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Professor of Allergy and Respiratory Medicine, Department of Clinical Pharmacology and Therapeutics and Department of Respiratory Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.
The drug therapy of asthma has remained essentially unchanged over the past 3 decades, comprising use of glucocorticoids, ß2-agonists, and theophyllines. The antileukotrienes and particularly the leukotriene antagonists represent an important new class of drug therapy for asthma. At present, the use of the 5-lipoxygenase inhibitor zileuton is somewhat limited due to its four-times-daily dosing regimen and the need to monitor biochemical liver function tests. The advantages of the available leukotriene antagonists are the use of once-daily (montelukast) or twice-daily (zafirlukast) dosing in terms of improved compliance, as well as there being no need to routinely monitor liver function. The leukotriene antagonists seem to be effective over a wide range of asthma disease severity, although their precise role in asthma management guidelines has yet to be established due to the relatively small published database on long-term clinical efficacy.
One of the fundamental questions regarding the leukotriene antagonists is whether they should be positioned in the guidelines for use as first-line preventive monotherapy as an alternative to inhaled glucocorticoids, or whether their use should be restricted to second-line controller therapy in addition to inhaled glucocorticoids. Interestingly, in the United States, both zafirlukast and montelukast have been approved for use as monotherapy, whereas in Europe, montelukast has been approved for use as add-on therapy in patients with persistent asthma whose disease is inadequately controlled with inhaled glucocorticoids.
The cysteinyl leukotrienes (leukotrienes C4, D4, and E4) are potent inflammatory mediators in the pathophysiology of asthma as well as producing bronchial smooth muscle constriction.1 It is therefore not surprising perhaps that the leukotriene antagonists exhibit effects that are attributable to both bronchodilator and anti-inflammatory activity. The glucocorticoids, by contrast, have more widespread effects on a variety of inflammatory and structural cells in the airway as well as their inhibitory effects on cytokines and transcription factors. There are also good data from biopsy studies to show that inhaled glucocorticoids have marked effects on asthmatic airway inflammation.2 This is backed up by long-term clinical studies showing sustained effects of inhaled glucocorticoids on markers of asthmatic disease control as well as established benefits of early intervention therapy.3 Until comparable data are available for the leukotriene antagonists, there seems to be little justification for their use as first-line preventive therapy instead of inhaled glucocorticoids, particularly as the leukotriene antagonists interfere only with one part of the inflammatory pathway.
There are perhaps compliance arguments in favor of using a once- or twice-daily tablet with montelukast as an alternative option to low-dose inhaled glucocorticoid for patients with mild persistent asthma, in keeping with the current US guidelines.4 The compliance factor with leukotriene antagonists may be reinforced by their peak onset of action within the first 24 h of treatment in contrast to the more gradual effects of inhaled glucocorticoids over several weeks. The potential problems with delivering inhaled glucocorticoids by metered-dose inhalers can easily be overcome by using a breath-actuated pressurized aerosol, a spacer attachment, or a dry powder inhaler device. Furthermore, the use of a once-daily dosing regimen with inhaled glucocorticoids is as effective as twice daily, at doses of up to 800 µg/d in patients with mild-to-moderate asthma.5 The choice between leukotriene antagonist and low-dose inhaled glucocorticoid will therefore depend on other factors such as patient preference, degree of long-term disease control, and cost. With respect to the latter, low-dose inhaled glucocorticoid (400 µg/d of beclomethasone dipropionate, triamcinoclone acetonide, or budesonide) is less expensive compared with a leukotriene antagonist.
