, Volume 59, Issue 4, pp 891–928


A Review of its Therapeutic Potential in Persistent Asthma
Adis Drug Evaluation



Montelukast is a cysteinyl leukotriene receptor antagonist used to treat persistent asthma in patients aged ≥6 years.

The drug has a rapid onset of action. Improvements in lung function and reductions in as-needed β2-agonist usage are apparent within 1 day of initiating montelukast treatment in adults and adolescents (aged ≥15 years treated with 10 mg/day) or children (aged 6 to 14 years treated with 5 mg/day) with persistent asthma as shown in clinical trials.

In two 12-week, multicentre, randomised, double-blind studies in adults and adolescents aged ≥15 years with persistent asthma [forced expiratory volume in 1 second (FEV1) = 50 to 85% predicted] there was significantly (p ≤ 0.05) greater improvement in FEV1, symptom scores, peak expiratory flow (PEF), as-needed β2-agonist use, peripheral eosinophil counts and health-related quality of life (QOL) in patients treated with montelukast 10 mg/day than in recipients of placebo. Improvements were significantly greater in patients treated with inhaled beclomethasone 400 μg/day than in recipients of montelukast 10 mg/day in 1 of these studies. Nonetheless, 42% of montelukast recipients experienced ≥11% improvement in FEV1, the median improvement in this parameter in beclomethasone-treated patients.

In an 8-week multicentre, randomised, double-blind, study in children aged 6 to 14 years with persistent asthma (FEV1 50 to 85% predicted), montelukast 5 mg/day produced significantly greater improvements in FEV1, clinic PEF, as-needed β2-agonist use, peripheral eosinophil counts, asthma exacerbations and QOL scores than placebo.

The combination of montelukast 10 mg/day plus inhaled beclomethasone 200μg twice daily provided significantly better asthma control than inhaled beclomethasone 200μg twice daily in adults with poorly controlled asthma (mean FEV1 = 72% predicted) despite 4 weeks treatment with inhaled beclomethasone. Patients receiving the combination experienced significant improvements in FEV1 and morning PEF, significant reductions in daytime symptom scores, as-needed β2 agonist usage and night-time awakenings with asthma, and had significantly lower peripheral blood eosinophil counts after 16 weeks in this multicentre, randomised, double-blind, placebo-controlled study.

Among adults (FEV1 ≥70%) treated with montelukast 10 mg/day for 12 weeks, inhaled corticosteroid dosages were titrated downward by 47% (vs 30% in placebo recipients), 40% of patients were tapered off of inhaled corticosteroids (vs 29%), and significantly fewer patients (16 vs 30%) experienced failed corticosteroid rescues in a multicentre, randomised, double-blind study.

During clinical studies, the frequency of adverse events in montelukast-treated adults, adolescents and children was similar to that in placebo recipients.

In conclusion, montelukast is well tolerated and effective in adults and children aged ≥6 years with persistent asthma including those with exercise-induced bronchoconstriction and/or aspirin sensitivity. Furthermore, montelukast has glucocorticoid sparing properties. Hence, montelukast, as monotherapy in patients with mild persistent asthma, or as an adjunct to inhaled corticosteroids is useful across a broad spectrum of patients with persistent asthma.

Pharmacodynamic Properties

Cysteinyl leukotrienes [leukotriene C4 (LTC4), D4 (LTD4) and E4 (LTE4)] are important pro-inflammatory mediators in asthma. Montelukast is a competitive antagonist of these substances at the cysteinyl leukotriene type 1 (cysLT1) receptor. The affinity of montelukast (50% inhibitory concentration = ≥2.3 nmol/L) for the cloned human cysLT1 receptor was 2.5 to 5-fold lower than that of LTD4 and was generally similar to that of other commercially available cysLT1 receptor antagonists.

Montelukast 5 mg/day for ≥2 weeks reduced nitric oxide levels in exhaled air, a marker of inflammation, by ≥20% in children with mild asthma.

Peripheral blood eosinophil levels were significantly reduced from baseline in adult and paediatric patients treated with clinically relevant dosages of montelukast for ≥4 weeks.

Over a broad dose range (5 to 250mg), and at both peak and trough plasma concentrations, montelukast inhibited acute LTD4-induced bronchoconstriction in patients with asthma. Moreover, the onset of the antagonist effect of montelukast was readily apparent after absorption of a single dose.

Significant improvements in FEV1 were noted within 15 minutes of administration of montelukast 7mg intravenously.

Single oral doses of montelukast 100 or 250mg produced significant improvements in forced expiratory volume in 1 second (FEV1) within 1 hour of drug administration in patients with asthma including those receiving ongoing inhaled corticosteroids. Importantly, these improvements did not preclude a bronchodilator response to inhaled salbutamol (albuterol).

After 2 doses, montelukast 10 mg/day provided a significant protective effect against both early (EAR) and late asthmatic responses (LAR) in patients with mild asthma (FEV1 = 79 to 109% predicted) after allergen challenge in a double-blind, placebo-controlled, crossover study.

Montelukast reduced the deterioration in lung function after a standard exercise challenge (6-minute treadmill test) in patients with persistent asthma and exercise-induced bronchoconstriction treated for 8 or 12 weeks in well-designed trials. There was no evidence of tolerance to the protective effects of montelukast 10 mg/day, which were apparent within 3 days, in patients with exercise-induced bronchoconstriction. However, in patients treated with inhaled salmeterol 42μg twice daily, tolerance became apparent after an initial favourable response.

The frequency of as-needed β2-agonist usage after exercise challenge was significantly lower among patients treated with montelukast than placebo or salmeterol.

In children aged 6 to 14 years with exercise-induced bronchoconstriction, montelukast 5 mg/day for 2 days had similar protective effects to those achieved to those achieved in adults with 10 mg/day.

Pharmacokinetic Properties

After oral administration, approximately 64% of a 10mg dose of montelukast is absorbed, and maximum plasma concentrations are achieved within 3 to 4 hours. Steady state plasma concentrations are achieved on the second day of administration in volunteers. Montelukast is eliminated primarily by biliary excretion and hepatic oxidative metabolism. Oxidative metabolism of montelukast was attributed to cytochrome P450 isozymes (CYP3A4 and CYP2C9).

The pharmacokinetics of oral montelukast 10mg were generally similar in elderly volunteers (aged ≥65 years) and younger adults (aged 20 to 45 years).

In children aged 6 to 14 years, a 5mg dose administered as a chewable tablet provided similar systemic exposure to that obtained in adults after a 10mg dose.

Montelukast appears to have a low potential for drug-drug interactions. No pharmacokinetic drug-drug interactions were evident in patients receiving clinically significant doses of montelukast (10 mg/day) and warfarin, digoxin, terfenadine, fexofenadine, combined oral contraceptives, theophylline, prednisone or prednisolone.

Phenobarbital appeared to increase the metabolism of montelukast; however, dosage adjustments are not warranted in patients receiving this combination.

Therapeutic Potential in Patients With Persistent Asthma

Montelukast has been evaluated in randomised, placebo-controlled studies in adults, adolescents and children with persistent asthma. The drug was administered in the evening in all clinical trials.

In multicentre randomised, double-blind, placebo-controlled trials of 8 or 12 weeks’ duration in adults (aged ≥15 years) or children (aged 5 to 14 years) montelukast had a rapid onset of action (i.e. within 1 day).

In Adults

Adult patients with persistent asthma (FEV1 = 50 to 85% predicted) received montelukast 10 mg/day or placebo (n = 681) in 1 study, and montelukast 10 mg/day, inhaled beclomethasone 400 μg/day or placebo in another trial (n = 895). After 12 weeks of treatment in both studies, significant improvements in all outcome variables (FEV1, daytime symptom scores, morning and evening peak expiratory flow rate (PEF), frequency of as-needed β2-agonist usage, frequency of nocturnal awakenings, health-related quality of life scores and peripheral eosinophil counts) were obtained in montelukast- or inhaled beclomethasone-treated patients, but not in recipients of placebo. Improvements with inhaled beclomethasone were significantly greater than with montelukast. Recipients of montelukast or inhaled beclomethasone experienced significantly more asthma control days and significantly fewer asthma exacerbation days than placebo recipients in these trials.

