Farmacologia clinica
Gli antileucotrieni
ANTILEUKOTRIENES
FERNANDO MARIA DE BENEDICTIS, LUIGI FERRARO
Clinica Pediatrica dell’Universitŕ di Perugia
Gennaio 1999 - pagg. 41 -46
Abstract
Leukotrienes play an important role in the etiopathogenesis of asthma. Leukotriene synthesis
inhibitors and leukotriene receptor antagonists have been synthetised. Among these Zileuton,
Zafirlukast, Pranlukast and Montelukast were shown to be effective in the treatment
of chronic asthma, although only Montelukast has been approved for paediatric age. This
molecule is effective in reducing exercise-induced bronchospasm, but studies were made
only in patients with mild asthma and in the majority of patients the effect was partial. Specific
indications for antileukotrienes may be patients with analgesic-induced asthma and
patients with side effects due to inhaled steroids. Further studies are necessary to evaluate
the indications and safety of these molecules in the paediatric age.
Parole chiave
Suggerite dall'AI
Classificazione MeSH
Bibliografia
1.Holgate ST, Bradding P, Sampson AP:
Leukotriene antagonists and synthesis inhibitors:
new directions in asthma therapy. J Al2. O’Byrne PM, Israel E, Drazen JM: Antileukotrienes
in the treatment of asthma. Ann
Intern Med 127, 472-80, 1997.
3. Horwitz RJ, McGill KA, Busse WW: The role of leukotriene modifiers in the treatment of asthma. Am J Repir Crit Care Med 157, 1363-71, 1998.
4. Arm JP, Lee TH: Chemical mediators: Leukotrienes and eicosanoids. In: Weiss EB, Stein M, Bronchial asthma: mechanisms and therapeutics. Boston, Little Brown, 112-34, 1993.
5. Thien FCK, Walters EH: Eicosanoids and asthma: an update. Prostaglandins Leukotrienes and Essential Fatty Acids 52, 271-88, 1995.
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 323, 645-55, 1990.
7. Arm JP, Lee TH: Sulphidopeptide leukotrienes in asthma. Clin Sci 84, 501-10, 1993.
8. Coleman RA, Eglen RM, Jones RL, et al: Prostanoids and leukotriene receptors: a progress report from the UPHAR working parties on classification and nomenclature. Adv Prostaglandin Tromboxane Leukot Res 23, 283-5, 1995.
9. Rachelefsky G: Childhood asthma and allergic rhinitis: The role of leukotrienes. J Pediatr 131, 348-55, 1997.
10. de Benedictis FM, Troiani S: Il ruolo dei leucotrieni nelle malattie allergiche. Riv Ital Broncopneumol Pediatr 1, 110-3, 1998.
11. Drazen J: Clinical pharmacology of leukotriene receptor antagonists and 5-lipoxygenase inhibitors. Am Rev Repir Crit Care Med 157, S233-7, 1998.
12. Ford-Hutchinson AW: Activation of the 5- lipoxygenase pathway of arachidonic acid metabolism. In: Chung KF, Barnes PJ, (Eds), Pharmacology of the respiratory tract: experimental and clinical research. New York, Marcel Dekker Inc., 375-414, 1993.
13. Vierucci A, Lombardi E, Novembre E. Nuovi farmaci nella terapia dell’asma bronchiale. Prospettive in Pediatria 27, 75-86, 1997.
14. McMillan RM, Bird TGC, Crawley GC, et al: Methoxyalkyl thiazoles: a novel series of potent, orally active and enantioselective inhibitors of 5-lipoxygenase. Agents Actions 34, 110-2, 1991.
15. Rouzer CA, Riendeau D, Folgueyret JP, et al: Inhibition of human leukocyte 5-lipoxygenase by a 4-hydroxybenzofuran, L-656,224. Biochem Pharmacol 41, 1365-73, 1991.
16. Cohn J: Zileuton (A-64077): a 5-lipoxygenase inhibitor. In: Lewis A, Furst DE, (Eds), Nonsteroidal anti-inflammatory drugs: mechanisms and clinical uses, 367-90, 1994.