Multicenter studies in adults and children have shown superiority of montelukast or zafirlukast over placebo when given to patients with mild-to-moderate asthma for a period of up to 13 weeks.6 ,7 ,8 ,9 In this issue of CHEST (see page 336), Kemp and coworkers report on a pooled subgroup analysis of data from four clinical trials in which zafirlukast 20 mg twice daily or placebo were given as monotherapy over a 13-week period to 261 patients identified as having severe persistent asthma. Their results showed significant improvements in all efficacy outcome measures as compared with placebo. The main problem with this study is that zafirlukast was evaluated in severe persistent asthmatics who prior to randomization were being treated inappropriately with ß2-agonists alone.4 Such patients would normally be taking an optimized dose of inhaled glucocorticoid before adding in a leukotriene antagonist. Indeed it is evident that despite their taking zafirlukast, the patients' asthma remained inadequately controlled and that the differences from placebo, although statistically significant, were of relatively small magnitude, as compared with what one would normally expect with optimized inhaled glucocorticoid as monotherapy in these types of asthmatics. This points to the importance of following the recommended management guidelines in terms of using inhaled glucocorticoid as first-line anti-inflammatory therapy in step 3 or step 4 in patients with moderate or severe persistent asthma.4
Another important issue is whether leukotriene antagonists confer additional benefits to low-dose inhaled glucocorticoid when used as adjunctive controller therapy. This hypothesis was tested in a multicenter study of 642 adult patients with mild-to-moderate chronic asthma who were randomized to receive treatment for 16 weeks with placebo, beclomethasone dipropionate 400 µg daily via a spacer, montelukast 10 mg once daily, or montelukast 10 mg once daily plus beclomethasone dipropionate 400 µg daily.10 There was also an initial 4-week run-in period when all of the patients received beclomethasone 400 µg daily, followed by tapered withdrawal of morning and evening doses of beclomethasone after 2 and 4 weeks of active treatment, in the groups receiving montelukast alone or placebo. Follow-up over the subsequent 12 weeks of the study showed that compared with placebo, there was significantly better control with montelukast alone, which in turn was less effective than beclomethasone alone, with the combination of montelukast plus beclomethasone being superior to beclomethasone alone. Similar findings have been reported with zafirlukast 40 mg twice daily in addition to 336 µg daily of beclomethasone dipropionate in comparison to monotherapy with 672 µg daily of beclomethasone dipropionate, in terms of an equivalent degree of improvement in asthma control over a 13-week follow-up period.11 The use of montelukast 10 mg once daily compared with placebo has also been shown to permit a significantly lower effective maintenance dose of inhaled glucocorticoid during tapered step-down over a 12-week period, as assessed in 226 adult patients with chronic asthma requiring moderate to high doses of inhaled glucocorticoid.12 In this respect, it is interesting to note that oral or inhaled glucocorticoid therapy is not effective in inhibiting increased synthesis of cysteinyl leukotrienes in response to allergen challenge.13 ,14 Moreover in vitro studies have demonstrated glucocorticoids to increase expression of 5-lipoxygenase activity.15 The additive effects of leukotriene antagonists on asthma control may at least in part be due to their anti-inflammatory activity, as shown by their effects on airway inflammatory cells, in terms of sputum eosinophil levels or BAL segmental antigen challenge.16 ,17
Long-acting inhaled ß2-agonists such as salmeterol and formoterol also have additive effects on asthma control on top of inhaled glucocorticoid therapy,18 although regular therapy is associated with ß2-adrenoceptor down-regulation and a tolerance of clinical efficacy.19 The development of tolerance with long-acting ß2-agonists is greater for bronchoprotector than bronchodilator activity, as has been demonstrated with their functional antagonism against methacholine or exercise-induced bronchconstriction.20 ,21 A randomized double-blind comparison of salmeterol 50 µg twice daily and montelukast 10 mg once daily was made in 191 adult asthmatics, with exercise challenge performed at trough (24 h for montelukast and 12 h for salmeterol) after the first dose and after 4 and 8 weeks of treatment.22 The results showed that montelukast produced a higher level of maintained protection when comparing the first and last dose effects (60% vs 57% inhibition of area under curve), whereas salmeterol showed a marked degree of tolerance at the same time points (41% vs 17%). As salmeterol is devoid of anti-inflammatory activity23 and may actually mask uncontrolled inflammation,24 it might seem more prudent to use a leukotriene antagonist instead as additive second-line controller therapy in view of its anti-inflammatory properties as well as its lack of tolerance. Another potential spinoff of leukotriene antagonists is that they are also effective in treating coexistent allergic rhinitis.25 Further longer-term follow-up studies are indicated to compare the effects of leukotriene antagonists and long-acting ß2-agonists as second-line therapy to look at long-term disease control and exacerbation rates, particularly in patients with moderate-to-severe persistent asthma.
The use of regular treatment with once- or twice-daily sustained-release theophylline may also confer improvements in asthma control in addition to inhaled glucocorticoid therapy,26 and like leukotriene antagonists, theophylline has been shown to possess anti-inflammatory properties.27 Theophyllines have a less predictable pharmacokinetic profile than leuko-triene antagonists and are less well tolerated with potential drug interactions, as well as requiring therapeutic drug monitoring. However, as theophyllines are less expensive than leukotriene antagonists, they may be considered as a reasonable option for second-line controller therapy, particularly when there are more rigorous pharmacoeconomic constraints, as for example with managed health-care provision or in the National Health Service. It is also worth pointing out that there is a degree of variability in the clinical efficacy response to leukotriene antagonists that may be related to regulation of cysteinyl leukotriene synthesis by genetic polymorphism of 5-lipoxygenase enzyme activity.28
The next 5 years of basic science and clinical research into leukotriene antagonists will hopefully help to define a clearer role for these agents in asthma management guidelines, in terms of use for first-line preventive monotherapy or second-line additive controller therapy. Clinicians and the pharmaceutical industry need to collaborate closely together so that appropriate research studies are performed to answer these important clinical questions.
Acknowledgements
The author wishes to acknowledge the secretarial assistance of Anne Muirhead in preparing this manuscript.
References
This article has been cited by other articles:
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  Are Leukotriene Antagonists Effective in Severe Asthma? Journal Watch (General), March 16, 1999; 1999(316): 5 - 5. [Full Text]
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