Conclusions
The biological activities of the leukotrienes and the fact that they are produced in elevated amounts in asthmatic subjects are consistent with their playing a role in IgE-mediated diseases. Clinical trials of results obtained with potent leukotriene D4 receptor antagonists such as MK-571, MK-679 and ICI 204,219 are consistent with leukotriene D4 receptor activation being a central feature of the disease. Such receptor antagonists will also be of use in defining the role of leukotriene D4 receptor activation in other IgE-mediated human diseases such as allergic conjunctivitis and allergic rhinitis. The role of leukotriene B4 in diseases mediated through IgE reactions remains to be defined. First generation leukotriene biosynthesis inhibitors such as Zileuton and MK-886 have not shown efficacy comparable to potent leukotriene D4 receptor antagonists, consistent with the fact that they have not been fully effective at suppressing leukotriene production in man. It will clearly be of interest to test more potent leukotriene biosynthesis inhibitors such as ICI D2318 and MK-0591 in chronic IgE-mediated diseases and compare the results with those already obtained with leukotriene D4 receptor antagonists.
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References
Arm JP, Spur BW, Lee TH (1988) The effects of inhaled leukotriene E4 on the airway responsiveness to histamine in subjects with asthma and normal subjects. J Allergy Clin Immunol 82:654
Barnes N, Piper PJ, Costello J (1987) The effect of an oral leukotriene antagonist L-649,923 on histamine and leukotriene D4-induced bronchoconstriction in normal man. J Allergy Clin Immunol 79:816
Bel EH, van derVeen H, Kramps JA, Dijkman JH, Sterk PJ (1987) Maximal airway narrowing to inhaled leukotriene D4 in normal subjects, comparison and interaction with methacholine. Am Rev Respir Dis 136:979
Bel EH, Timmers MC, Dijkman JH, Stahl EG, Sterk PJ (1990) The effect of an inhaled leukotriene antagonist, L-648,051, on early and late asthmatic reactions and subsequent increase in airway responsiveness in man. J Allergy Clin Immunol 85:1067
Brideau C, Chan C, Charleson S, Denis D, Evans JF, Ford-Hutchinson AW, Fortin R, Gillard JW, Guay J, Guévremont D, Hutchinson JH, Jones TR, Leger S, Mancini JA, McFarlane CS, Pickett C, Piechuta H, Prasit P, Riendeau D, Rouzer CA, Tagari P, Vickers PJ, Young RN (1992) Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)-indol-2-yl 2,2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol 70:799
Britton JR, Hanley SP, Tattersfield AE (1987) The effect of an oral leukotriene D4 antagonist L-649,923 on the response to inhaled antigen in asthma. J Allergy Clin Immunol 79:811
Brocklehurst WE (1962) Slow reacting substance and related compounds. Prog Allergy 6:539
Carter GW, Young PR, Albert DH, Bouska J, Dyer R, Bell RL, Summers JB, Brooks DW (1991) 5-Lipoxygenase inhibitory activity of Zileuton. J Pharmacol Exp Ther 256:929
Charleson S, Prasit P, Leger S, Gillard JW, Vickers PJ, Mancini JA, Charleson P, Guay J, Ford-Hutchinson AW, Evans JF (1992) Characterization of a 5-lipoxygenase activating protein binding assay: correlation of affinity for 5-lipoxygenase-activating protein with leukotriene synthesis inhibition. Mol Pharmacol 41:873
Clark JD, Lin L-L, Kriz RW, Ramesha CS, Sultzman LA, Lin AY, Milona N, Knopf JL (1991) A novel arachidonic acid selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell 65:1043
