Leukotrienes in Asthma

  • Jeffrey M. Drazen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 525)


One of the major reasons for pursuing the chemical structure of the biological material known as slow-reacting substance of anaphylaxis (SRS-A) was that this material was known to be a potent bronchoconstrictor substance in guinea pigs [1] and in isolated human airways [2]. Thirty years ago, the simple concept was that SRS-A was released from sensitized cells following antigen sensitization and challenge, and that the released material transduced a signal at an as yet to be identified receptor leading to smooth muscle constriction and therefore the manifestations of human asthmA. It has been almost 25 years since the elucidation of the structure of SRS-A as a mixture of the cysteinyl leukotrienes (LT) [3] and just over 5 years since agents that act on leukotriene pathway have been available as asthma treatments [4,5]. What have we learned about asthma from the use of these agents and what is the role of these agents in the treatment of asthma?


Fluticasone Propionate Asthma Treatment Moderate Asthma Late Asthmatic Response Late Asthmatic Reaction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Drazen JM, Austen KF. Effects of intravenous administration of slow-reacting substance of anaphylaxis, histamine, bradykinin, and prostaglandin F2alpha on pulmonary mechanics in the guinea piG. J Clin Invest 1974; 53:1679–1685.PubMedCrossRefGoogle Scholar
  2. 2.
    Brocklehurst WE. The release of histamine and the formation of a slow-reacting substance (SRS-A) during anaphylactic shock. J Physiol (Lond) 1960; 151:416–435.Google Scholar
  3. 3.
    Murphy RC, Hammarstrom S, Samuelsson B. Leukotriene C: a slow-reacting substance from murine mastocytoma cells. Proc Natl Acad Sci USA 1979; 76:4275–4279.PubMedCrossRefGoogle Scholar
  4. 4.
    Obyrne PM, Israel E, Drazen JM. Antileukotrienes in the treatment of asthma. Ann Intern Med 1997; 127(6):472–480.Google Scholar
  5. 5.
    Drazen JM, Israel E, Obyrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999; 340(3):197–206.PubMedCrossRefGoogle Scholar
  6. 6.
    Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. N Engl J Med 1990; 323:645–655.PubMedCrossRefGoogle Scholar
  7. 7.
    Dahlen SE, Hedqvist P, Hammarstrom S, Samuelsson B. Leukotrienes are potent constrictors of human bronchi. Nature 1980; 288:484–486.PubMedCrossRefGoogle Scholar
  8. 8.
    Weiss JW, Drazen JM, Coles N, McFadden ERJ, Weller PF, Corey EJ et al. Bronchoconstrictor effects of leukotriene C in humans. Science 1982; 216:196–198.PubMedCrossRefGoogle Scholar
  9. 9.
    Hammarstrom S, Orning L, Bernstrom K. Metabolism and excretion of cysteinyl-leukotrienes. Adv Prost Thromb Leukot Res 1986; 16:383–396.Google Scholar
  10. 10.
    Taylor GW, Taylor I, Black P, Maltby NH, Turner N, Fuller RW et al. Urinary leukotriene E4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet 1989; 1:584–588.PubMedCrossRefGoogle Scholar
  11. 11.
    Drazen JM, Obrien J, Sparrow D, Weiss ST, Martins MA, Israel E et al. Recovery of Leukotriene-E4 from the Urine of Patients with Airway Obstruction. Am Rev Respir Dis 1992; 146:104–108.PubMedGoogle Scholar
  12. 12.
    Asano K, Lilly CM, Odonnell WJ, Israel E, Fischer A, Ransil BJ et al. Diurnal variation of urinary leukotriene E4 and histamine excretion rates in normal subjects and patients with mild-to-moderate asthmA. J Allergy Clin Immunol 1995; 96(5 Part 1):643–651.Google Scholar
  13. 13.