The combination of montelukast 10 mg/day plus inhaled beclomethasone 200μg twice daily provided significantly better asthma control than inhaled beclomethasone 200μg twice daily in patients with poorly controlled asthma (mean FEV1 = 72% predicted, n = 642) despite 4 weeks treatment with inhaled beclomethasone. Patients were randomised to 1 of 4 double-blind treatments (montelukast 10mg daily plus inhaled placebo, inhaled beclomethasone 200μgtwice daily plus oral placebo, montelukast plus beclomethasone, or oral and inhaled placebos) in the study. When compared with patients continuing on inhaled beclomethasone alone, patients receiving the combination experienced significant improvements in FEV1 and morning PEF, significant reductions in daytime symptom scores, as-needed β2 agonist usage and night-time awakenings with asthma, and had significantly lower peripheral blood eosinophil counts after 16 weeks. Asthma control generally deteriorated in patients assigned to placebo and the frequency of discontinuation from the study because of worsening asthma was 15, 11.4, 4 and 1%, respectively, among patients who received placebo, montelukast, inhaled beclomethasone or the 2 drugs combined. These findings indicate that montelukast is not suitable for monotherapy in patients with moderate or severe persistent asthma.

Montelukast 10 mg/day allowed for significant reductions in inhaled cortico-steroid dosages in patients with persistent asthma receiving ongoing treatment with inhaled corticosteroids. Between the start of treatment and the end of a randomised, double-blind, 12-week study, the mean daily dosage of inhaled corticosteroid was decreased by 47 and 30% in patients treated with montelukast or placebo, respectively. A higher proportion of montelukast (40%) than placebo recipients (29%) were successfully tapered off of inhaled corticosteroids and significantly fewer patients discontinued montelukast than placebo because of failed corticosteroid rescues (16 vs 30%).

Montelukast 10 mg/day plus loratadine 20 mg/day produced significantly greater improvements in FEV1, symptom scores and β2-agonist use than montelukast plus placebo in a 2-week, randomised, crossover study in patients with mild to severe persistent asthma.

Meta-analysis of data from 4 multicentre, placebo-controlled trials demonstrated that there was no apparent differences in the magnitude of improvement in clinical end-points between patients with or without a history of allergic rhinitis after treatment with montelukast 10 mg/day.

In aspirin-sensitive adults with persistent asthma, 4 weeks’ treatment with montelukast 10 mg/day produced significant improvements in most outcome measures (i.e. FEV1, morning PEF, β2-agonist usage and nocturnal, but not daytime symptom scores) compared with placebo.

In Children

In paediatric patients aged 6 to 14 years, montelukast 5 mg/day for 8 weeks produced significant improvements in FEV1, the primary outcome variable, in a multicentre, randomised, double-blind study. Significant improvement was also obtained in many (frequency of as-needed β2-agonist use, clinic PEF, Paediatric AQLQ scores and peripheral eosinophil counts) but not all secondary outcome variables (daytime symptom scores, morning and evening PEF in patient diaries, nocturnal awakenings). Montelukast significantly reduced the frequency of days with asthma exacerbations and the proportion of patients with asthma exacerbations compared with placebo.

Among children randomised to further treatment with montelukast or inhaled beclomethasone at the end of this study the mean change from baseline in FEV1 was similar (6.47 and 6.39%) after 1.4 years of follow-up.

Four weeks of treatment with montelukast 5 mg/day was compared with inhaled sodium cromoglycate 1.6 mg four times daily in 2 randomised, crossover studies in children aged 6 to 11 years with persistent asthma. Withdrawal rates were greater during treatment with sodium cromoglycate than montelukast. ≥86% of parents and ≥79% of patients expressed a preference for montelukast. In 1 of these studies, in which adherence with inhaled sodium cromoglycate was poor compared with montelukast (45 vs 82%, respectively), as-needed β2-agonist usage was significantly lower during treatment with montelukast.


During clinical trials in adults or children with persistent asthma the frequencyof adverse events in montelukast-treated patients was similar to that in placebo recipients. Headache was the most frequent adverse event, reported by 18.4 and 18.1% of adult recipients of montelukast and placebo, respectively.

In paediatric patients treated for 8 weeks, diarrhoea, laryngitis, pharyngitis, nausea, otitis, sinusitis and viral infections occurred in more than 2% of patients treated with montelukast and were more prevalent in recipients of montelukast 5 mg/day than placebo.

Churg-Strauss syndrome has been reported rarely in adult patients during treatment with montelukast; however, it is unlikely that there is a causal relationship between the drug and the emergence of this condition.

Dosage and Administration

Montelukast is indicated for the treatment of persistent asthma in patients aged ≥6 years. The recommended dosage of montelukast is 10 mg/day in adults and adolescents aged ≥15 years and 5 mg/day in children aged 6 to 14 years. The drug is administered in the evening with or without food. Dosage adjustments are not required in elderly patients or in those with renal or mild to moderate hepatic dysfunction.