Cloud M, Enans GC, Kemp J, Platts-Mills T, Altman LC, Townley RE, Tinkelman D, King T Jr, Middleton E, Sheffer AL, McFadden ER Jr, Farlow DS (1989) A specific LTD4/LTE4 receptor antagonist improves pulmonary function in patients with mild chronic asthma. Am Rev Respir Dis 140:1336
Crawley GC, Dowell RI, Edwards PN, Foster SJ, McMillan RM, Walker ERH, Waterson D, Bird TGC, Brueau P, Girodeau J-M (1992) Methoxytetrahydropyrans. A new series of selective and orally potent 5-lipoxygenase inhibitors. J Med Chem 35:2600
Dahlen B, Kumlin M, Larsson C, Johansson H, Zetterstrom O, Malmstrom K, Brunner-Ferber F, Margolskee DJ, Dahlen S-E (1992) The leukotriene antagonist MK-0679 improves baseline pulmonary function and blocks aspirin-induced airway obstruction in aspirin-sensitive asthmatics. Am Rev Respir Dis 145: A15
Dixon RAF, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, Gillard JW, Miller DK (1990) Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 343:282
Dugas B, Paul-Eugene N, Cairns J, Gordon J, Calenda A, Mencia-Huerta JM, Braquet P (1990) Leukotriene B4 potentiates the expression and release of FCɛRII/CD23, and proliferation and differentiation of human B lymphocytes induced by EL-4. J Immunol 145:3406
Evans JF, Nathaniel DJ, Zamboni RJ, Ford-Hutchinson AW (1985) Leukotriene A3. A poor substrate but a potent inhibitor of rat and human neutrophil leukotriene A4 hydrolase. J Biol Chem 260:10966
Evans J, Barnes NC, Zakrzewski JT, Piper PJ, Costello JF (1988) L-648,051, a specific leukotriene antagonist active by the inhaled route in man. Thorax 43:836p
Evans JM, Barnes NC, Zakrzewski JP, Glenny HP, Piper PJ, Costello JF (1988) The activity of an inhaled leukotriene antagonist (SK&F 104,353-Z2) on bronchoconstriction induced by leukotriene D2 and histamine in man. Br J Clin Pharmacol 26:677P
Feldberg W, Kellaway CH (1938) Liberation of histamine and formation of lysocithin-like substances by cobra venom. J Physiol (Lond) 94:187
Ford-Hutchinson AW (1990) Leukotriene B4 in inflammation. Crit Rev Immunol 10:1
Ford-Hutchinson AW (1991) FLAP: a novel drug target for inhibiting the synthesis of leukotrienes. Trends Pharmacol Sci 12:68
Ford-Hutchinson AW, Bray NM, Doig MV, Shipley ME, Smith MJH (1980) Leukotriene B, a potent chemokinetic and aggregating substance released from a polymorphonuclear leukocytes. Nature 286:264
Friedman BS, Bel EH, Buntinx A, Tanaka W, Han Y-HR, Shingo S, Sterk P (1993) An oral leukotriene inhibitor (MK-886) blocks allergen-induced airway responses. Am Rev Respir Dis (in press)
Gaddy JN, Margolskee DJ, Bush RK, Williams VC, Busse WW (1992) Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma. Am Rev Respir Dis 148:358
Gillard J, Ford-Hutchinson AW, Chan C, Charleson S, Denis D, Foster A, Fortin R, Leger S, McFarlane CS, Morton H, Piechuta H, Riendeau D, Rouzer CA, Rokach J, Young R, MacIntyre DE, Peterson L, Bach T, Eirrmann G, Hople S, Humes J, Hupe L, Luell S, Metzger J, Meurer R, Miller DK, Opas E, Pacholok S (1989) L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol 67:456
Goetzel EJ, Pickett WC (1980) The human PMN leukocyte chemotactic activity of complex hydroxy-eicosatetraenoic acids (HETEs). J Immunol 125:1789
Goldman DW, Goetzl EJ (1982) Specific binding of leukotriene B4 to receptors on human polymorphonuclear leukocytes. J Immunol 129:1600