17. Israel E, Demarkarian R, Rosemberg M, et al: The effects of a 5-lipoxygenase inhibitor on asthma induced by cold dry air. N Engl J Med 323, 1740-4, 1990.
18. Meltzer SS, Hasday JD, Cohn J, et al: Inhibition of exercise-induced bronchospasm by zileuton: a 5-lipoxygenase inhibitor. Am J Respir Crit Care Med 153, 931-5, 1996.
19. Israel E, Fisher AR, Rosemberg MA, et al: The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis 48, 1447- 51, 1993.
20. Hui KP, Taylor IK, Taylor GW, et al: The effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax 46, 184-9, 1991.
21. Kane GC, Pollice M, Kim CJ, et al: A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental allergen challenge in human beings. J Allergy Clin Immunol 97, 646- 54, 1996.
22. Israel E, Rubin P, Kemp JP, et al: The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med 119, 1059-66, 1993.
23. Israel E, Cohn J, Dubč L, Drazen JM: Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma: a randomized controlled trial. JAMA 275, 931-6, 1996.
24. Liu MC, Dubč LM, Lancaster J, and the Zileuton Study Group: Acute and chronic effect of 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. J Allergy Clin Immunol 98, 859-71, 1996.
25. Fischer AR, McFadden CA, Frantz R, et al: Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects. Am J Respir Crit Care Med 152, 1203-7, 1995.
26. Wenzel SE, Trudeau JB, Kaminsky DA, et al: Effect of 5-lipoxygenase inhibition of bronchoconstriction and airway inflammation in nocturnal asthma. Am J Respir Crit Care Med 152, 897-905, 1995.
27. O’Connor BJ, Godard P, Dube LM, et al: The comparative effect of zileuton, a 5-lipoxygenase inhibitor, plus low dose inhaled beclomethasone vs higher dose beclomethasone for asthma. J Allergy Clin Immunol 97, 250A, 1996.
28. Schwartz HJ, Petty T, Dubč L, et al: A randomized controlled trial comparing zileuton with theophylline in moderate asthma. Arch Intern Med 158, 141-8, 1998.
29. Dahlen B, Nizankowska E, Szczeklik A, et al: Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatic. Am J Respir Crit Care Med 157, 1187-94, 1998.
30. Richards IM, Sun FF, Taylor BM, et al: Contribution of leukotriene B4 to airway inflammation and the effect of antagonists. Ann NY Acad Sci 629, 274-87, 1991.
31. Bernstein PR: Chemistry and structureactivity relationships of leukotriene receptor antagonists. Am J Respir Crit Care Med 157, S220-6, 1998.
32. Aharony D: Pharmacology of leukotriene receptor antagonists. Am J Respir Crit Care Med 157, S214-9, 1998.
33. Adkins JC, Brogden RN: Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma. Drug 55, 121-44, 1998.
34. Smith LJ, Geller S, Ebright L, et al: Inhibition of leukotriene D4-induced bronchoconstriction in normal subjects by oral LTD4 receptor antagonist ICI-204,219. Am Rev Respir Dis 141, 988-92, 1990.
35. Smith LJ, Glass M, Minkwitz MC: Inhibition of leukotriene D4-induced bronchoconstriction in subjects with asthma: a concentration- effect study of ICI-204,219. Clin Pharmacol Ther 54, 430-6, 1993.
36. Kidney JC, Ridge SM, Chung KF, Barnes PJ: Inhibition of platelet activating factor-induced bronchoconstriction by the leukotriene D4 receptor antagonist ICI-204,219. J Allergy Clin Immunol 147, 215-7, 1993.
37. Lazarus SC, Wong HH, Watts MJ, et al: The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma. Am J Respir Crit Care Med 156, 1725-30, 1997.
38. Finnerty JP, Wood-Baker R, Thomson H, Holgate ST: Role of leukotrienes in exerciseinduced asthma: inhibitory effect of ICI- 204,219, a potent leukotriene D4 receptor antagonist. Am Rev Respir Dis 145, 746-9, 1992.