  1. 1.
    Sheffer AL, Bartal M, Bousquet J, et al. Global initiative for asthma. Global strategy for asthma management and prevention [on line]. [Accessed 22 Mar, 2000] NHLBI/WHO workshop report. National Institutes of Health. National Heart, Lung and Blood Institute. 1995 Mar; Publication No. 95-3659. Available at http://www.ginasthma.com
  2. 2.
    National Asthma Education and Prevention Program. Expert Panel Report II: Guidelines for the diagnosis and management of asthma [on line]. [Accessed 2 Jul, 1999] Bethesda: National Institutes of Health, National Heart Lung and Blood Institute. 1997 Jul; Publication no. 97-4051. Available at: http://www.nhbli.nih.gov.pdf
  3. 3.
    British Thoracic Society, National Asthma Campaign, Royal College of Physicians of London, et al. The British guidelines on asthma management 1995 review and position statement. Thorax 1997 Feb; 52 Suppl. 1: S1–21CrossRefGoogle Scholar
  4. 4.
    Malmstrom K, Meltzer E, Prenner B, et al. Effects of montelukast (a leukotriene receptor antagonist), loratadine, montelukast + loratadine and placebo in seasonal allergic rhinitis and conjunctivitis [abstract]. J Allergy Clin Immunol 1998 Jan; 101 (Pt 2): S97Google Scholar
  5. 5.
    Sheftell FD, Rapoport AM, Walker B, et al. Leukotriene (LK) antagonists in the prophylaxis of migraine: a potential role for a new class of agents [abstract]. Headache 1999 May; 39(5): 381Google Scholar
  6. 6.
    Markham A, Faulds D. Montelukast. Drugs 1998 Aug; 56: 251–6PubMedCrossRefGoogle Scholar
  7. 7.
    Drazen JM, Israel E, O’Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999 Jan 21; 340: 197–206PubMedCrossRefGoogle Scholar
  8. 8.
    Crooks SW, Stockley RA. Leukotriene B4. International Journal of Biochemistry and Cell Biology 1998; 30: 173–8PubMedCrossRefGoogle Scholar
  9. 9.
    Peters-Golden M, Brock TG. Intracellular compartmentalization of leukotriene biosynthesis. Am J Respir Crit Care Med 2000; 161 Suppl.: S36–40PubMedGoogle Scholar
  10. 10.
    Samuelsson B. The discovery of the leukotrienes. Am J Respir Crit Care Med 2000; 161 Suppl.: S2–6PubMedGoogle Scholar
  11. 11.
    Dahlén S-E. Pharmacological characterization of leukotriene receptors. Am J Respir Crit Care Med 2000; 161 Suppl.: S41–5PubMedGoogle Scholar
  12. 12.
    Busse W. The role and contribution of leukotrienes in asthma. Ann Allergy Asthma Immunol 1998 Jul; 81: 17–29PubMedCrossRefGoogle Scholar
  13. 13.
    Rodger IW. Leukotrienes, asthma, and the preclinical science of montelukast. Eur Resp Rev 1998 Sep; 8: 358–60Google Scholar
  14. 14.
    Howarth PH. ABC of allergies: pathogenic mechanisms: a rational basis for treatment. BMJ 1998 Mar 7; 316: 758–61PubMedCrossRefGoogle Scholar
  15. 15.
    O’Byrne PM, Israel E, Drazen JM. Antileukotrienes in the treatment of asthma. Ann Intern Med 1997 Sep 15; 127: 472–80PubMedGoogle Scholar
  16. 16.
    Rachelefsky G. Childhood asthma and allergic rhinitis: the role of leukotrienes. J Pediatr 1997; 131(3): 348–55PubMedCrossRefGoogle Scholar
  17. 17.
    Leff JA. Leukotriene modifiers as novel therapeutics in asthma. Clin Exp Allergy 1998 Nov; 28 Suppl. 5: 147–53PubMedCrossRefGoogle Scholar
  18. 18.
    Lazarus SC. Inflammation, inflammatory mediators, and mediator antagonists in asthma. J Clin Pharmacol 1998; 38: 577–82PubMedGoogle Scholar
  19. 19.
    Claesson H-E, Dahlén S-E. Asthma and leukotrienes: anti-leukotrienes as novel anti-asthmatic drugs. J Intern Med 1999; 245: 205–27PubMedCrossRefGoogle Scholar
  20. 20.
    Wenzel SE. Inflammation, leukotrienes and the pathogenesis of the late asthmatic response [editorial]. Clin Exp Allergy 1999; 29: 1–3PubMedCrossRefGoogle Scholar
  21. 21.
    Devillier P, Baccard N, Advenier C. Leukotrienes, leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma: an update. Part II: clinical studies with leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma. Pharmacol Res 1999; 40(1): 15–29Google Scholar
  22. 22.
    Devillier P, Baccard N, Advenier C. Leukotrienes, leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma: an update. Part I: synthesis, receptors and role of leukotrienes in asthma. Pharmacol Res 1999; 40(1): 3–13Google Scholar
  23. 23.
    Drazen JM. Leukotrienes as mediators of airway obstruction. Am J Respir Crit Care Med 1998; 158: S193–200PubMedGoogle Scholar
  24. 24.
    Holgate ST, Sampson AP. Antileukotriene therapy: future directions. Am J Respir Crit Care Med 2000; 161 Suppl.: S147–53PubMedGoogle Scholar
  25. 25.
    Leff AR. Role of leukotrienes in bronchial hyperresponsiveness and cellular responses in airways. Am J Respir Crit Care Med 2000; 161 Suppl.: S125–32PubMedGoogle Scholar
  26. 26.
    Calhoun WJ, Lavins BJ, Minkwitz MC, et al. Effect of zafirlukast (Accolate) on cellular mediators of inflammation. Am J Respir Crit Care Med 1998; 157: 1381–9PubMedGoogle Scholar
  27. 27.
    Pavord ID, Ward R, Woltmann G, et al. Induced sputum eicosanoid concentrations in asthma. Am J Respir Crit Care Med 1999; 160: 1905–9PubMedGoogle Scholar
  28. 28.
    Tagari P, Rasmussen JB, Delorme D, et al. Comparison of urinary leukotriene E4 and 16-carboxytetranordihydro leukotriene E4 excretion in allergic asthmatics after inhaled antigen. Eicosanoids 1990; 3: 75–80PubMedGoogle Scholar
  29. 29.
    Dworski R, Sheller JR. Urinary mediators and asthma [editorial]. Clin Exp Allergy 1998; 28: 1309–12PubMedCrossRefGoogle Scholar
  30. 30.
    O’Sullivan S, Roquet A, Dahlén B, et al. Urinary excretion of inflammatory mediators during allergen-induced early and late phase asthmatic reactions. Clin Exp Allergy 1998; 28: 1332–9PubMedCrossRefGoogle Scholar
  31. 31.
    Kumlin M. Measurements of leukotrienes in the urine: strategies and applications. Allergy 1997; 52: 124–35PubMedCrossRefGoogle Scholar
  32. 32.
    Dahlén SE, Kumlin M. Can asthma be studied in urine? [editorial]. Clin Exp Allergy 1998; 28: 129–33PubMedCrossRefGoogle Scholar
  33. 33.
    Drazen JM, Austen KF. Leukotrienes and airway responses. Am Rev Respir Dis 1987; 136: 985–98PubMedCrossRefGoogle Scholar
  34. 34.
    Barnes NC, Piper PJ, Costello JF. Comparative effects of inhaled leukotriene C4, leukotriene D4, and histamine in normal human subjects. Thorax 1984; 39: 500–4PubMedCrossRefGoogle Scholar
  35. 35.
    Ellis JL, Undem BJ. Role of cysteinyl-leukotrienes and histamine in mediating intrinsic tone in isolated human bronchi. Am J Respir Crit Care Med 1994; 149: 118–22PubMedGoogle Scholar
  36. 36.
    Watson N, Magnussen H, Rabe KF. Inherent tone of human bronchus: role of eicosanoids and the epithelium. Br J Pharmacol 1997; 121: 1099–104PubMedCrossRefGoogle Scholar
  37. 37.
    O’Byrne PM. Leukotriene bronchoconstriction induced by allergen and exercise. Am J Respir Crit Care Med 2000; 161 Suppl.: S68–72PubMedGoogle Scholar
  38. 38.
    Foster A, Chan CC. Peptide leukotriene involvement in pulmonary eosinophil migration upon antigen challenge in the actively sensitized guinea pig. Int Arch Allergy Appl Immunol 1991; 96(3): 279–84PubMedCrossRefGoogle Scholar
  39. 39.
    Underwood DC, Osborn RR, Newsholme SJ, et al. Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig. Am J Respir Crit Care Med 1996; 154: 850–7PubMedGoogle Scholar
  40. 40.
    Laitinen LA, Laitinen A, Haahtela T, et al. Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet 1993 Apr 17; 341: 989–90PubMedCrossRefGoogle Scholar
  41. 41.
    Diamant Z, Hiltermann JT, van Rensen EL, et al. The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma. Am J Respir Crit Care Med 1997; 155: 1247–53PubMedGoogle Scholar
  42. 42.