Goldman DW, Goetzl EJ (1984) Heterogeneity of human polymorphonuclear leukocyte receptors for leukotriene B4: identification of a subset of high affinity receptors that transduce the chemotactic response. J Exp Med 159:1027
Heisterkamp N, Rajpert-de Meyts E, Uribe L, Forman HJ, Groffen J (1991) Identification of a human gamma-glutamyl cleaving enzyme related to, but distinct from, gamma-glutamyl transpeptidase. Proc Natl Acad Sci USA 88:6303
Hui KP, Barnes NC (1991) Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist. Lancet 337:1062
Hui KP, Taylor IK, Taylor GW, Rubin P, Kesterson J, Barnes NC, Barnes PJ (1991) Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax 46:184
Ishii A, Nakagawa T, Nambu F, Motoishi M, Miyamoto T (1990) Inhibition of endogenous leukotriene-mediated lung anaphylaxis in guinea pigs by a novel receptor antagonist ONO-1078. Int Arch Allergy Appl Immunol 92:404
Israel E, Dermarkarian R, Rosenberg M, Sperling R, Taylor G, Rubin P, Drazen JM (1990) The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med 323:1740
Israel E, Drazen J, Pearlman H, Cohn J, Rubin P (1992) A double-blind multicentre study of zileuton, a potent 5-lipoxygenase inhibitor versus placebo in the treatment of spontaneous asthma in adults. J Allergy Clin Immunol 89:236
Jones TR, Guindon Y, Young R, Champion E, Charette L, Denis D, Ethier D, Hamel R, Ford-Hutchinson AW, Fortin R, Letts G, Masson P, McFarlane C, Piechuta H, Rokach J, Yoakim C (1986) L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]-γ-oxo-benzenebutanoate: a leukotriene D4 receptor antagonist. Can J Physiol Pharmacol 64:1535
Jones TR, Young R, Champion E, Charette L, Denis D, Ford-Hutchinson AW, Frenette R, Gauthier J-Y, Guindon Y, Kakushima M, Masson P, McFarlane C, Piechuta H, Rokach J, Zamboni R (1986) L-649,923, sodium (β-S*), γR*)-4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio-γ-hydroxy-β-methylbenzenebutanoate, a selective, orally active leukotriene receptor antagonist. Can J Physiol Pharmacol 64:1068
Jones TR, Zamboni R, Belley M, Champion E, Charette L, Ford-Hutchinson AW, Frenette R, Gauthier J-Y, Leger S, Masson P, McFarlane CS, Piechuta H, Rokach J, Williams H, Young RN, DeHaven RN, Pong SS (1989) Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist. Can J Physiol Pharmacol 67:17
Jones TR, Zamboni R, Belley M, Champion E, Charette L, Ford-Hutchinson AW, Gauthier J-Y, Leger S, Lord A, Masson P, McFarlane CS, Metters KM, Pickett C, Piechuta H, Young RN (1991) Pharmacology of the leukotriene antagonist verlukast: the (R)-enantiomer of MK-571. Can J Physiol Pharmacol 69:1847
Kellaway CH, Trethewie ER (1940) The liberation of a slow-reacting smooth-muscle-stimulating substance in anaphylaxis. Q J Exp Physiol 30:121
Kips JC, Joos GF, DeLepeleire I, Margolskee DJ, Buntinx A, Pauwels R, Van DerStraeten ME (1991) MK-571: a potent antagonist of leukotriene-D4-induced bronchoconstriction in the human. Am Rev Respir Dis 144:617
Kips J, Margolskee D, DeLepeleire I, Joos G, Williams V, Buntinx A, Pauwels R (1991) MK-0679 is a potent and selective LTD4 antagonist in asthmatic men. Am Rev Respir Dis 143:A599
Knapp HR (1990) Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor. N Engl J Med 323:1745
Krell RD, Aharony D, Buckner CK, Keith RA, Kusner EJ, Snyder DW, Bernstein PR, Matassa VG, Yee YK, Brown FJ, Hesp B, Giles RE (1990) The preclinical pharmacology of ICI 204,219. Am Rev Respir Dis 141:978
