 Advertisement | ||||||||
 | ||||||||
|
||||||||
 |
 |
 |
 |
 |
 |
 |
||
Leukotrienes appear to be important biochemical mediators in asthma. They can cause bronchoconstriction, mucous hypersecretion and increased airway vascular permeability resulting in airway wall edema.9-11 Their action in human airway obstruction rests on the stimulation of specific receptors now termed cysteinyl leukotriene type 1 (CysLT1) receptors.12
The identification of the structure of the cysteinyl leukotrienes, C4, D4 and E4, and their potential importance in the pathogenesis of asthma has led to development of several classes of drugs collectively known as the antileukotrienes. Some inhibit the synthesis of leukotrienes by effector cells of asthma, and it is theoretically possible to stop their production by inhibition of any of the enzymes in their biosynthetic pathway. However, the only enzyme that has been selectively inhibited is 5-lipoxygenase (5-LO).13 (Zileuton, a 5-LO inhibitor, may not be marketed in Canada, because it must be administered 4 times daily and requires monitoring of liver enzymes.) It has also been possible to interrupt leukotriene formation by preventing the binding of arachidonic acid to the 5-LO activating protein.14 Some pharmaceutical molecules are being investigated to modify the function of this protein, but none is available for clinical use.
A number of chemically distinct, specific, selective antagonists have been identified and used in studies of human asthma.15-17 These compounds have been extremely important in establishing the central role of the cysteinyl leukotrienes in the pathogenesis of various manifestations of asthma, including exercise-induced bronchoconstriction,6,18 allergen-induced bronchoconstriction19-21 and aspirin-induced asthma.22,23 They have also been evaluated as possible therapy for chronic persisting asthma. Zafirlukast and montelukast are CysLT1-receptor antagonists currently available for clinical use in Canada (Table 1). Montelukast may be used in the treatment of children with asthma as young as 6 years of age; zafirlukast may be used at age 12 years and over. Another antagonist, pranlukast, is not yet available in North America.
|
Efficacy in chronic persistent asthma
Adults
Clinical trials of up to 26 weeks duration have tested 4 antileukotrienes in patients with chronic persistent asthma. In the earliest,24 LY171883, a less potent CysLT1-receptor antagonist was shown to increase FEV1) slightly but significantly (approximately 300 mL). Moreover, in patients who used inhaled ß2-agonists more frequently before randomized treatment began, this use decreased while their FEV1 increased. In 2 other trials of 4-6 weeks' duration, the effectiveness of treatment with the 5-LO inhibitor, zileuton,25 or the CysLT1-receptor antagonist, zafirlukast,26 was compared with placebo. Patients receiving higher doses of either antileukotriene had a significantly greater increase in FEV1 than did patients taking placebo; patients receiving lower doses of treatment had an intermediate increase in FEV1. Chronic treatment with either antileukotriene was also associated with significant decreases in the use of asthma medication and in asthma symptoms and an increase in morning peak expiratory flow. Two short-term studies27,28 comparing the CysLT1-antagonist montelukast with placebo over 1.5-12 weeks of treatment demonstrated a mean improvement of 14%-16% in FEV1. These results indicate that, in patients with chronic persistent asthma, the leukotrienes mediate a clinically significant component of airway obstruction.
These findings have been confirmed and extended in 13-week and 26-week studies in patients with chronic persistent asthma in which the efficacy of treatment with zileuton was compared with that of placebo.29,30 All patients were being treated only with inhaled ß2-agonists and had prebronchodilator FEV1 levels that were about 60% of the predicted normal. Zileuton treatment was associated with an approximate 15% improvement in FEV1, a decrease in asthma symptoms and reduced use of ß2-agonist. Also, in both trials over 2.5 times the number of patients receiving placebo treatment required glucocorticosteroid rescue treatment than did patients receiving high-dose zileuton treatment. There was no significant deterioration in the improvement in FEV1 during the course of either study, thus showing that patients do not become tolerant of the effects of 5-LO inhibition. Studies using compounds that block the effects of leukotrienes (both LTRAs and 5-LO inhibitors) have shown that asthma control is improved in adults and in children older than 12 years of age.
