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Leukotrienes as a Target in Asthma Therapy

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Summary

Asthma is a chronic inflammatory condition characterised by bronchial hyper-responsiveness and reversible airways obstruction. Research has demonstrated that these effects are mediated by a wide range of compounds. In the last decade leukotrienes have been identified as products of arachidonic acid metabolism. Their effects mimic the pathological changes seen in asthma both in vitro and in vivo. Further research has demonstrated increased production of leukotrienes both during episodes of asthma and in patients with stable asthma.

The demonstration that leukotrienes have proinflammatory biological properties relevant to the pathogenesis of asthma has stimulated the development of many potential therapeutic compounds to block these actions. Early studies in laboratory-induced asthma in human volunteers have shown the efficacy of some of these compounds. They have been shown to attenuate the bronchoconstriction caused by allergen challenge, exercise, aspirin and exposure to cold air. Most encouraging of all have been recent placebo-controlled studies in clinical asthma where significant improvements in terms of spirometry, symptoms and β2-agonist use have been demonstrated.

Leukotriene receptor antagonists and synthesis inhibitors are the first mediator antagonists to have been shown to be effective in treating clinical asthma and as such represent one of the most interesting new classes of antiasthma drugs in development at present.

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References

  • Adams GK, Lichtenstien LM. Antagonism of antigen induced contraction of guinea pig and human airways. Nature 270: 255–257, 1977

    Article  PubMed  Google Scholar 

  • Adelroth E, Morris MM, Hargreave FE, O’Byrne PM. Airway responsiveness to LTC4 and D4 and to methacholine in patients with asthma and normal controls. New England Journal of Medicine 315: 480–484, 1986

    Article  PubMed  CAS  Google Scholar 

  • Aharony D, Krell RD. Pharmacology of peptide leukotriene receptor antagonists. Annals of the New York Academy of Sciences 629: 125–132, 1991

    Article  PubMed  CAS  Google Scholar 

  • Barnes NC, Piper PJ, Costello JF. Comparative effects of inhaled leukotriene C4, leukotriene D4, and histamine in normal human subjects. Thorax 39: 500–504, 1984

    Article  PubMed  CAS  Google Scholar 

  • Barnes NC, Piper PJ, Costello J. The effect of an oral leukotriene antagonist L-649923 on histamine and leukotriene D4 induced bronchoconstriction in normal man. Journal of Allergy and Clinical Immunology 79: 816–821, 1987

    Article  PubMed  CAS  Google Scholar 

  • Barnes PJ, Chung KF, Page CP. Platelet-activating factor as a mediator of allergic disease. Journal of Allergy and Clinical Immunology 81: 919–934, 1988

    Article  PubMed  CAS  Google Scholar 

  • Bel EH, De Smet H, Rossing TH, Timmers MC, Dijkman JH, et al. The effect of a specific oral PAF antagonist, MK 287, on antigen induced early and late asthmatic responses in man. Abstract. American Review of Respiratory Disease 143: A811, 1991

    Google Scholar 

  • Bellia V, Cuttitta G, Mirabella A, Profita M, Bonanno A, et al. Urinary leukotriene E4 as a marker of nocturnal asthma. Abstract. American Review of Respiratory Disease 145 (Suppl. A16), 1992

  • Bisgard H, Groth S, Madsen F. Bronchial hyperreactivity to leukotriene D4 and histamine in exogenous asthma. British Medical Journal 290: 1468–1471, 1985

    Article  Google Scholar 

  • Bisgard H, Poulson L, Sondergaard I. Nebulisation and selective deposition of LTD4 in human lungs. Allergy 42: 336–342, 1987

    Article  Google Scholar 

  • Braquet P, Touqui L, Shen TY, Vargaftig BB. Perspectives in platelet-activating research. Pharmacology Review 39: 97–145, 1987

    CAS  Google Scholar 

  • Brideau C, Chan C, Charlson S, Denis D, Evans JF, et al. Pharmacology of MK 0591, a potent, orally active leukotriene biosynthesis inhibitor. Canadian Journal of Physiology and Pharmacology, in press, 1994

  • Britton JR, Hanky SP, Tattersfield AE. The effect of an oral leukotriene D4 antagonist L649,923 on the response to inhaled antigen in asthma. Journal of Allergy and Clinical Immunology 79: 811–886, 1989

    Article  Google Scholar 

  • Camp RDR, Coutts AA, Greaves MW, Kay, Walfort MJ. Responses of human skin to intradermal injection of leukotrienes C4, D4, B4. British Journal of Pharmacology 80: 497–502, 1980