Mancini JA, Prasit P, Coppolino MG, Charleson P, Leger S, Evans JF, Gillard JW, Vickers PJ (1992) 5-Lipoxygenase-activating protein is the target of a novel hybrid of two classes of leukotriene biosynthesis. Mol Pharmacol 41:267
Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O'Byrne PM (1990) Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4 receptor antagonist. N Engl J Med 323:1736
Margolskee D, Bodman S, Dockhorn R, Israel E, Kemp J, Mansmann H, Minotti DA, Spector S, Stricker W, Tinkelman D, Townley R, Winder J, Williams V (1991) The therapeutic effects of MK-571, a potent and selective leukotriene (LT)D4 receptor antagonist, in patients with chronic asthma. J Allergy Clin Immunol 87:309
Margolskee D, Friedman B, Williams V, Botto A, Noonan N, Altman L, Bone R, Dockhorn R, Ellis E, Eschenbacher W, Findlay S, Grant J, Grossman J, Hendeles L, Israel E, Kemp J, Nelson H, Pearlman D, Stricker W, Tinkelman D, Townley R, Vandewalker M, Wanderer A, Weisberg S, Winder J (1992) The therapeutic effects of MK-0679, a selective leukotriene D4 receptor antagonist, in patients with chronic asthma. 8th International Conference on Prostaglandins and Related Compounds, Montreal. Abstract 639
Miller DK, Gillard JW, Vickers PJ, Sadowski S, Léveillé C, Mancini JA, Charleson P, Dixon RAF, Ford-Hutchinson AW, Fortin R, Gauthier J-Y, Rodkey J, Rosen R, Rouzer C, Sigal IS, Strader CD, Evans JF (1990) Identification and isolation of a membrane protein necessary for leukotriene production. Nature 343:278
Minami M, Ohno S, Kawasaki H, Rådmark O, Samuelsson B, Jörnvall H, Shimizu T, Seyama Y, Suzuki K (1987) Molecular cloning of a cDNA coding for human leukotriene A44 hydrolase: complete primary structure of an enzyme involved in eicosanoid synthesis. J Biol Chem 262:13873
Morris HR, Taylor GW, Piper PJ, Tippins JR (1980) Structure of slow reacting substance of anaphylaxis from guinea-pig lung. Nature 285:104
Murphy RC, Hammarström S, Samuelsson B (1979) Leukotriene C: a slow reacting substance from murine mastocytoma cells. Proc Natl Acad Sci USA 76:4275
Nicholson DW, Ali A, Klemba MW, Munday NA, Zamboni RJ, Ford-Hutchinson AW (1992) Human leukotriene C4 synthase expression in dimethylsulfoxide-differentiated U937 cells. J Biol Chem 267:17849
Nicholson ND, Klemba MW, Rasper DM, Zamboni RJ, Ford-Hutchinson AW (1992) Purification of human LTC4 synthase from dimethylsulfoxide-differentiated U937 cells. Eur J Biochem 209:725
Nguyen T, Falgueyret J-P, Abramovitz M, Riendeau D (1991) Evaluation of the role of conserved His and Met residues among lipoxygenases by site-directed mutagenesis of recombinant human 5-lipoxygenase. J Biol Chem 266:22057
Örning L, Hammarström S (1980) Inhibition of leukotriene C and leukotriene D biosynthesis. J Biol Chem 255:8023
Örning L, Hammarström S, Samuelsson B (1980) Leukotriene D: a low reacting substance from rat basophilic leukemia cells. Proc Natl Acad Sci USA 77:2014
Payan DG, Missirian-Bastian A, Goetzl EJ (1984) Human T lymphocyte subset specificity of the regulatory effects of leukotriene B4. Proc Natl Acad Sci USA 81:3501
Percival MD (1991) Human 5-lipoxygenase contains an essential iron. J Biol Chem 266:10058
Phillips GD, Rafferty P, Holgate ST (1987) LY-171883 as an oral leukotriene D4 antagonist in non-asthmatic subjects. Thorax 42:723