    Mulder A, Gauvreau GM, Watson RM, et al. Effect of inhaled leukotriene D4 on airway eosinophilia and airway hyperresponsiveness in asthmatic subjects. Am J Respir Crit Care Med 1999; 159: 1562–7PubMedGoogle Scholar
  43. 43.
    Hisada T, Salmon M, Nasuhara Y, et al. Cysteinyl-leukotrienes partly mediate eotaxin-induced bronchial hyperresponsiveness and eosinophilia in IL-5 transgenic mice. Am J Respir Crit Care Med 1999 Aug; 160(2): 571–5PubMedGoogle Scholar
  44. 44.
    Weersink EJM, Postma DS, Aalbers R, et al. Early and late asthmatic reaction after allergen challenge. Respir Med 1994; 88: 103–14PubMedCrossRefGoogle Scholar
  45. 45.
    Diamant Z, Grootendorst DC, Veselic-Charvat M, et al. The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma. Clin Exp Allergy 1999 Jan; 29(1): 42–51PubMedCrossRefGoogle Scholar
  46. 46.
    Roquet A, Dahlén 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 1997; 155: 1856–63PubMedGoogle Scholar
  47. 47.
    Hamilton A, Faiferman I, Stober P, et al. Pranlukast, a cysteinyl leukotriene receptor antagonist, attenuates allergen-induced early- and late-phase bronchoconstriction and airway hyperresponsiveness in asthmatic subjects. J Allergy Clin Immunol 1998; 102: 177–83PubMedCrossRefGoogle Scholar
  48. 48.
    Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin Immunol 1999 Jul; 104(1): 5–13PubMedCrossRefGoogle Scholar
  49. 49.
    Cowburn AS, Sladek K, Soja J, et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 1998; 101: 834–46PubMedCrossRefGoogle Scholar
  50. 50.
    Sanak M, Simon H-U, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 1997 Nov 29; 350: 1599–600PubMedCrossRefGoogle Scholar
  51. 51.
    Holgate ST. Genetic and environmental interaction in allergy and asthma. J Allergy Clin Immunol 1999 Dec; 104(6): 1139–46PubMedCrossRefGoogle Scholar
  52. 52.
    Szczeklik A, Sanak M. Genetic mechanisms in aspirin-induced asthma. Am J Respir Crit Care Med 2000; 161 Suppl.: S142–6PubMedGoogle Scholar
  53. 53.
    Yoshida S, Sakamoto H, Ishizaki Y, et al. Efficacy of leukotriene receptor antagonist in bronchial hyperresponsiveness and hypersensitivity to analgesic in aspirin-intolerant asthma. Clin Exp Allergy 2000; 30: 64–70PubMedCrossRefGoogle Scholar
  54. 54.
    Daffern PJ, Muilenburg D, Hugli TE, et al. Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses. J Allergy Clin Immunol 1999 Sep; 104 (3 Pt 1): 559–64PubMedCrossRefGoogle Scholar
  55. 55.
    Dahlén B. Treatment of aspirin-intolerant asthma with anti-leukotrienes. Am J Respir Crit Care Med 2000; 161 Suppl.: S137–41PubMedGoogle Scholar
  56. 56.
    Szczeklik A. Mechanism of aspirin-induced asthma. Allergy 1997 Jun; 52(6): 613–9PubMedCrossRefGoogle Scholar
  57. 57.
    Dahlén B, Margolskee DJ, Zetterstrom O, et al. Effect of the leukotriene receptor antagonist MK-069 on baseline pulmonary function in aspirin sensitive asthmatic subjects. Thorax 1993; 48: 1205–10PubMedCrossRefGoogle Scholar
  58. 58.
    Dahlén B, Nizankowska E, Szczeklik A, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 1998; 157: 1187–94PubMedGoogle Scholar
  59. 59.
    Lynch KR, O’Neill GP, Liu Q, et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 1999 Jun 24; 399: 789–93PubMedCrossRefGoogle Scholar
  60. 60.
    Chan CC, Ecclestone P, Nicholson DW, et al. Leukotriene D4-induced increases in cytosolic calcium in THP-1 cells: dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists. J Pharmacol Exp Ther 1994 Jun; 269(3): 891–6PubMedGoogle Scholar
  61. 61.
    Metters KM, Zamboni RJ. Photoaffinity labeling of the leukotriene D4 receptor in guinea pig lung. J Biol Chem 1993 Mar 25; 268(9): 6487–95PubMedGoogle Scholar
  62. 62.
    Hoshino M, Izumi T, Shimizu T. Leukotriene D4 activates mitogen-activated protein kinase through a protein kinase Cα-Raf-1-dependent pathway in human monocytic leukemia THP-1 cells. J Biol Chem 1998 Feb 27; 273(9): 4878–82PubMedCrossRefGoogle Scholar
  63. 63.
    Jones TR, Labelle M, Belley M, et al. Pharmacology of montelukast sodium (Singulair), a potent and selective leukotriene D4 receptor antagonist [published erratum appears in Can J Physiol Pharmacol 1995 Jun; 73(6): 747]. Can J Physiol Pharmacol 1995 Feb; 73: 191–201PubMedCrossRefGoogle Scholar
  64. 64.
    Labelle M, Belley M, Gareau Y, et al. Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enzyme induction. Bioorg Med Chem Lett 1995; 5(3): 283–8CrossRefGoogle Scholar
  65. 65.
    Guay D, Gauthier JY, Dufresne C, et al. A series of non-quinoline cysLT1 receptor antagonists: SAR study on pyridyl analogs of Singulair. Bioorg Med Chem Lett 1998; 8: 453–8PubMedCrossRefGoogle Scholar
  66. 66.
    Arakida Y, Suwa K, Ohga K, et al. In vitro pharmacologic profile of YM158, a new dual antagonist for LTD4 and TXA2 receptors. J Pharmacol Exp Ther 1998 Nov; 287: 633–9PubMedGoogle Scholar
  67. 67.
    Ihaku D, Cameron L, Suzuki M, et al. Montelukast, a leukotriene receptor antagonist, inhibits the late airway response to antigen, airway eosinophilia, and IL-5-expressing cells in Brown Norway rats. J Allergy Clin Immunol 1999 Dec; 104(6): 1147–54PubMedCrossRefGoogle Scholar
  68. 68.
    Therattil J, Wang YC, Than S, et al. In vitro effects of montelukast on levels of IL-5 mRNA and cysteinyl leukotrienes (CysLT) in allergen-stimulated peripheral blood mononu-clear cells (PBMC) from patients with asthma [abstract]. Ann Allergy Asthma Immunol 1999 Jan; 82: 80Google Scholar
  69. 69.
    Volovitz B, Tabachnik E, Nussinovitch M, et al. Montelukast, a leukotriene receptor antagonist, reduces the concentration of leukotrienes in the respiratory tract of children with persistent asthma. J Allergy Clin Immunol 1999 Dec; 104(6): 1162–7PubMedCrossRefGoogle Scholar
  70. 70.
    Bisgaard H, Loland L, Anhøj J. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med 1999; 160: 1227–31PubMedGoogle Scholar
  71. 71.
    Bratton DL, Lanz MJ, Miyazawa N, et al. Exhaled nitric oxide before and after montelukast sodium therapy in school-age children with chronic asthma: a preliminary study. Pediatr Pulmonol 1999 Dec; 28(6): 402–7PubMedCrossRefGoogle Scholar
  72. 72.
    Ramsay C, Li D, Wang T, et al. Bronchial biopsy specimen variability: requirement for large sample size and repeat measurements to improve reliability [abstract]. Am J Respir Crit Care Med 1999; 159(3): A655Google Scholar
  73. 73.
    Pizzichini E, Leff JA, Reiss TF, et al. Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J 1999; 14: 12–8PubMedCrossRefGoogle Scholar
  74. 74.
    Sue-Chu M, Sandsund M, Reinertsen R, et al. Montelukast does not have any ergogenic effects in non-asthmatic elite athletes [abstract]. Am J Respir Crit Care Med 1999 Mar; 159 (3 Pt 2): A640Google Scholar
  75. 75.
    Barnes PJ, Chung KF, Page CP. Inflammatory mediators of asthma: an update. Pharmacol Rev 1998; 50 (4 515-596)Google Scholar
  76. 76.
    Jatakanon A, Lim S, Kharitonov SA, et al. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 1998; 53: 91–5PubMedCrossRefGoogle Scholar
  77. 77.
    Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Arch Intern Med 1998 Jun 8; 158: 1213–20PubMedCrossRefGoogle Scholar
  78. 78.
    Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, controlled trial. Ann Intern Med 1999 Mar 16; 130: 487–95PubMedGoogle Scholar
  79. 79.
    Knorr B, Matz J, Bernstein JA, et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized double-blind trial. JAMA 1998 Apr 15; 279(15): 1181–6PubMedCrossRefGoogle Scholar
  80. 80.
    Laviolette M, Malmstrom K, Lu S, et al. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999; 160: 1862–8PubMedGoogle Scholar
  81. 81.
    Nakamura H, Weiss ST, Israel E, et al. Eotaxin and impaired lung function in asthma. Am J Respir Crit Care Med 1999; 160: 1952–6PubMedGoogle Scholar