39. Makker HK, Lau LC, Thomson HW, et al: The protective effect of inhaled leukotriene D4 receptor antagonist ICI-204,219 against exercise-induced asthma. Am Rev Respir Dis 147, 1413-8, 1993.
40. Taylor I, O’Shaughnessy K, Fuller R, Dollery C: Effect of cysteinyl-leukotriene receptor antagonist ICI 204,219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet 337, 690- 7, 1991.
41. 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 89, 1040-5, 1992.
42. Roquet A, Dahlen B, Kumlin M, et al: Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med 155, 1856-63, 1997.
43. Calhoun WJ, Lavins BJ, Minkwitz MC, et al: Effect of Zafirlukast (Accolate) on cellular mediators of inflammation. Am J Respir Crit Care Med 157, 1381-9, 1998.
44. Nathan RA, Glass M, Minkwitz MC. Inhaled ICI-204,219 blocks antigen-induced bronchoconstriction in subjects with bronchial asthma. Chest 105, 483-8, 1994.
45. O’Shaughnessy KM, Taylor IK, O’Connor B, et al: Potent leukotriene D4 receptor antagonist ICI-204,219 given by the inhaled route inhibits the early but not the late phase allergen- induced bronchoconstriction. Am Rev Respir Dis 147, 1431-5, 1993.
46. Spector SL, Smith LJ, Glass M: 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 Med150, 618-23, 1994.
47. Suissa S, Dennis R, Ernst P, et al: Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to moderate asthma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 126, 177-83, 1997.
48. Virchow J Chr, Hassall SM, Summerton L, et al: Reduction of asthma exacerbations with zafirlukast in patients on inhaled corticosteroids. Eur Respir J 10, Suppl 25, 420 (A 2717), 1997.
49. Virchow J Chr, Hassall SM, Summerton L, Harris A: Improved asthma control over 6 weeks in patients on high dose inhaled corticosteroids. Eur Respir J 10, Suppl 25, 437 (AP 2804), 1997.
50. Obata T, Nambu F, Kitagawa H, et al: ONO-1708: an antagonist of leukotrienes. Adv Prostaglandin Tromboxane Leukot Res 17, 540-3, 1987.
51. Taniguchi Y, Tamura G, Honna M, et al: The effect of an oral leukotriene antagonist, ONO-1708, on allergen-induced immediate bronchoconstriction in asthmatic subjects. J Allergy Clin Immunol 92, 507-12, 1993.
52. Yamamoto H, Nagata M, Kuramitsu K, et al: Inhibition of analgesic-induced asthma by leukotriene receptor antagonist ONO-1078. Am J Respir Crit Care Med 150, 254-7, 1994. La bibliografia continua nel PDF.
3. Horwitz RJ, McGill KA, Busse WW: The role of leukotriene modifiers in the treatment of asthma. Am J Repir Crit Care Med 157, 1363-71, 1998.
4. Arm JP, Lee TH: Chemical mediators: Leukotrienes and eicosanoids. In: Weiss EB, Stein M, Bronchial asthma: mechanisms and therapeutics. Boston, Little Brown, 112-34, 1993.
5. Thien FCK, Walters EH: Eicosanoids and asthma: an update. Prostaglandins Leukotrienes and Essential Fatty Acids 52, 271-88, 1995.
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 323, 645-55, 1990.
7. Arm JP, Lee TH: Sulphidopeptide leukotrienes in asthma. Clin Sci 84, 501-10, 1993.
8. Coleman RA, Eglen RM, Jones RL, et al: Prostanoids and leukotriene receptors: a progress report from the UPHAR working parties on classification and nomenclature. Adv Prostaglandin Tromboxane Leukot Res 23, 283-5, 1995.
9. Rachelefsky G: Childhood asthma and allergic rhinitis: The role of leukotrienes. J Pediatr 131, 348-55, 1997.
10. de Benedictis FM, Troiani S: Il ruolo dei leucotrieni nelle malattie allergiche. Riv Ital Broncopneumol Pediatr 1, 110-3, 1998.