    Article  Google Scholar 

  • Cloud ML, Enas GC, Kemp J, Platt-Mills T, Altman LC, et al. A specific LTD4 / LTE4 -receptor antagonist improves pulmonary function in patients with mild, chronic asthma. American Review of Respiratory Disease 140: 1336–1339, 1989

    Article  PubMed  CAS  Google Scholar 

  • Coles ST, Neill KH, Reid LM, Austen KF, Nii Y. Effects of leukotrienes C4 and D4 on glycoproteins and lysosyme secretion by human bronchial mucosa. Prostaglandins 25 (2): 155–170, 1983

    Article  PubMed  CAS  Google Scholar 

  • Dahlen B, Margolskee DJ, Zetterstrom O, Dahlen SE. The effect of the leukotriene receptor antagonist MK 0679 on baseline pulomary function in aspirin sensitive patients. Thorax, in press, 1994

  • Dahlen SE, Hedqvest P, Hammastrom S, Samuelsson B. Leukotrienes are potent constrictors of human bronchi. Nature 228: 484–486, 1980

    Article  Google Scholar 

  • Davidson AE, Lee TH, Scanlon PD, Solway J, McFadden R. Bronchoconstrictor effects of LTE4 in normal and asthmatic subjects. American Review of Respiratory Disease 135: 333–137, 1987

    PubMed  CAS  Google Scholar 

  • Djukanovic R, Roche WR, Wilson JW, Beasley CRW, Twentyman OP. Mucosal Inflammation in asthma. American Review of Respiratory Disease 142: 434–457, 1990

    PubMed  CAS  Google Scholar 

  • Drazen JM. Comparative contractile responses to sulfidopeptide leukotrienes in normal and asthmatic human subjects. Annals of the New York Academy of Sciences 524: 289–297, 1988

    Article  PubMed  CAS  Google Scholar 

  • Drazen JM. Leukotrienes in asthma and rhinitis. In Busse & Holgate (Eds) Asthma and rhinitis. Blackwells, in press, 1994

  • Drazen JM, Austen KF. Leukotrienes and airway responses. American Review of Respiratory Disease 136: 985–998, 1987

    Article  PubMed  CAS  Google Scholar 

  • Drazen JM, O’Brien J, Sparrow D, Weiss ST, Martins MA. Recovery of leukotriene E4 from the urine of patients with airways obstruction. American Review of Respiratory Disease 146: 104–108, 1992

    PubMed  CAS  Google Scholar 

  • Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteriods reduce the severity of bronchial hyperresponsiveness in asthma but oral theophylline does not. American Review of Respiratory Disease 136: 1174–1178, 1987

    Article  PubMed  CAS  Google Scholar 

  • Evans TW, Rogers DF, Aursulky B, Chung KF, Barnes PJ. Regional and time dependant effects of inflammatory mediators on airway microvascular permeability in the guinea pig. Clinical Science 76: 479–485, 1989

    PubMed  CAS  Google Scholar 

  • Fabbri LM, Boschetto P, Zocca E, Milani G, Piviotto F. Bronchoalveolar neutrophilia during lateasthmatic reactions induced by toluene diisocyanate. American Review of Respiratory Disease 136: 36–42, 1987

    Article  PubMed  CAS  Google Scholar 

  • Feldberg W, Kellaway CH. Liberation of histamine and formation of lysocithin like substances by cobra venom. Journal of Physiology (Cambridge England) 94: 187–226, 1938

    CAS  Google Scholar 

  • Finnerty JP, Wood-Baker R, Thomson H, Holgate ST. Role of leukotrienes in exercise induced asthma. American Review of Respiratory Disease 145: 746–749, 1992

    PubMed  CAS  Google Scholar 

  • Ford-Hutchinson AW. Leukotriene antagonists and inhibitors as modulators of IgE mediated reactions. Springer Seminars in Immunopathology 15, in press, 1993

  • Ford-Hutchinson AW, Bray WM, Doig MV, Shipley ME, Smith MJH. Leukotriene B4, a potent chemokinetic and aggregrating substance released from PMN leucocytes. Nature 286: 264–263, 1980

    Article  PubMed  CAS  Google Scholar 

  • Frietag A, Watson RM, Matsos G, Eastwood C, O’Bryne PM. Effect of a platelet activating factor antagonist (WEB 2086) on allergen induced asthmatic responses. Thorax 48: 594–98, 1993