  82. 82.
    Pizzichini E, Pizzichini MMM, Efthimiadis A, et al. Measuring airway inflammation in asthma: eosinophils and eosinophilic cationic protein in induced sputum compared with peripheral blood. J Allergy Clin Immunol 1997; 99: 539–44PubMedCrossRefGoogle Scholar
  83. 83.
    Horn BR, Robin ED, Theodore J, et al. Total eosinophil counts in the management of bronchial asthma. N Engl J Med 1975 May 29; 1975(22): 1152–5CrossRefGoogle Scholar
  84. 84.
    De Lepeleire I, Reiss TF, Rochette F, et al. Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the airways of patients with asthma. Clin Pharmacol Ther 1997 Jan; 61: 83–92PubMedCrossRefGoogle Scholar
  85. 85.
    Paterson MC, Wilson AM, Dempsey OJ, et al. The effect of combination therapy with salmeterol and montelukast in asthmatic patients receiving inhaled corticosteroids (abstracts-on-disk). Annual Congress European Respiratory Society, Madrid Spain, 9–13 Oct. 1999 Abstract P3490Google Scholar
  86. 86.
    Leff JA, Busse WW, Pearlman D, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction [see comments]. N Engl J Med 1998 Jul 16; 339: 147–52PubMedCrossRefGoogle Scholar
  87. 87.
    Reiss TF, Sorkness CA, Stricker W, et al. Effects of montelukast (MK-0476); a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled corticosteroids. Thorax 1997 Jan; 52: 45–8PubMedCrossRefGoogle Scholar
  88. 88.
    Dockhorn RJ, Baumgartner RA, Leff JA, et al. Comparison of the effects of intravenous and oral montelukast on airway function: a double blind, placebo controlled, three period, crossover study in asthmatic patients. Thorax 2000; 55: 260–5PubMedCrossRefGoogle Scholar
  89. 89.
    Kuitert LM, Barnes NC. Leukotriene receptor antagonists: useful in acute asthma? [editorial]. Thorax 2000; 55: 255–6PubMedCrossRefGoogle Scholar
  90. 90.
    Bronsky EA, Kemp JP, Zhang J, et al. Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval. Clin Pharmacol Ther 1997 Nov; 62: 556–61PubMedCrossRefGoogle Scholar
  91. 91.
    Reiss TF, Hill JB, Harman E, et al. Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 1997 Dec; 52: 1030–5PubMedCrossRefGoogle Scholar
  92. 92.
    Villaran C, O’Neill SJ, Helbling A, et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. J Allergy Clin Immunol 1999 Sep; 104 (3 Pt 1): 547–53PubMedCrossRefGoogle Scholar
  93. 93.
    Edelman JM, Turpin JA, Bronsky EA, et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction: a randomized, double-blind trial. Ann Intern Med 2000 Jan 18; 132(2): 97–104PubMedGoogle Scholar
  94. 94.
    Turpin JA, Edelman JM, DeLucca PT, et al. Chronic administration of montelukast (MK-476) is superior to inhaled salmeterol in the prevention of exercise-induced bronchoconstriction (EIB) [abstract]. Am J Respir Crit Care Med 1998 Mar; 157 (Pt 2 Suppl.): A456Google Scholar
  95. 95.
    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 1996 Mar; 153(3): 931–5PubMedGoogle Scholar
  96. 96.
    Dessanges J-F, Préfaut C, Taytard A, et al. The effect of zafirlukast on repetitive exercise-induced bronchoconstriction: the possible role of leukotrienes in exercise-induced refractoriness. J Allergy Clin Immunol 1999 Dec; 104(6): 1155–61PubMedCrossRefGoogle Scholar
  97. 97.
    Hansen-Flaschen J, Schotland H. New treatments for exercise-induced asthma. N Engl J Med 1998 Jul 16; 339: 192–3PubMedCrossRefGoogle Scholar
  98. 98.
    Ramage L, Lipworth BJ, Ingram CG, et al. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994; 88: 363–8PubMedCrossRefGoogle Scholar
  99. 99.
    Nelson JA, Strauss L, Skowronski M, et al. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med 1998; 339: 141–6PubMedCrossRefGoogle Scholar
  100. 100.
    Simons FER, Gerstner TV, Cheang MS. Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics 1997 May; 99(5): 655–9PubMedCrossRefGoogle Scholar
  101. 101.
    Reiss TF. Exercise-induced asthma [letter]. N Engl J Med 1998 Dec 10; 339: 1785Google Scholar
  102. 102.
    Kemp JP, Dockhorn RJ, Shapiro GG, et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6-to 14-year-old children with asthma. J Pediatr 1998 Sep; 133: 424–8PubMedCrossRefGoogle Scholar
  103. 103.
    Pearlman DS, Ostrom NK, Bronsky EA, et al. The leukotriene D4-receptor antagonist zafirlukast attenuates exercise-induced bronchoconstriction in children. J Pediatr 1999 Mar; 134(3): 273–9PubMedCrossRefGoogle Scholar
  104. 104.
    Merck and Co. Inc. Singulair (montelukast) prescribing information. Merck and Co. Inc. Rahway NJ USA. Feb 1998Google Scholar
  105. 105.
    Zhao JJ, Rogers JD, Holland SD, et al. Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers. Biopharm Drug Dispos 1997 Dec; 18: 769–77PubMedCrossRefGoogle Scholar
  106. 106.
    Balani SK, Xu X, Pratha V, et al. Metabolic profiles of montelukast sodium (Singulair), a potent cysteinyl leukotriene, receptor antagonist, in human plasma and bile. Drug Metab Dispos 1997 Nov; 25: 1282–7PubMedGoogle Scholar
  107. 107.
    Chiba M, Xu X, Nishime JA. Hepatic microsomal metabolism of montelukast, a potent leukotriene D4 receptor antagonist, in humans. Drug Metab Dispos 1997 Sep; 25: 1022–31PubMedGoogle Scholar
  108. 108.
    Liu L, Cheng H, Zhao JJ, et al. Determination of montelukast (MK-0476) and its S-enantiomer in human plasma by stereoselective high-performance liquid chromatography with column-switching. J Pharmaceutical and Biomedical Analysis 1997; 15: 631–8CrossRefGoogle Scholar
  109. 109.
    Knorr B, Larson P, Chervinsky P, et al. Selection of a montelukast dose in 6- to 14-year-olds by a comparison of pediatric and adult single-dose pharmacokinetic profiles [abstract]. Clin Pharmacol Ther 1998 Feb; 63: 191Google Scholar
  110. 110.
    Knorr B, Nguyen H, Villaran C, et al. Selection of a montelukast dose in 2- to 5-year-olds by a comparison of pediatric and adult single-dose population pharmacokinetic profiles [abstract]. Clin Pharmacol Ther 1998 Feb; 63: 191Google Scholar
  111. 111.
    Holland S, Shahane A, Rogers JD, et al. Metabolism of montelukast is increased by multiple doses of phenobarbital [abstract]. Clin Pharmacol Ther 1998 Feb; 63: 231Google Scholar
  112. 112.
    Malmstrom K, Schwartz J, Reiss TF, et al. Effect of montelukast on single-dose theophylline pharmacokinetics. Am J Ther 1998 May; 5: 189–95PubMedCrossRefGoogle Scholar
  113. 113.
    Van Hecken A, Depre M, Verbesselt R, et al. Effect of montelukast on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. J Clin Pharmacol 1999 May; 39(5): 495–500PubMedGoogle Scholar
  114. 114.
    Depre M, Van Hecken A, Verbesselt R, et al. Effect of multiple doses of montelukast, a CysLT1 receptor antagonist, on digoxin pharmacokinetics in healthy volunteers. J Clin Pharmacol 1999 Sep; 39(9): 941–4PubMedCrossRefGoogle Scholar
  115. 115.
    Holland S, Gertz B, DeSmet M, et al. Montelukast has no effect on terfenadine pharmacokinetics (PK) or QTc [abstract]. Clin Pharmacol Ther 1998 Feb; 63: 232Google Scholar
  116. 116.
    Schwartz J, Larson P, Ebel D, et al. Lack of impact of a leukotriene (LT) D4 receptor antagonist, montelukast (M), on ethinyl estradiol (EE) and norethindrone (NET) serum concentrations [abstract]. 98th Annual Meeting American Society for Clinical Pharmacology and Therapeutics, San Diego, CA, USA 1997 Mar 5: 162Google Scholar
  117. 117.
    Noonan MJ, Chervinsky P, Brandon M. Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma. Eur Respir J 1998 Jun; 11: 1232–9PubMedCrossRefGoogle Scholar
  118. 118.
    Altaian LC, Munk Z, Seltzer J, et al. A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. J Allergy Clin Immunol 1998 Jul; 102: 50–6CrossRefGoogle Scholar
  119. 119.