11. Drazen J: Clinical pharmacology of leukotriene receptor antagonists and 5-lipoxygenase inhibitors. Am Rev Repir Crit Care Med 157, S233-7, 1998.
12. Ford-Hutchinson AW: Activation of the 5- lipoxygenase pathway of arachidonic acid metabolism. In: Chung KF, Barnes PJ, (Eds), Pharmacology of the respiratory tract: experimental and clinical research. New York, Marcel Dekker Inc., 375-414, 1993.
13. Vierucci A, Lombardi E, Novembre E. Nuovi farmaci nella terapia dell’asma bronchiale. Prospettive in Pediatria 27, 75-86, 1997.
14. McMillan RM, Bird TGC, Crawley GC, et al: Methoxyalkyl thiazoles: a novel series of potent, orally active and enantioselective inhibitors of 5-lipoxygenase. Agents Actions 34, 110-2, 1991.
15. Rouzer CA, Riendeau D, Folgueyret JP, et al: Inhibition of human leukocyte 5-lipoxygenase by a 4-hydroxybenzofuran, L-656,224. Biochem Pharmacol 41, 1365-73, 1991.
16. Cohn J: Zileuton (A-64077): a 5-lipoxygenase inhibitor. In: Lewis A, Furst DE, (Eds), Nonsteroidal anti-inflammatory drugs: mechanisms and clinical uses, 367-90, 1994.
17. Israel E, Demarkarian R, Rosemberg M, et al: The effects of a 5-lipoxygenase inhibitor on asthma induced by cold dry air. N Engl J Med 323, 1740-4, 1990.
18. Meltzer SS, Hasday JD, Cohn J, et al: Inhibition of exercise-induced bronchospasm by zileuton: a 5-lipoxygenase inhibitor. Am J Respir Crit Care Med 153, 931-5, 1996.
19. Israel E, Fisher AR, Rosemberg MA, et al: The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis 48, 1447- 51, 1993.
20. Hui KP, Taylor IK, Taylor GW, et al: The effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax 46, 184-9, 1991.
21. Kane GC, Pollice M, Kim CJ, et al: A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental allergen challenge in human beings. J Allergy Clin Immunol 97, 646- 54, 1996.
22. Israel E, Rubin P, Kemp JP, et al: The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med 119, 1059-66, 1993.
23. Israel E, Cohn J, Dubč L, Drazen JM: Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma: a randomized controlled trial. JAMA 275, 931-6, 1996.
24. Liu MC, Dubč LM, Lancaster J, and the Zileuton Study Group: Acute and chronic effect of 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. J Allergy Clin Immunol 98, 859-71, 1996.
25. Fischer AR, McFadden CA, Frantz R, et al: Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects. Am J Respir Crit Care Med 152, 1203-7, 1995.
26. Wenzel SE, Trudeau JB, Kaminsky DA, et al: Effect of 5-lipoxygenase inhibition of bronchoconstriction and airway inflammation in nocturnal asthma. Am J Respir Crit Care Med 152, 897-905, 1995.
27. O’Connor BJ, Godard P, Dube LM, et al: The comparative effect of zileuton, a 5-lipoxygenase inhibitor, plus low dose inhaled beclomethasone vs higher dose beclomethasone for asthma. J Allergy Clin Immunol 97, 250A, 1996.
28. Schwartz HJ, Petty T, Dubč L, et al: A randomized controlled trial comparing zileuton with theophylline in moderate asthma. Arch Intern Med 158, 141-8, 1998.
29. Dahlen B, Nizankowska E, Szczeklik A, et al: Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatic. Am J Respir Crit Care Med 157, 1187-94, 1998.
30. Richards IM, Sun FF, Taylor BM, et al: Contribution of leukotriene B4 to airway inflammation and the effect of antagonists. Ann NY Acad Sci 629, 274-87, 1991.
31. Bernstein PR: Chemistry and structureactivity relationships of leukotriene receptor antagonists. Am J Respir Crit Care Med 157, S220-6, 1998.