Piper PJ (1985) Leukotrienes: potent mediators of airway constriction. Int Arch Allergy Appl Immunol 76[Suppl 1]:43
Rasmussen JB, Eriksson L-O, Margolskee DJ, Tagari P, Williams VC, Andersson KB (1992) Leukotriene D4 receptor blockade inhibit the immediate and late bronchoconstrictor responses to inhaled antigen in asthmatic patients. J Allergy Clin Immunol 90:193
Riendeau D, Falgueyret J-P, Guay J, Ueda N, Yamamoto S (1991) Pseudoperoxidase activity of 5-lipoxygenase stimulated by potent benzofuranol and N-hydroxyurea inhibitors of the lipoxygenase reaction. Biochem J 274:287
Rola-Pleszczynski M, Borgeat P, Sirois P (1982) Leukotriene B4 induces human suppressor lymphocytes. Biochem Biophys Res Commun 108:1531
Rouzer CA, Ford-Hutchinson AW, Morton HE, Gillard JW (1990) MK-886 a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes. J Biol Chem 265:1436
Rouzer CA, Riendeau D, Falgueyret JP, Lau CK, Gresser MJ (1991) Inhibition of human leukocyte 5-lipoxygenase by a 4-hydroxybenzofuran, L-656,224. Biochem Pharmacol 41:1365
Smith LJ, Geller S, Ebright L, Glass M, Thyrum PT (1990) Inhibition of leukotriene D4-induced bronchoconstriction in normal subjects by oral LTD4 receptor antagonist ICI 204,219. Am Rev Respir Dis 141:988
Smith LJ, Geller S, Ebright L, Glass M, Thyrum PT (1990) Inhibition of leukotriene (LT)D4-induced bronchoconstriction in asthmatic subjects by the oral LTD4 receptor antagonist ICI 204,219. Am Rev Respir Dis 141:A33
Smith MJH, Ford-Hutchinson AW, Bray MA (1980) Leukotriene B: a potential mediator of inflammation. J Pharm Pharmacol 32:517
Snyder DW, Fleisch JH (1989) Leukotriene receptor antagonists as potential therapeutic agents. Annu Rev Pharmacol Toxicol 29:123
Tanaka W, Dallob A, Winchell G, Kline W, Spector R, Bjornsson T, DeSchepper P (1990) Safety-pharmacokinetics and leukotriene B4 (LTB4) inhibition after MK-886 administration in normal male volunteers. Am Rev Respir Dis 141: A32
Tanaka W, Dallob A, Friedman BS, Brecher EB, Seibold JR, Wood R (1992) Biochemical activity of a potent, orally active, leukotriene biosynthesis inhibitor (MK-0591) in healthy male volunteers. 8th International Conference on Prostaglandins and Related Compounds, Montreal. Abstract 643
Taylor IK, O'Shaughnessy KM, Fuller RW, Dollery CT (1991) Effect of cystienyl-leukotriene receptor antagonist ICI 204,219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subject. Lancet 337:690
Wahedna I, Wisniewski AS, Tattersfield AE (1991) Effect of RG 12525 an oral leukotriene D4 antagonist, on the airway response to inhaled leukotriene D4 in subjects with mild asthma. Br J Clin Pharmacol 32:512
Yamaoka KA, Claésson H-E, Rosén A (1989) Leukotriene B4 enhances activation, proliferation, and differentiation of human B lymphocytes. J Immunol 143:1996
Yates RA, McMillan RM, Ellis SH, Hutchison M, Gilmore E, Wilkinson D, Williams AJ (1992) A new non redox 5-lipoxygenase inhibitor ICI D2138 is well tolerated and inhibits blood leukotriene synthesis in healthy volunteers. Am Rev Respir Dis 145:A745
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Ford-Hutchinson, A.W. Leukotriene antagonists and inhibitors as modulators of IgE-mediated reactions. Springer Semin Immunopathol 15, 37–50 (1993). https://doi.org/10.1007/BF00204625
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DOI: https://doi.org/10.1007/BF00204625