    Lu S, Reiss TF. The dose selection of montelukast sodium (MK-0476). Eur Resp Rev 1998 Sep; 8: 361–5Google Scholar
  120. 120.
    Skalky CS, Edelman JM, Polis A, et al. Montelukast sodium (MK) compared to inhaled beclomethasone dipropionate (BD) in adult asthmatics: a randomized clinical trial [abstract]. J Allergy Clin Immunol 1999 Jan; 103 (Pt 2): 228Google Scholar
  121. 121.
    Löfdahl C-G, Reiss TF, Leff JA, et al. Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 1999 July 10; 319: 87–90PubMedCrossRefGoogle Scholar
  122. 122.
    Baumgartner RA, Polis A, Angner R, et al. Comparison between montelukast and inhaled beclomethasone therapy in chronic asthma: a double-blind, placebo-controlled, parallel study in asthmatic patients [abstract]. Am J Respir Crit Care Med 1999 Mar; 159 (3 Pt 2): A640Google Scholar
  123. 123.
    Dahlén SE, Malmstrom K, Kuna P, et al. Improvement of asthma in aspirin-intolerant patients by montelukast (MK-0476) a potent and specific CYSLT1 receptor antagonist: correlations with patient’s baseline characteristics [abstract]. Eur Respir J 1997 Sep; 10 Suppl. 25: 419SGoogle Scholar
  124. 124.
    Reicin AS, Weinstein SF, White R, et al. Montelukast (M) + loratadine(L) compared to M alone provides additional benefit in the treatment of chronic asthma [abstract]. Am J Respir Crit Care Med 1998 Mar; 157 (Pt 2 Suppl.): A416Google Scholar
  125. 125.
    Edelman JM, Milewski KA, Turpin JA, et al. Effectiveness and safety of montelukast, a leukotriene receptor antagonist, compared to inhaled cromolyn in moderate asthmatic children ages 6 to 11 [abstract no. 510]. J Allergy Clin Immunol 1999 Jan; 103 (1 Pt 2): 134Google Scholar
  126. 126.
    Volovitz B, Duenas-Meza E, Chmielewska-Szewczyk D, et al. Montelukast versus cromolyn for treatment of 6–11 year old children with asthma [abstract]. Am J Respir Crit Care Med 1999 Mar; 159 (3 Pt 2): A140Google Scholar
  127. 127.
    Malmstrom K, Meltzer EO, Prenner BP, et al. Concomitant montelukast and loratadine provide rapid significant improvement in seasonal allergic rhinitis compared with loratadine alone [abstract]. Eur Respir J 1998 Sep; 12 Suppl. 28: 274SGoogle Scholar
  128. 128.
    Santanello NC, Barber BL, Reiss TF, et al. Measurement characteristics of two asthma symptom diary scales for use in clinical trials. Eur Respir J 1997; 10: 646–51PubMedGoogle Scholar
  129. 129.
    Santanello NC, Davies G, Galant SP, et al. Validation of an asthma symptom diary for interventional studies. Arch Dis Child 1999 May; 80: 414–20PubMedCrossRefGoogle Scholar
  130. 130.
    Sculpher MJ, Buxton MJ. The episode-free day as a composite measure of effectiveness: an illustrative economic evaluation of formoterol versus salbutamol in asthma therapy. Pharmacoeconomics 1993; 4(5): 345–52PubMedCrossRefGoogle Scholar
  131. 131.
    Juniper EF, Guyatt GH, Epstein RS, et al. Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax 1992; 47: 76–83PubMedCrossRefGoogle Scholar
  132. 132.
    Juniper EF, Guyatt GH, Ferrie PJ, et al. Measuring quality of life in asthma. Am Rev Respir Dis 1993; 147: 832–8PubMedGoogle Scholar
  133. 133.
    Juniper EF, Guyatt GH, Willan A, et al. Determining a minimal important change in a disease-specific quality of life questionnaire. J Clin Epidemiol 1994; 47(1): 81–7PubMedCrossRefGoogle Scholar
  134. 134.
    Juniper EF, Guyatt GH, Feeny DH, et al. Measuring quality of life in children with asthma. Qual Life Res 1996; 5: 35–46PubMedCrossRefGoogle Scholar
  135. 135.
    Santanello NC, Zhang J, Seidenberg B, et al. What are minimal important changes for asthma measures in a clinical trial? Eur Respir J 1999; 14: 23–7PubMedCrossRefGoogle Scholar
  136. 136.
    Reiss TF, Storms W, White R, et al. Montelukast (MK-0476), a CysLT1 receptor antagonist, improves the signs and symptoms of asthma over one year of treatment [abstract]. Allergy Asthma Proc 1998 Jul–Aug; 19: 205–6CrossRefGoogle Scholar
  137. 137.
    Noonan G, Reiss TF, Shingo S, et al. Montelukast (MK-0476) maintains long-term asthma control in adult and pediatric patients (aged ≥6 years) [abstract]. Am J Respir Crit Care Med 1999 Mar; 159 (3 Pt 2): A640Google Scholar
  138. 138.
    Lu S, Malmstrom K, Wei LX. Effect of montelukast on asthma end points in patients with and without a history of allergic rhinitis [abstract]. J Allergy Clin Immunol 1999 Jan; 103 (Pt 2): 135Google Scholar
  139. 139.
    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: 957–8PubMedCrossRefGoogle Scholar
  140. 140.
    Leukotriene antagonists: a new class of asthma treatment. Curr Probl Pharmacovig 1998 Aug; 24: 14Google Scholar
  141. 141.
    Reiss TF, Altaian LC, Chervinsky P, et al. Effects of montelukast (MK-0476), a new potent cysteinyl leukotriene (LTD4) receptor antagonist, in patients with chronic asthma. J Allergy Clin Immunol 1996 Sep; 98: 528–34PubMedCrossRefGoogle Scholar
  142. 142.
    D’Cruz DP, Barnes NC, Lockwood CM. Difficult asthma or Churg-Strauss syndrome? Steroids may be masking undiagnosed cases of Churg-Strauss syndrome. BMJ 1999 Feb 20; 318: 475–6PubMedCrossRefGoogle Scholar
  143. 143.
    Haranath SP, Freston C, Fucci M, et al. Montelukast associated Churg-Strauss syndrome [abstract]. Am J Respir Crit Care Med 1999; 159(3): A641Google Scholar
  144. 144.
    Wechsler ME, Finn D, Jordan M, et al. Montelukast and the Churg-Strauss syndrome [abstract]. Am J Respir Crit Care Med 1999; 159(3): A641Google Scholar
  145. 145.
    Franco J, Artés MJ. Pulmonary eosinophilia associated with montelukast. Thorax 1999; 54(6): 558–60PubMedCrossRefGoogle Scholar
  146. 146.
    Kinoshita M, Shiraishi T, Koga T, et al. Churg-Strauss syndrome after corticosteroid withdrawal in an asthmatic patient treated with pranlukast. J Allergy Clin Immunol 1999 Mar; 103 (3 Pt 1): 534–5PubMedCrossRefGoogle Scholar
  147. 147.
    Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA 1998 Feb 11; 279(6): 455–7PubMedCrossRefGoogle Scholar
  148. 148.
    Knoell DL, Lucas J, Allen JN. Churg-Strauss syndrome associated with zafirlukast. Chest 1998 Jul; 114(1): 332–4PubMedCrossRefGoogle Scholar
  149. 149.
    Green RL, Vayonis AG. Churg-Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment. Lancet 1999 Feb 27; 353(9154): 725–6PubMedCrossRefGoogle Scholar
  150. 150.
    Katz RS, Papernik M. Zafirlukast and Churg-Strauss syndrome [letter]. JAMA 1998 Jun 24; 279(24): 1949PubMedCrossRefGoogle Scholar
  151. 151.
    Rosenberg JL, Edlow D, Sneider R. Liver disease and vasculitis in a patient taking cromolyn. Arch Intern Med 1978 Jun; 138: 989–91PubMedCrossRefGoogle Scholar
  152. 152.
    Löbel H, Machtey I, Eldror MY. Pulmonary infiltrates with eosinophilia in an asthmatic patient treated with disodium cromoglycate [letter]. Lancet 1972 Nov 11; II: 1032CrossRefGoogle Scholar
  153. 153.
    Burgher LW, Kass I, Schenken JR. Pulmonary allergic granulomatosis: a possible drug reaction in a patient receiving cromolyn sodium. Chest 1974 Jul; 66(1): 84–6PubMedCrossRefGoogle Scholar
  154. 154.
    Slater EE. Cardiac tamponade and peripheral eosinophilia in a patient receiving cromolyn sodium. Chest 1978 Jun; 73(6): 878PubMedCrossRefGoogle Scholar
  155. 155.
    Churg A, Brallas M, Cronin SR, et al. Formes frustes of Churg-Strauss syndrome. Chest 1995; 108: 320–3PubMedCrossRefGoogle Scholar
  156. 156.
    Priori R, Tomassini M, Magrini L, et al. Churg-Strauss syndrome during pregnancy after steroid withdrawal. Lancet 1998 Nov 14; 352(9140): 1599–600PubMedCrossRefGoogle Scholar
  157. 157.