    Article  Google Scholar 

  • Fujimura M, Sakahoto S, Kamis Y, Matsuda T. Effect of a leukotriene antagonist ONO 1078 on bronchial hyperresponsiveness in patients with asthma. Respiratory Medicine 87: 133–138, 1993

    Article  PubMed  CAS  Google Scholar 

  • Fujimura M, Sasaki F, Nakatsumi Y, Takakashi M, Hifumi S, et al. Effects of a thromboxane synthetase inhibitor (OKY-046) and a lipoxygenase inhibitor (AA 861) on bronchial responsiveness to acetycholine in asthmatic subjects. Thorax 41: 955–959, 1986

    Article  PubMed  CAS  Google Scholar 

  • Fuller RW, Black PN, Dollery CT. Effect of the oral leukotriene D4 antagonist LY171883 on inhaled and intradermal challenge with antigen and LTD4 in atopic subjects. Journal of Allergy and Clinical Immunology 83: 939–944, 1989

    Article  PubMed  CAS  Google Scholar 

  • Griffin M, Weiss JW, Leitch AG et al. Effects of leukotriene D4 on the airways in asthma. New England Journal of Medicine 308: 436–439, 1983

    Article  PubMed  CAS  Google Scholar 

  • Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S. Comparison of a β2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly diagnosed asthma. New England Journal of Medicine 325: 388–392, 1991

    Article  PubMed  CAS  Google Scholar 

  • Holroyde MC, Altounyan REC, Cole M, Dixon M, Eliott EV. Bronchoconstriction produced in man by leukotrienes C and D. Lancet 2: 17–18, 1981

    Article  PubMed  CAS  Google Scholar 

  • Hui KP, Barnes NC. Lung function improvement in asthma with a cysteinyl leukotriene receptor antagonist. Lancet 337: 1062–1063, 1991

    Article  PubMed  CAS  Google Scholar 

  • Israel E, Dermarkarian R, Rosenberg M, Sperling R, Taylor G. The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. New England Journal of Medicine 323: 1740–1744, 1990

    Article  PubMed  CAS  Google Scholar 

  • Israel E, Juniper EF, Callaghan JT, Mathur PN, Morris MM. Effect of a leukotriene antagonist LY 171883 on cold air induced bronchoconstriction in asthmatics. American Review of Respiratory Disease 140: 1348–1353, 1989

    Article  PubMed  CAS  Google Scholar 

  • Israel E, Robin JL, Drazen JM. Differential effects of Ca2+ channel blockers on LT C4 and D4 induced contraction in guinea pig pulmonary parenchymal strips. Journal of Pharmacology and Experimental Therapeutics 243: 424–429, 1987

    PubMed  CAS  Google Scholar 

  • Johnson HG, Chinn RA, Chow AW, Bach MK, Nadel JA. Leukotriene C4 enhances mucus production from submucosal glands in canine tracheas in vivo. International Journal of Immunopharmacology 5: 391–396, 1983

    Article  PubMed  CAS  Google Scholar 

  • Johnston S, Spence D, Calverley P, Winter J, Dhillon P, et al. WEB 2086, a platelet activating factor antagonist, has no steroid sparing effect in asthmatic subjects requiring inhaled corticosteriods. Abstract 871. Thorax 47, 1992

  • Jones TR, Davis C, Daniel EE. Pharmacological study of the contractile activity of leukotriene C4 and D4 on isolated human airway smooth muscle. Canadian Journal of Physiology and Pharmacology 60: 638–643, 1982

    Article  PubMed  CAS  Google Scholar 

  • Jorg A, Henderson WR, Murphy RC, Klebanoff SJ. Leukotriene generation by eosinophils. Journal of Experimental Medicine 155: 390–402, 1982

    Article  PubMed  CAS  Google Scholar 

  • Kaliner MA, Eggleston PA, Mathews KP. Rhinitis and Asthma. Journal of the American Medical Association 258: 2851–2871, 1987

    Article  PubMed  CAS  Google Scholar 

  • Kellaway CH, Trethewie RE. The liberation of a slow reacting smooth muscle stimulating substance of anaphylaxis. Journal of Experimental Physiology 30: 121–45, 1940

    CAS  Google Scholar 

  • Kuitert LM, Hui KP, Uthayarkumar S, Burke W, Newland AC. Effect of a platelet activating factor antagonist, UK 74,505 on allergen induced early and late response. Abstract. American Review of Respiratory Disease 145: A292, 1992