32. Aharony D: Pharmacology of leukotriene receptor antagonists. Am J Respir Crit Care Med 157, S214-9, 1998.
33. Adkins JC, Brogden RN: Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma. Drug 55, 121-44, 1998.
34. Smith LJ, Geller S, Ebright L, et al: Inhibition of leukotriene D4-induced bronchoconstriction in normal subjects by oral LTD4 receptor antagonist ICI-204,219. Am Rev Respir Dis 141, 988-92, 1990.
35. Smith LJ, Glass M, Minkwitz MC: Inhibition of leukotriene D4-induced bronchoconstriction in subjects with asthma: a concentration- effect study of ICI-204,219. Clin Pharmacol Ther 54, 430-6, 1993.
36. Kidney JC, Ridge SM, Chung KF, Barnes PJ: Inhibition of platelet activating factor-induced bronchoconstriction by the leukotriene D4 receptor antagonist ICI-204,219. J Allergy Clin Immunol 147, 215-7, 1993.
37. Lazarus SC, Wong HH, Watts MJ, et al: The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma. Am J Respir Crit Care Med 156, 1725-30, 1997.
38. Finnerty JP, Wood-Baker R, Thomson H, Holgate ST: Role of leukotrienes in exerciseinduced asthma: inhibitory effect of ICI- 204,219, a potent leukotriene D4 receptor antagonist. Am Rev Respir Dis 145, 746-9, 1992.
39. Makker HK, Lau LC, Thomson HW, et al: The protective effect of inhaled leukotriene D4 receptor antagonist ICI-204,219 against exercise-induced asthma. Am Rev Respir Dis 147, 1413-8, 1993.
40. Taylor I, O’Shaughnessy K, Fuller R, Dollery C: Effect of cysteinyl-leukotriene receptor antagonist ICI 204,219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet 337, 690- 7, 1991.
41. 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 89, 1040-5, 1992.
42. Roquet A, Dahlen B, Kumlin M, et al: Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med 155, 1856-63, 1997.
43. Calhoun WJ, Lavins BJ, Minkwitz MC, et al: Effect of Zafirlukast (Accolate) on cellular mediators of inflammation. Am J Respir Crit Care Med 157, 1381-9, 1998.
44. Nathan RA, Glass M, Minkwitz MC. Inhaled ICI-204,219 blocks antigen-induced bronchoconstriction in subjects with bronchial asthma. Chest 105, 483-8, 1994.
45. O’Shaughnessy KM, Taylor IK, O’Connor B, et al: Potent leukotriene D4 receptor antagonist ICI-204,219 given by the inhaled route inhibits the early but not the late phase allergen- induced bronchoconstriction. Am Rev Respir Dis 147, 1431-5, 1993.
46. Spector SL, Smith LJ, Glass M: 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 Med150, 618-23, 1994.
47. Suissa S, Dennis R, Ernst P, et al: Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to moderate asthma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 126, 177-83, 1997.
48. Virchow J Chr, Hassall SM, Summerton L, et al: Reduction of asthma exacerbations with zafirlukast in patients on inhaled corticosteroids. Eur Respir J 10, Suppl 25, 420 (A 2717), 1997.
49. Virchow J Chr, Hassall SM, Summerton L, Harris A: Improved asthma control over 6 weeks in patients on high dose inhaled corticosteroids. Eur Respir J 10, Suppl 25, 437 (AP 2804), 1997.
50. Obata T, Nambu F, Kitagawa H, et al: ONO-1708: an antagonist of leukotrienes. Adv Prostaglandin Tromboxane Leukot Res 17, 540-3, 1987.
51. Taniguchi Y, Tamura G, Honna M, et al: The effect of an oral leukotriene antagonist, ONO-1708, on allergen-induced immediate bronchoconstriction in asthmatic subjects. J Allergy Clin Immunol 92, 507-12, 1993.
52. Yamamoto H, Nagata M, Kuramitsu K, et al: Inhibition of analgesic-induced asthma by leukotriene receptor antagonist ONO-1078. Am J Respir Crit Care Med 150, 254-7, 1994. La bibliografia continua nel PDF.