    Glaxo Wellcome Inc. Flovent (letter to health care professionals)[on line]. [Accessed 29 June, 1999] US Food and Drug Administration. Medwatch. The FDA Medical Products Reporting Program. 21 Jan 1999. Available at http://www.fda.gov/medwatch/safety/1999/floven.htm
  158. 158.
    Bili A, Condemi JJ, Bottone SM, et al. Seven cases of complete and incomplete forms of Churg-Strauss syndrome not related to leukotriene receptor antagonists. J Allergy Clin Immunol 1999 Nov; 104(5): 1060–5PubMedCrossRefGoogle Scholar
  159. 159.
    Martin RM, Wilton LV, Mann RD. Prevalence of Churg-Strauss syndrome, vasculitis, eosinophilia and associated conditions: retrospective analysis of 58 prescription-event monitoring cohort studies. Pharmacoepidemiol Drug Saf 1999; 8: 179–89PubMedCrossRefGoogle Scholar
  160. 160.
    Rosenwasser LJ. Leukotriene modifiers: new drugs, old and new reactions [Erratum appears in J Allergy Clin Immunol 1999 Aug; 104 (2 Pt 1)]. J Allergy Clin Immunol 1999; 103 (3 Pt 1): 374–5PubMedCrossRefGoogle Scholar
  161. 161.
    Frosi A, Foresi A, Bozzoni M, et al. Churg-Strauss syndrome and antiasthma therapy [letter]. Lancet 1999 Mar 27; 353(9158): 1102PubMedCrossRefGoogle Scholar
  162. 162.
    Stirling RG, Chung KF. Leukotriene antagonists and Churg-Strauss syndrome: the smoking gun. Thorax 1999; 54: 865–6PubMedCrossRefGoogle Scholar
  163. 163.
    Churg A, Churg J. Steroids and Churg-Strauss syndrome. Lancet 1998 Jul 4; 352(9121): 32–3PubMedCrossRefGoogle Scholar
  164. 164.
    Wechsler ME, Pauwels R, Drazen JM. Leukotriene modifiers and Churg-Strauss syndrome: adverse effect or response to corticosteroid withdrawal? Drug Saf 1999 Oct; 21(4): 241–51PubMedCrossRefGoogle Scholar
  165. 165.
    Wechsler M, Drazen JM. Churg-Strauss syndrome [letter]. Lancet 1999 Jun 5; 353(9168): 725–6CrossRefGoogle Scholar
  166. 166.
    Merck Pharmaceuticals. Summary of product characteristics. Merck Pharmaceuticals, West Drayton, Middlesex UK, 15 Jan 1998Google Scholar
  167. 167.
    British Medical Association, Royal Pharmaceutical Society of Great Britain. British National Formulary No. 38. London: The Pharmaceutical Press, 1999 Sep: 125–145Google Scholar
  168. 168.
    Meijer RJ, Kerstjens HAM, Postma DS. Comparison of guidelines and self-management plans in asthma. Eur Respir J 1997; 10: 1163–72PubMedCrossRefGoogle Scholar
  169. 169.
    Bousquet J, Knani J, Henry C, et al. Undertreatment in a non-selected population of adult patients with asthma. J Allergy Clin Immunol 1996 Sep; 98: 514–21PubMedCrossRefGoogle Scholar
  170. 170.
    Gaist D, Hallas J, Hansen N-CG, et al. Are young adults with asthma treated sufficiently with inhaled steroids? A population-based study of prescription data from 1991 and 1994. Br J Clin Pharmacol 1996; 41: 285–9PubMedCrossRefGoogle Scholar
  171. 171.
    Kauer B, Anderson HR, Austin J, et al. Prevalence of asthma symptoms, diagnosis, and treatment in 12–14 year old children across Great Britain (international study of asthma and allergies in childhood, ISAAC UK). BMJ 1998 Jan 10; 316: 118–24CrossRefGoogle Scholar
  172. 172.
    Ferrante E, Muzzolon R, Fuso L, et al. Bronchial asthma: still an inadequately assessed and improperly treated disease. J Asthma 1994; 31(2): 117–21PubMedCrossRefGoogle Scholar
  173. 173.
    Van Ganse E, Hubloue I, Vincken W, et al. Actual use of inhaled corticosteroids and risk of hospitalisation: a case control study. Eur J Clin Pharmacol 1997; 51: 449–54PubMedCrossRefGoogle Scholar
  174. 174.
    Griffiths C, Naish J, Sturdy P, et al. Prescribing and hospital admissions for asthma in east London. BMJ 1996 Feb 24; 312: 481–2PubMedCrossRefGoogle Scholar
  175. 175.
    Doerschug KC, Peterson MW, Dayton CS, et al. Asthma guidelines: an assessment of physician understanding and practice. Am J Respir Crit Care Med 1999; 159: 1735–41PubMedGoogle Scholar
  176. 176.
    Enright PL, McClelland RL, Newman AB, et al. Underdiagnosis and undertreatment of asthma in the elderly. Chest 1999 Sep; 116(3): 603–13PubMedCrossRefGoogle Scholar
  177. 177.
    Lagerløv P, Veninga CCM, Muskova M, et al. Asthma knowledge in five European countries: doctors’ knowledge, attitudes and prescribing behaviour. Eur Respir J 2000; 15: 25–9PubMedGoogle Scholar
  178. 178.
    Jatulis DE, Meng Y-Y, Elashoff RM, et al. Preventive pharmacologic therapy among asthmatics: five years after publication of guidelines. Ann Allergy Asthma Immunol 1998 Jul; 81: 82–8PubMedCrossRefGoogle Scholar
  179. 179.
    Legorreta AP, Christian-Herman J, O’Connor RD, et al. Compliance with national asthma management guidelines and specialty care: a health maintenance organization experience. Arch Intern Med 1998 Mar 9; 158: 457–64PubMedCrossRefGoogle Scholar
  180. 180.
    Mawhinney H, Spector SL, Kinsman RA, et al. Compliance in clinical trials of two nonbronchodilator, antiasthma medications. Ann Allergy 1991 Apr; 66: 294–9PubMedGoogle Scholar
  181. 181.
    Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 1994 Jun 27; 154: 1349–53PubMedCrossRefGoogle Scholar
  182. 182.
    Lipworth BJ. The emerging role of leukotriene antagonists in asthma therapy. Chest 1999 Feb; 115: 313–6PubMedCrossRefGoogle Scholar
  183. 183.
    Lipworth BJ. Leukotriene-receptor antagonists. Lancet 1999 Jan 2; 353(9146): 57–62PubMedCrossRefGoogle Scholar
  184. 184.
    Lipworth BJ. Modern drug treatment of chronic asthma. BMJ 1999 Feb 6; 318: 380–4PubMedCrossRefGoogle Scholar
  185. 185.
    Kercsmar CM. Leukotriene receptor antagonist treatment of asthma: are we there yet? J Pediatr 1999 Mar; 134: 256–9PubMedCrossRefGoogle Scholar
  186. 186.
    Scardella AT. Asthma clinical practice guidelines: the evolving role of leukotriene modifiers. Dis Manage Clin Outcomes 1998 Sep–Oct; 1: 161–5CrossRefGoogle Scholar
  187. 187.
    Wenzel SE. Antileukotriene drugs in the management of asthma. JAMA 1998 Dec 23–30; 280: 2068–9PubMedCrossRefGoogle Scholar
  188. 188.
    Szefler SJ. Leukotriene modifiers: what is their position in asthma therapy? [editorial]. J Allergy Clin Immunol 1998 Aug; 102: 170–2PubMedCrossRefGoogle Scholar
  189. 189.
    Drazen JM, Israel E. Should antileukotriene therapies be used instead of inhaled corticosteroids in asthma? Yes [editorial]. Am J Respir Crit Care Med 1998 Dec; 158: 1697–8PubMedGoogle Scholar
  190. 190.
    Wenzel SE. Should antileukotriene therapies be used instead of inhaled corticosteroids in asthma? No [editorial]. Am J Respir Crit Care Med 1998 Dec; 158: 1699–701PubMedGoogle Scholar
  191. 191.
    Smith LJ. Newer asthma therapies [editorial]. Ann Intern Med 1999 Mar 16; 130(6): 531–2PubMedGoogle Scholar
  192. 192.
    Nathan RA, Minkwitz MC, Bonuccelli CM. Two first-line therapies in the treatment of mild asthma: use of peak flow variability as a predictor of effectiveness. Ann Allergy Asthma Immunol 1999 May; 82: 497–503PubMedCrossRefGoogle Scholar
  193. 193.
    Dworski R, Fitzgerald GA, Oates JA, et al. Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am J Respir Crit Care Med 1994; 149: 953–9PubMedGoogle Scholar
  194. 194.
    Manso G, Baker AJ, Taylor IK, et al. In vivo and in vitro effects of glucocorticoids on arachidonic acid metabolism and monocyte function in nonasthmatic humans. Eur Respir J 1992; 5: 712–6PubMedGoogle Scholar
  195. 195.
    O’Shaughnessy KM, Wellings R, Gillies B, et al. Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion. Am Rev Respir Dis 1993; 147: 1472–6PubMedGoogle Scholar
  196. 196.
    Riddick CA, Ring WL, Baker JR, et al. Dexamethasone increases expression of 5-lipoxygenase and its activating protein in human monocytes and THP-1 cells. Eur J Biochem 1997 May 15; 246(1): 112–8PubMedCrossRefGoogle Scholar
  197. 197.
    Tamaoki J, Kondo M, Sakai N, et al. Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. Am J Respir Crit Care Med 1997; 155: 1235–40PubMedGoogle Scholar