There is some evidence that antileukotrienes may be even more effective in patients with severe asthma. Their effect added to the bronchodilation achieved even with high doses of inhaled ß2-agonists31,32 suggests that they may have a place in the treatment of the severe bronchoconstriction associated with acute severe asthma, although this has not been evaluated in clinical studies. A clinical benefit of their addition has also been demonstrated in patients with poor asthma control, who are already taking high doses of inhaled glucocorticosteroids.33 In one study,34 the receptor antagonist pranlukast prevented asthma exacerbations in patients in whom the doses of inhaled glucocorticosteroids were reduced by half.
Two studies22,23 that specifically assessed the role of antileukotrienes in patients with aspirin-sensitive asthma showed that these drugs effectively blocked the ASA-induced asthmatic responses.
In adults with exercise-induced bronchoconstriction, the regular use of inhaled ß2-agonists will reduce the ability of inhaled ß2-agonists to protect against exercise-induced bronchoconstriction.35,36 Antileukotrienes were effective in this setting6,18 without tolerance developing.
Children
There is little information about the use of cysteinyl LTRAs in the treatment of children with asthma. Most studies have been in adult populations, although many have included adolescents as young as 12 years of age. Only one study of chronic use of an LTRA in younger children has been published.37 In it, the efficacy and safety of montelukast (in the form of a 5-mg chewable pill) were studied during an 8-week double-blind, placebo-controlled trial. The patients were 6-14 year old children with poorly controlled asthma (FEV1 of 72% predicted); 35% regularly used inhaled glucocorticosteroids. Compared with placebo, the montelukast group showed a greater and sustained improvement in FEV1 (8.2% versus 3.6%), a decrease in the use of ß2-agonist for symptom relief, and there was significant decrease in the percentage of days and patients with asthma exacerbations. An asthma-specific questionnaire38 revealed significant overall improvement in quality of life and significant improvement in terms of symptoms, activity and emotions. These effects were seen in younger as well as older children, and equally in those receiving concomitant inhaled glucocorticosteroids compared with those with no regular anti-asthma medication on entry to the study.
In a 6-month open follow-up study of 121 of these patients39 the effect of montelukast on FEV1 was consistent and the increase in FEV1 was not significantly different from that in a control group regularly treated with beclomethasone. Quality of life, as measured by the Asthma Specific Quality of Life Questionnaire, remained significantly improved throughout the 6-month open treatment and was also not significantly different from that of the beclomethasone control group.
A study of zafirlukast involving children over 12 years of age and adults40 showed a significant increase in days without symptoms, fewer days on which ß2-agonists were required and fewer episodes of asthma per month in the treatment group versus the control group. There were also fewer health care contacts and fewer days of absence from school in children or work in adults.
The role of LTRAs in the treatment of exercise-induced bronchoconstriction in children has been investigated in 2 studies.41,42 In patients 6-14 years of age, a crossover study demonstrated a significant decrease in exercise-induced bronchoconstriction 20-24 hours after taking a 5-mg chewable tablet of montelukast after 2 days of treatment.41 Twenty to 24 hours after the second dose, montelukast decreased the area under the curve for FEV1 following exercise bronchoprovocation by approximately 50% and significantly blunted the fall in peak FEV1 (an 18% fall versus 27% for the placebo group). In a study of the effect of zafirlukast on exercise-induced bronchoconstriction in children aged 6-14 years,24 the maximum fall in FEV1 from the baseline and the area under the curve for FEV1 were significantly reduced 4 h after a single dose of 5, 20 or 40 mg of zafirlukast compared with placebo, but not after a 10-mg dose of zafirlukast. In this study of 39 patients, 20 patients received 5 and 20 mg zafirlukast and 19 received 10 and 40 mg zafirlukast. The peak fall in FEV1 was 8%-10% for the zafirlukast groups compared with a 17% fall in the placebo group.