    Google Scholar 

  • Kumlin M, Dahlen B, Bjorck T, Zetterstrom O, Granstrom E, et al. Urinary Excretion of leukotriene E4 and 11-dehydro-Thromboxane B2 in response to bronchial provocation with allergen, aspirin, leukotriene D4 and histamine in asthmatics. American Review of Respiratory Disease 146: 96–103, 1992

    PubMed  CAS  Google Scholar 

  • Lam S, Chan H, LeRiche JC, Chan-Yeung M, Salari H. Release of leukotrienes in patients with bronchial asthma. Journal of Allergy and Clinical Immunology 81: 711–717, 1988

    Article  PubMed  CAS  Google Scholar 

  • Lammers JWJ, Van Daele P, Van den Elshout FMJ, Decraneer M, Buntinsc A. Bronchodilator properties of an inhaled leukotriene D4 antagonist (Verlukast-MK-0679) in asthmatic patients. Pulmonary Pharmacology 5: 121–125, 1992

    Article  PubMed  CAS  Google Scholar 

  • Lee TH, Walport MJ, Wilkinson AH, Turner-Warwick M, Kay AB. Slow reacting substances of anaphylaxis antagonist FPL55712 in chronic asthma. Lancet 2: 304–305, 1981

    Article  PubMed  CAS  Google Scholar 

  • MacGlashan DW Jr, Schleimer RP, Peters SP, Schulman ES, Adams GK, et al. Comparative studies of human basophils and mast cells. Federal Proceedings 42: 2504–2509, 1983

    CAS  Google Scholar 

  • Makker HK, Lau LC, Thomson HW, Binks SM, Holgate ST. The protective effect of inhaled LTD4 receptor antagonist ICI 204219 against exercise induced asthma. American Review of Respiratory Disease 147: 1413–1418, 1993

    PubMed  CAS  Google Scholar 

  • Mann JS, Robinson C, Sheridan AQ, Clement P, Bach MK, et al. Effect of inhaled piriprost (U60,257) a novel leukotriene inhibitor on allergen and exercise induced bronchoconstriction in asthma. Thorax 41: 746–752, 1986

    Article  PubMed  CAS  Google Scholar 

  • Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JL, et al. Inhibition of exercise induced bronchoconstriction by MK 571, a potent leukotriene D4 receptor antagonist. New England Journal of Medicine 323: 1736–1739, 1990

    Article  PubMed  CAS  Google Scholar 

  • Margolskee DJ, Bodman S, Dockhorn R, Israel E, Kemp J, et al. The therapeutic effects of MK 571 a potent and selective leukotriene D4 receptor agonist, in patients with chronic asthma. Abstract. Journal of Allergy and Clinical Immunology 87: 309, 1991

    Article  Google Scholar 

  • Marom Z, Shelhamer JH, Bach MK, Morton DR, Kaliner MA. Slow reacting substances, leukotrienes C4 and D4 increase the release of mucus from human airways in vitro. American Review of Respiratory Disease 126: 449–451, 1982

    PubMed  CAS  Google Scholar 

  • Metzger WJ, Richerson HB, Worden K, Monick M, Hunninghake GW. Bronchoalveolar lavage of allergic asthmatic patients following allergen bronchoprovocation. Chest 131: 477–483, 1986

    Article  Google Scholar 

  • Nagy L, Lee TH, Goetzl EJ, Pickett WC, Kay AB. Complement receptor enhancement and chemotaxis of human neutrophils and eosinophils by leukotrienes and other lipoxygenase products. Clinical and Experimental Immunology 71: 394–398, 1983

    Google Scholar 

  • Okuho T, Takahashi H, Sumitano M, Shimdoh K, Suzuki S. Plasma levels of leukotrienes C4 and D4 during wheezing attacks in asthmatic patients. International Archives of Allergy and Applied Immunology 84: 149–155, 1987

    Article  Google Scholar 

  • Owen WF Jr, Soberman RJ, Yoshimoto T, Sheffer AL, Lewis RA, et al. Synthesis and release of leukotriene C4 by human eosinophils. Journal of Immunology 138: 532–538, 1987

    CAS  Google Scholar 

  • Piacentini GL, Kaliner MA. The potential roles of leukotrienes in bronchial asthma. American Review of Respiratory Disease 143: S96–S99, 1991

    PubMed  CAS  Google Scholar 

  • Rasmussen JB, Eriksson LO, Margolskee DJ, Tagari P, Williams VC, et al. Leukotriene D4 receptor blockade inhibits the immediate and late bronchoconstrictor responses to inhaled antigen in patients with asthma. Journal of Allergy and Clinical Immunology 90: 193–201, 1992