  198. 198.
    Nayak AS, Anderson P, Charous BL, et al. Equivalence of adding zafirlukast versus double-dose inhaled corticosteroids in asthmatic patients symptomatic on low-dose inhaled corticosteroids [abstract no. 965]. J Allergy Clin Immunol 1998 Jan; 101 (1 Pt 2): S223CrossRefGoogle Scholar
  199. 199.
    Bateman ED, Holgate ST, Binks SM, et al. A multicentre study to assess the steroid-sparing potential of accolate (zafirlukast; 20 mg bd) [abstract no. P-0709]. Allergy 1995; 50 Suppl. 26: 320Google Scholar
  200. 200.
    Laitinen LA, Zetterström O, Holgate ST, et al. Effects of ACCOLATE (zafirlukast; 20 mg bd) in permitting reduced therapy with inhaled steroids: a multicenter trial in patients with doses of inhaled steroid optimised between 800 and 2000 mcg per day [abstract no. p-0710]. Allergy 1995; 50 Suppl. 26: 320Google Scholar
  201. 201.
    Tattersfield AE, Harrison TW. Step 3 of the asthma guidelines [editorial]. Thorax 1999; 54: 753–4PubMedCrossRefGoogle Scholar
  202. 202.
    Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med 1997 Jul 3; 337(1): 8–14PubMedCrossRefGoogle Scholar
  203. 203.
    Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999 May 10; 159: 941–55PubMedCrossRefGoogle Scholar
  204. 204.
    Ledford D, Apter A, Brenner AM, et al. Osteoporosis in the corticosteroid-treated patient with asthma. J Allergy Clin Immunol 1998; 102: 353–62PubMedCrossRefGoogle Scholar
  205. 205.
    Garbe E, Suissa S, LeLorier J. Association of inhaled corticosteroid use with cataract extraction in elderly patients. JAMA 1998 Aug 12; 280(6): 539–43PubMedCrossRefGoogle Scholar
  206. 206.
    Garbe E, LeLorier J, Boivin J-F, et al. Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma. JAMA 1997 Mar 5; 9: 722–7CrossRefGoogle Scholar
  207. 207.
    Russell G. Inhaled corticosteroid therapy in children: an assessment of the potential for side effects. Thorax 1994; 49: 1185–8PubMedCrossRefGoogle Scholar
  208. 208.
    O’Byrne P. Are new asthma therapies needed? J Clin Pharmacol 1999; 39: 230–6PubMedGoogle Scholar
  209. 209.
    McCowan C, Neville RG, Thomas GE, et al. Effect of asthma and its treatment on growth: four year follow up of cohort of children from general practices in Tayside, Scotland. BMJ 1998 Feb 28; 316: 668–72PubMedCrossRefGoogle Scholar
  210. 210.
    Russell G. Childhood asthma and growth — a review of the literature. Respir Med 1994; 88 Suppl. A: 31–7PubMedCrossRefGoogle Scholar
  211. 211.
    Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994; 88: 373–81PubMedCrossRefGoogle Scholar
  212. 212.
    Brook CGD. Short stature never killed anybody [editorial]. J Pediatr 1998 Nov; 133: 591–2PubMedCrossRefGoogle Scholar
  213. 213.
    Heuck C, Wolthers OD, Kollerup G, et al. Adverse effects of inhaled budesonide (800 mcg) on growth and collagen turnover in children with asthma: a double-blind comparison of once-daily versus twice-daily administration. J Pediatr 1998 Nov; 133(5): 608–12PubMedCrossRefGoogle Scholar
  214. 214.
    Wagener JS, Wojtczak HA. Inhaled steroids in children: risks versus rewards [editorial]. J Pediatr 1998 Mar; 132 (3 Pt 1): 381–3PubMedCrossRefGoogle Scholar
  215. 215.
    Crowley S, Trivedi P, Risteli L, et al. Collagen metabolism and growth in prepubertal children with asthma treated with inhaled steroids. J Pediatr 1998 Mar; 132 (3 Pt 1): 409–15PubMedCrossRefGoogle Scholar
  216. 216.
    Doull IJM, Campbell MJ, Holgate ST. Duration of growth suppressive effects of regular inhaled corticosteroids. Arch Dis Child 1998 Feb; 78: 172–3PubMedCrossRefGoogle Scholar
  217. 217.
    Harding SM. The dull-edged sword of inhaled corticosteroids. Chest 1999 Oct; 116: 854–6PubMedCrossRefGoogle Scholar
  218. 218.
    Evans DJ, Taylor DA, Zetterstrom O, et al. A comparison of low-dose inhaled budesonide plus theophylline and high dose inhaled budesonide for moderate asthma. N Engl J Med 1997 Nov 13; 337(20): 1412–8PubMedCrossRefGoogle Scholar
  219. 219.
    Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996 May 23; 334(21): 1380–8PubMedCrossRefGoogle Scholar
  220. 220.
    Markham A, Faulds D. Theophylline: a review of its potential steroid sparing effects in asthma. Drugs 1998 Dec; 56: 1081–91PubMedCrossRefGoogle Scholar
  221. 221.
    Shannon M. Life-threatening events after theophylline overdose: a 10-year prospective analysis. Arch Intern Med 1999 May 10; 159: 989–94PubMedCrossRefGoogle Scholar
  222. 222.
    McFadden Jr ER, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994 May 12; 330(19): 1362–7PubMedCrossRefGoogle Scholar
  223. 223.
    Cabral ALB, Conceição GM, Fonseca-Guedes CHF, et al. Exercise-induced bronchospasm in children: effects of asthma severity. Am J Respir Crit Care Med 1999; 159: 1819–23PubMedGoogle Scholar
  224. 224.
    Menendez R, Venzor J, Ortiz G. Failure of zafirlukast to prevent ibuprofen-induced anaphylaxis. Ann Allergy Asthma Immunol 1998 Mar; 80: 225–2226PubMedCrossRefGoogle Scholar
  225. 225.
    Nathan RA, Bernstein JA, Bielory L, et al. Zafirlukast improves asthma symptoms and quality of life in patients with moderate reversisble airflow obstruction. J Allergy Clin Immunol 1998 Dec; 102 (6 Pt 1): 935–42PubMedCrossRefGoogle Scholar
  226. 226.
    Tashkin DP, Nathan RA, Howland WC, et al. An evaluation of zafirlukast in the treatment of asthma with exploratory subset analyses. J Allergy Clin Immunol 1999 Feb; 103 (2 Pt 1): 246–54PubMedCrossRefGoogle Scholar
  227. 227.
    Kemp JP, Minkwitz MC, Bonuccelli CM, et al. Therapeutic effect of zafirlukast as monotherapy in steroid-naive patients with severe persistent asthma. Chest 1999 Feb; 115: 336–42PubMedCrossRefGoogle Scholar
  228. 228.
    Fish JE, Kemp JP, Lockey RF, et al. Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. Clin Ther 1997 Jul–Aug; 19(4): 675–90PubMedCrossRefGoogle Scholar
  229. 229.
    Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J Allergy Clin Immunol 1996 Nov; 98 (5 Pt 1): 859–71PubMedCrossRefGoogle Scholar
  230. 230.
    Israel E, Cohn J, Dube L, et al. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial Zileuton Clinical Trial Group. JAMA 1996 Mar 27; 275(12): 931–6Google Scholar
  231. 231.
    Barnes NC, Pujet J-C. Pranlukast, a novel leukotriene receptor antagonist: results of the first European, placebo controlled, multicentre clinical study in asthma. Thorax 1997; 52: 523–7PubMedCrossRefGoogle Scholar
  232. 232.
    Grossman J, Faiferman I, Dubb JW, et al. Results of the first U.S. double-blind, placebo-controlled, multicenter clinical study in asthma with pranlukast, a novel leukotriene receptor antagonist. J Asthma 1997; 34(4): 321–8Google Scholar
  233. 233.
    Barnes NC. Effects of antileukotrienes in the treatment of asthma. Am J Respir Crit Care Med 2000; 161 Suppl.: S73–6PubMedGoogle Scholar
  234. 234.
    Schwartz HJ, Petty T, Dube LM, et al. A randomized controlled trial comparing zileuton with theophyllin in moderate asthma. The Zileuton Study Group. Arch Intern Med 1998 Jan 26; 1998 (2): 141–8Google Scholar
  235. 235.
    Busse W, Nelson H, Wolfe J, et al. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J Allergy Clin Immunol 1999 Jun; 103(6): 1075–80PubMedCrossRefGoogle Scholar
  236. 236.
    AstraZeneca. Accolate (zafirlukast) prescribing information. AstraZeneca, Wilmington, Delaware, USA, Mar, 1999Google Scholar
  237. 237.
    Abbott Laboratories. Zyflo (zileuton) prescribing information. Abbott Laboratories, North Chicago, Illinois, 60064 USA, Mar, 1998Google Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

Personalised recommendations