Safety
Because this entire class of drugs is new, patient exposure to these agents is limited. Nevertheless, a number of issues have emerged. In a safety study of over 3000 patients, about 4.5% receiving zileuton, but only 1.1% of those receiving placebo had reversible elevations in hepatic transaminases to more than 3 times the upper limit of the reference range. These elevations occur in the first 2-3 months after initiation of treatment; later, the incidence of increased hepatic transaminases falls to the levels observed in the control group.29
At the recommended doses of zafirlukast and montelukast, hepatotoxicity has not been identified as a problem. Both medications have a remarkable safety profile. Yet, a recent study identified a small group of patients with severe asthma who developed the clinical manifestations of eosinophilic vasculitis (Churg-Strauss syndrome) after being treated with zafirlukast (and more recently with montelukast) and stopping or reducing doses of oral glucocorticosteroids.43 The authors have suggested that the disease was unmasked after glucocorticosteroid withdrawal.
Conclusions
Antileukotrienes constitute an important novel therapy for asthma. Current data indicate that inhibition of leukotriene synthesis or action has a beneficial effect in the treatment of both induced and spontaneously occurring asthma. There does not appear to be any indication for the use of antileukotrienes in patients with very mild, intermittent asthma, in whom infrequent use of inhaled ß2-agonists is adequate to control symptoms. However, for some patients with moderate and severe persistent asthma, it is clear that antileukotrienes will have a place in asthma consensus guidelines. These patients do not usually achieve optimum control of their asthma with low doses of inhaled glucocorticosteroids. The number of studies on the role of LTRAs in controlling symptoms and lung function compared with doubling or further increasing the dose of inhaled glucocorticosteroids in patients with persistent symptoms despite glucocorticosteroid and short-acting ß2-agonist therapy are fewer than for long-acting ß2-agonists; however, we believe LTRAs could be considered in the former situation.
In patients with mild asthma but persisting symptoms, in whom disease control is not achieved with infrequent ß2-agonist use, the current consensus guidelines on the management of asthma suggest that inhaled glucocorticosteroids are the most effective treatment. It is likely that the antileukotrienes will be effective in some patients with mild persistent asthma, suggesting that, in some situations, they may be used earlier. However, low doses of inhaled glucocorticosteroids, which are free of systemic unwanted effects, are very effective in this patient population; thus, antileukotrienes cannot be recommended (unless patients cannot or will not use inhaled corticosteroids) until studies comparing them with low doses of inhaled glucocorticosteroids have reported on their potential to control asthma and antagonize airway inflammation. If an antileukotriene is chosen as the next line of treatment, a therapeutic trial of 2-4 weeks will allow a decision to be made about the efficacy of the treatment. If the treatment is ineffective, it should not be continued beyond this time.
Suggestions for future research
• What is the comparative efficacy of antileukotrienes compared with low doses of inhaled corticosteroids (500 µg/d or less of beclomethasone dipropionate or its equivalent)?
• Is there a role for antileukotrienes as a first-line controller treatment in asthma (issues of potential adherence and ease of administration compared with benefits of inhaled glucocorticosteroids should be assessed in prospective studies)?
• For patients with asthma that is poorly controlled with moderate doses of an inhaled glucocorticosteroid (< 1000 µg/d), is the optimum strategy the addition of a long-acting inhaled ß2-agonist, the addition of an antileukotriene or an increase in the dose of inhaled glucocorticosteroids?
• What is the long-term effect of the earlier use of antileukotrienes on the natural history of asthma?
• What is the most effective antileukotriene?
• What is the effect of LTRAs on parameters of airway inflammation?
• What is the long-term effect on lung growth in children with asthma treated with LTRAs compared with regular treatment with inhaled glucocorticosteroids?
Recommendations
• Leukotriene-receptor antagonists (LTRAs) may be considered as an alternative to increased doses of inhaled glucocorticosteroids. LTRAs may be used as adjunct therapy to moderate or higher doses of inhaled glucocorticosteroids to achieve control of persistent asthma symptoms (level II).
• There is insufficient evidence to recommend LTRAs as first-line anti-inflammatory therapy in place of inhaled glucocorticosteroids; however, for patients who cannot or will not use inhaled glucocorticosteroids, LTRAs should be the primary treatment choice (level IV).
References
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | HELP | SEARCH |
|
|||||
|
Copyright 1995-1999, Canadian Medical Association. All rights reserved. ISSN 1488-2329
(e) 0820-3946 (p)
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association. |
|||||
