma. Am Rev Respir Dis . 1993;;147:1413-1418.
20 +
Israel E, Fischer AR, Rosenberg MA, et al.  The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis . 1993;;148:1447-1451.
21 +
Christie PE, Smith CM, Lee TH.  The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353, inhibits aspirin-induced asthma. Am Rev Respir Dis . 1991;;144:957-958.
22 +
Dahlen B, Kumlin M, Margolskee DJ, et al.  The leukotriene-receptor antagonist MK-0679 blocks airway obstruction induced by bronchial provocation with lysine-aspirin in aspirin-sensitive asthmatics. Eur Respir J . 1993;;6:1018-1026.
23 +
Nasser SM, Bell GS, Foster S, et al.  Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax . 1994;;49:749-756.
24 +
National Heart, Lung, and Blood Institute, National Asthma Education Program, Expert Panel Report.  Guidelines for the diagnosis and management of asthma. J Allergy Clin Immunol . 1991;;88: 425-534.
25 +
Dykewicz MS, Greenberger PA, Patterson R, Halwig JM.  Natural history of asthma in patients requiring long-term systemic corticosteroids. Arch Intern Med . 1986;;146:2369-2372.
26 +
Cloud ML, Enas GC, Kemp J, et al.  A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma. Am Rev Respir Dis . 1989;;140:1336-1339.
27 +
Israel E, Rubin P, Kemp J, et al.  The effect of inhibition of 5-lipoxygenase by zileuton in mild to moderate asthma. Ann Intern Med . 1993;;119:1059-1066.
28 +
Spector SL, Smith LJ, Glass M, and the Accolate Asthma Trialists Group.  Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am J Respir Crit Care Med . 1994;; 150:618-623.
29 +
American Thoracic Society.  Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis . 1987;;136:225-244.
30 +
Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE.  Measuring quality of life in asthma. Am Rev Respir Dis . 1993;;147:832-838.
31 +
Juniper EF, Guyatt GH, Willan A, Griffith LE.  Determining a minimal important change in a disease-specific quality of life questionnaire. J Clin Epidemiol . 1994;;47:81-87.
32 +
Chapman KR, Verbeek PR, White JG, Rebuck AS.  Effect of a short course of prednisone in the prevention of early relapse after the emergency room treatment of acute asthma. N Engl J Med . 1991;;324:788-794.
33 +
Hui KP, Barnes NC.  Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist. Lancet . 1991;;337:1062-1063.
34 +
Gaddy JN, Margolskee DJ, Bush RK, Williams VC, Busse WW.  Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma. Am Rev Respir Dis . 1992;;146:358-364.
35 +
Impens N, Reiss TF, Teahan JA, et al.  Acute bronchodilation with an intravenously administered leukotriene D4 antagonist, MK-679. Am Rev Respir Dis . 1993;;147:1442-1446.
36 +
Dahlen B, Margolskee DJ, Zetterstrom O, Dahlen SE.  Effect of the leukotriene receptor antagonist MK-0679 on baseline pulmonary function in aspirin sensitive asthmatic subjects. Thorax . 1993;; 48:1205-1210.
37 +
Kane G, Pollice M, Cohn J, Murray J, Fish J, Peters S.  Controlled trial of the effect of a 5-LO inhibitor on lung inflammation produced by segmental antigen challenge. J Allergy Clin Immunol . 1994;;93:184. Abstract.
38 +
Johnson HM, Russell JK, Torres BA.  Second messenger role of arachidonic acid and its metabolites in interferon-gamma production. J Immunol . 1986;;137:3053-3056.
39 +
Israel E.  New agents in asthma treatment-inhibitors of the formation and action of products of the 5-lipoxygenase pathway of arachidonic acid.  In: Crommelin DJA, Midha KK, Nagai T, eds. Topics in Pharmaceutical Sciences . Stuttgart, Germany: Scientific Publishers; 1994;:89-102.

Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Lewis RA, Austen KF, Drazen JM, Clark DA, Marfat A, Corey EJ.  Slow reacting substances of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources. Proc Natl Acad Sci U S A . 1980;;77:3710-3714.
2 +
Owen WF Jr, Soberman RJ, Yoshimoto T, Sheffer AL, Lewis RA, Austen KF.  Synthesis and release of leukotriene C4 by human eosinophils. J Immunol . 1987;;138:532-538.
3 +
Brown GP, Monick MM, Hunninghake GW.  Human alveolar macrophage arachidonic acid metabolism. Am J Physiol . 1988;;254:C809-C815.
4 +
Drazen JM.  Inhalation challenge with sulfido-peptide leukotrienes in human subjects. Chest . 1986;; 89:414-419.
5 +
Adelroth E, Morris MM, Hargreave FE, O'Byrne PM.  Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls. N Engl J Med . 1986;;315:480-484.
6 +
Smith LJ, Greenberger PA, Patterson R, Krell RD, Bernstein PR.  The effect of inhaled leukotriene D4 in humans. Am Rev Respir Dis . 1985;; 131:368-372.
7 +
Dahlen SE, Bjork J, Hedqvist P.  Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci U S A . 1981;;78:3887-3891.
8 +
Marom Z, Shelhamer JH, Bach MK, Morton DR, Kaliner M.  Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro. Am Rev Respir Dis . 1982;; 126:449-451.
9 +
Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur BW, Lee TH.  Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet . 1993;;341:989-990.
10 +
Fuller RW, Black PN, Dollery CT.  Effect of the oral leukotriene D4 antagonist LY171883 on inhaled and intradermal challenge with antigen and leukotriene D4 in atopic subjects. J Allergy Clin Immunol . 1989;;83:939-944.
11 +
Taylor IK, O'Shaughnessy KM, Fuller RW, Dollery CT.  Effect of cysteinyl-leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet . 1991;;337:690-694.
12 +
Hui KP, Taylor IK, Taylor GW, et al.  Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax . 1991;;46:184-189.
13 +
Findlay SR, Barden JM, Easley CB, Glass M.  Effect of the oral leukotriene antagonist, ICI 204, 219, on antigen-induced bronchoconstriction in subjects with asthma. J Allergy Clin Immunol . 1992;; 89:1040-1045.
14 +
Friedman BS, Bel EH, Buntinx A, et al. Oral  leukotriene inhibitor (MK-886) blocks allergen-induced airway responses. Am Rev Respir Dis . 1993;; 147:839-844.
15 +
Israel E, Juniper EF, Callaghan JT, et al.  Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics. Am Rev Respir Dis . 1989;;140:1348-1353.
16 +
Israel E, Dermarkarian R, Rosenberg M, et al.  The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med . 1990;;323: 1740-1744.
17 +
Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O'Byrne PM.  Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med . 1990;;323:1736-1739.
18 +
Robuschi M, Riva E, Fuccella LM, et al.  Prevention of exercise-induced bronchoconstriction by a new leukotriene antagonist (SK&F 104353): a double-blind study versus disodium cromoglycate and placebo. Am Rev Respir Dis . 1992;;145:1285-1288.
19 +
Makker HK, Lau LC, Thomson HW, Binks SM, Holgate ST.  The protective effect of inhaled leukotriene receptor D4 receptor antagonist ICI 204,219 against exercise-induced asthma. Am Rev Respir Dis . 1993;;147:1413-1418.
20 +
Israel E, Fischer AR, Rosenberg MA, et al.  The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis . 1993;;148:1447-1451.
21 +
Christie PE, Smith CM, Lee TH.  The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353, inhibits aspirin-induced asthma. Am Rev Respir Dis . 1991;;144:957-958.
22 +
Dahlen B, Kumlin M, Margolskee DJ, et al.  The leukotriene-receptor antagonist MK-0679 blocks airway obstruction induced by bronchial provocation with lysine-aspirin in aspirin-sensitive asthmatics. Eur Respir J . 1993;;6:1018-1026.
23 +
Nasser SM, Bell GS, Foster S, et al.  Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax . 1994;;49:749-756.
24 +
National Heart, Lung, and Blood Institute, National Asthma Education Program, Expert Panel Report.  Guidelines for the diagnosis and management of asthma. J Allergy Clin Immunol . 1991;;88: 425-534.
25 +
Dykewicz MS, Greenberger PA, Patterson R, Halwig JM.  Natural history of asthma in patients requiring long-term systemic corticosteroids. Arch Intern Med . 1986;;146:2369-2372.
26 +
Cloud ML, Enas GC, Kemp J, et al.  A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma. Am Rev Respir Dis . 1989;;140:1336-1339.
27 +
Israel E, Rubin P, Kemp J, et al.  The effect of inhibition of 5-lipoxygenase by zileuton in mild to moderate asthma. Ann Intern Med . 1993;;119:1059-1066.
28 +
Spector SL, Smith LJ, Glass M, and the Accolate Asthma Trialists Group.  Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am J Respir Crit Care Med . 1994;; 150:618-623.
29 +
American Thoracic Society.  Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis . 1987;;136:225-244.
30 +
Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE.  Measuring quality of life in asthma. Am Rev Respir Dis . 1993;;147:832-838.
31 +
Juniper EF, Guyatt GH, Willan A, Griffith LE.  Determining a minimal important change in a disease-specific quality of life questionnaire. J Clin Epidemiol . 1994;;47:81-87.
32 +
Chapman KR, Verbeek PR, White JG, Rebuck AS.  Effect of a short course of prednisone in the prevention of early relapse after the emergency room treatment of acute asthma. N Engl J Med . 1991;;324:788-794.
33 +
Hui KP, Barnes NC.  Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist. Lancet . 1991;;337:1062-1063.
34 +
Gaddy JN, Margolskee DJ, Bush RK, Williams VC, Busse WW.  Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma. Am Rev Respir Dis . 1992;;146:358-364.
35 +
Impens N, Reiss TF, Teahan JA, et al.  Acute bronchodilation with an intravenously administered leukotriene D4 antagonist, MK-679. Am Rev Respir Dis . 1993;;147:1442-1446.
36 +
Dahlen B, Margolskee DJ, Zetterstrom O, Dahlen SE.  Effect of the leukotriene receptor antagonist MK-0679 on baseline pulmonary function in aspirin sensitive asthmatic subjects. Thorax . 1993;; 48:1205-1210.
37 +
Kane G, Pollice M, Cohn J, Murray J, Fish J, Peters S.  Controlled trial of the effect of a 5-LO inhibitor on lung inflammation produced by segmental antigen challenge. J Allergy Clin Immunol . 1994;;93:184. Abstract.
38 +
Johnson HM, Russell JK, Torres BA.  Second messenger role of arachidonic acid and its metabolites in interferon-gamma production. J Immunol . 1986;;137:3053-3056.
39 +
Israel E.  New agents in asthma treatment-inhibitors of the formation and action of products of the 5-lipoxygenase pathway of arachidonic acid.  In: Crommelin DJA, Midha KK, Nagai T, eds. Topics in Pharmaceutical Sciences . Stuttgart, Germany: Scientific Publishers; 1994;:89-102.

Letters

Submit a Letter
CME Course for:


You need to register in order to view this quiz.


To understand the clinical management of acute heart failure syndromes.
Accreditation Information The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
To view and print your certificate and access a summary of your CME courses go to My CME.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
Submit a Response

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

© 2012 American Medical Association. All Rights Reserved.
Powered bySilverchair Information Systems