    Hui KP, Barnes NC. Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist. Lancet 1991; 337:1062–1063.PubMedCrossRefGoogle Scholar
  14. 14.
    Israel E, Rubin P, Kemp JP, Grossman J, Pierson WE, Siegel SC et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild to moderate asthma. Ann Intern Med 1993; 119:1059–1066.PubMedGoogle Scholar
  15. 15.
    Malmstrom K, Rodriguez-Gomez G, Guerra J, Villaran C, Pineiro A, Wei LX et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized controlled trial. Ann Int Med 1999; 130:487–495.PubMedGoogle Scholar
  16. 16.
    Drazen JM, Silverman EK, Lee TH. Heterogeneity of therapeutic responses in asthma. Brit Med Bull 2000; 56(4):1054–1070.PubMedCrossRefGoogle Scholar
  17. 17.
    Awni WM, Locke C, Dube LM, Cavanaugh JH. Evaluation of the diurnal variation in the pharmacokinetics of zileuton in healthy volunteers. J Clin Pharmacol 1997; 37(5):388–394.PubMedGoogle Scholar
  18. 18.
    Drazen JM, Yandava C, Dube L, Szczerback N, Hippensteel R, Pillari A et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genetics 1999; 22:170–172.CrossRefGoogle Scholar
  19. 19.
    Asano K, Shiomi T, Hasegawa N, Nakamura H, Kudo H, Matsuzaki T et al. Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT1 antagonist, in Japanese patients with moderate asthma. Pharmacogenetics 2002; 12:1–6.Google Scholar
  20. 20.
    Bleecker ER, Welch MJ, Weinstein SF, Kalberg C, Johnson M, Edwards L et al. Low-dose inhaled fluticasone propionate versus oral zafirlukast in the treatment of persistent asthma. J Allergy Clin Immunol 2000 Jun; 105(6 Pt 1):1123–9 2000; 105(6 Pt 1):1123-1129.PubMedCrossRefGoogle Scholar
  21. 21.
    Laviolette M, Malmstrom K, Lu S, Chervinsky P, Pujet JC, Peszek I et al. Montelukast added to inhaled beclomethasone in treatment of asthma. Amer J Respir Crit Care Med 1999; 160(6):1862–1868.Google Scholar
  22. 22.
    Yokoyama A, Kohno N, Sakai K, Hirasawa Y, Kondo K, Hiwada K. Effect of pranlukast, a leukotriene receptor antagonist, in patients with severe asthma refractory to corticosteroids. J Asthma 1998; 35(1):57–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Virchow JC, Prasse A, Naya I, Summerton L, Harris A. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Amer J Respir Crit Care Med 162[2], 578–585. 2000. Ref Type: Journal (Full)Google Scholar
  24. 24.
    Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 2001; 357(9273):2007–2011.PubMedCrossRefGoogle Scholar
  25. 25.
    Bel EH, Desmet M, Rossing TH, Timmers MC, Dijkman JH, Sterk PJ. The effect of a specific oral PAF-antagonist, MK-287, on antigen-induced early and late asthmatic reactions in man. American Review Respiratory Disease 143, A811. 1991. Ref Type: AbstractGoogle Scholar
  26. 26.
    Wilkens JH, Wilkens H, Uffmann J, Bovers J, Fabel H, Frolich JC. Effects of a PAF-antagonist (BN 52063) on bronchoconstriction and platelet activation during exercise induced asthma. Br J Clin Pharmacol 1990; 29:85–91.PubMedCrossRefGoogle Scholar
  27. 27.
    Bryan SA, Oconnor BJ, Matti S, Leckie MJ, Kanabar V, khan j et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsivness, amd the late asthmatic response. Lancet 2000; 356:2149–2153.PubMedCrossRefGoogle Scholar
  28. 28.
    Leckie MJ, ten Brincke A, khan j, Diamant Z, O’Connor BJ, Walls CM et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 2000; (In Press).Google Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Jeffrey M. Drazen
    • 1
  1. 1.Pulmonary and Critical Care Division Department of MedicineHarvard Medical SchoolMassachusettsUSA

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