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen JB, Eriksson LO, Tagari P, Stahl EG, Andersson KE. Reduced nonspecific bronchial reactivity and airway response to antigen in atopic asthmatic patients treated with the inhaled leukotriene D4 antagonist, L648,051. Allergy 47: 604–609, 1992

    Article  PubMed  CAS  Google Scholar 

  • Robuscki M, Riva E, Fuccella LM, Vida E, Barnabe R, et al. Prevention of excercise induced bronchoconstriction by a new leukotriene antagonist (SKF 104353). A double blind study versus disodium cromoglycate and placebo. American Review of Respiratory Disease 145: 1285–1288, 1992

    Google Scholar 

  • Samhoun MN, Conroy DM, Piper PJ. Pharmacological profile of leukotrienes E4, N-acetyl E4 and of four of their novel omega and beta oxidative metabolites in airways of guinea pig and men in vitro. British Journal of Pharmacology 98: 1406–1412, 1989

    PubMed  CAS  Google Scholar 

  • Sampson AP, Thomas RU, Costello JF, Piper PJ. Enhanced leukotriene synthesis in leukocytes of atopic and asthmatic subjects. British Journal of Pharmacology 33: 423–430, 1992

    Article  CAS  Google Scholar 

  • Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 220: 568–575, 1983

    Article  PubMed  CAS  Google Scholar 

  • Schleimer RP, MacGlashan DW Jr, Peters SP, Pinckard RN, Adkinson NF Jr et al. Characterisation of inflammatory mediator release from purified human lung mast cells. American Review of Respiratory Disease 133: 614–617, 1986

    PubMed  CAS  Google Scholar 

  • Sladek K, Szczeklik A. Leukotriene overproduction and mast cell activation during aspirin provoked bronchoconstriction in aspirin induced asthma. Abstract. American Review of Respiratory Disease 145: A17, 1992

    Google Scholar 

  • Soter NA, Lewis RA, Lorey EJ, Austen KF. Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4 and LTB4) in human skin. Journal of Investigative Dermatology 80: 115–119, 1983

    Article  PubMed  CAS  Google Scholar 

  • Spector SL, Glass M, Minkwitz, ICI Asthma Group. The effect of six weeks of therapy with oral doses of ICI 204,219 in asthmatics. Abstract. American Review of Respiratory Disease 145: A16, 1992

    Google Scholar 

  • Taylor IK, O’Shaughnessy KM, Fuller RW, Dollery CT. Effect of cysteinyl-leukotriene receptor antagonist ICI 204219 on allergen induced bronchconstriction and airways hyperreactivity in atopic subjects. Lancet 337: 690–694, 1991

    Article  PubMed  CAS  Google Scholar 

  • Taylor IK, Wellings R, Taylor GW, Fuller RW. Urinary leukotriene E4 excretion in exercise induced asthma. Journal of Applied Physiology 73: 743–748, 1992

    PubMed  CAS  Google Scholar 

  • US Department of Health and Human Services. International Consensus Report of diagnosis and management of Asthma. Publication No. 92–3091, 1992

  • Vathenen AS, Knox AJ, Wisniewski A, Tattersfield AE. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. American Review of Respiratory Disease 143: 1317–1321, 1991

    PubMed  CAS  Google Scholar 

  • Wardlaw AJ, Hay H, Cromwell O, Collins JW, Kay AB. Leukotrienes LTC4 and LTB4 in bronchoalveolar lavage in bronchial asthma and other respiratory diseases. Journal of Allergy and Clinical Immunology 84: 19–26, 1989

    Article  PubMed  CAS  Google Scholar 

  • Weiler PK, Lee AV, Foster, DW, Corey EJ, Austen KF, et al. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils; predominant production of leukotriene C4. Proceedings of the National Academy of Sciences of the United States of America 80: 7626–7630, 1983

    Article  Google Scholar 

  • Wilkens H, Wilkens JH, Bosse S, Kempe F, Fritz, et al. Effects of an inhaled PAF antagonist (WEB 2086 BS) on allergen induced early and late asthmatic responses and increased bronchial hyperresponsiveness to methacholine. American Review of Respiratory Disease 143: A812, 1991

    Google Scholar 

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  1. University Medicine, Centre Block, Level D, Southampton General Hospital, Tremona Rd, Southampton, SO9 4XY, England

    Nicholas Chanarin & Sebastian L. Johnston

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Chanarin, N., Johnston, S.L. Leukotrienes as a Target in Asthma Therapy. Drugs 47, 12–24 (1994). https://doi.org/10.2165/00003495-199447010-00002

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