Effects of Antileukotrienes in the Treatment of Asthma

N. C. BARNES

London Chest Hospital, London, United Kingdom

	INTRODUCTION

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Two approaches have been taken to developing antileukotriene drugs: the first is the development of synthesis inhibitors that are either direct inhibitors of the 5-lipoxygenase enzyme or antagonists of the essential cofactor 5-lipoxygenase-activating protein (FLAP) (1). The second approach has been to develop receptor antagonists. Many antagonists and synthesis inhibitors have been studied in humans. This review focuses on the drugs that have entered clinical practice and for which there are therefore the greatest number of clinical trials: the 5-lipoxygenase inhibitor zileuton (Zyflo) (2), licensed in the United States; the leukotriene receptor antagonist montelukast (Singular) (3), licensed worldwide; pranlukast (ONON) (4), licensed in Japan; and zafirlukast (Accolate) (5), licensed worldwide.

	ACUTE EFFECTS IN ASTHMA

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In many patients with asthma, even when they are taking effective antiasthmatic drugs, there is residual impaired lung function and a degree of tone in the asthmatic airway. Studies of bronchoalveolar lavage fluid had demonstrated increased levels of cysteinyl-leukotrienes in asthmatic airways compared with normal subjects (6). It was therefore hypothesized that some of the tone of the asthmatic airway was due to the presence of endogenous leukotrienes. In a study of 10 wheezy, bronchoconstricted patients with asthma, it was demonstrated that a single oral dose of zafirlukast (40 mg) caused a 6-7% improvement in FEV₁ (7). This improvement in FEV₁ came on rapidly, within 1 h of taking the medication; it was present in all subjects studied and, at the end of the study, when a large dose of nebulized salbutamol was given, the difference between the active and placebo days remained with an additive improvement in lung function.

These observations have been confirmed in other studies. In a study using MK-679 (8), which was administered intravenously, a bolus of the drug followed by an infusion over 6 h caused an approximately 12% improvement in FEV₁. This occurred immediately on giving the bolus injection and was sustained for the 6 h of the study. When the drug was followed by inhaled and then nebulized salbutamol, there was again an additive improvement in lung function. Reiss and coworkers (9) studied montelukast in a group of subjects with moderately severe asthma, half taking inhaled steroids. They again demonstrated a prompt improvement in lung function with an additive effect of inhaled ₂-agonists. The acute effect was seen both in patients taking and patients not taking inhaled steroids. Leukotriene receptor antagonists, when given to nonasthmatic subjects, caused no change in lung function, indicating that these drugs, unlike ₂-agonists, are not functional smooth muscle relaxants. The results indicate that in symptomatic asthma there is a continual generation of cysteinyl-leukotrienes within the airway and this has been further supported by studies with zileuton, which again demonstrated that when administered acutely, there is an improvement in pulmonary function within 1 h of ingestion (10). Furthermore, these studies indicate that there is leukotriene tone in the airways even in patients who are taking inhaled corticosteroids. The most surprising result of these studies is the finding of an additive improvement in lung function with ₂-agonists. The mechanism for this additive improvement in lung function is not known; it is unlikely to be due to bronchoconstriction, being resistant to the effect of ₂-agonists as after inhalation of leukotrienes, salbutamol causes rapid reversal of bronchoconstriction (11). Other possible mechanisms are that the improvement in lung function seen with the leukotriene receptor antagonists is not due to the effect on smooth muscle but is due to effects on edema, that leukotriene antagonists and ₂-agonists act at anatomically distinct sites within the airway, or that leukotriene antagonists sensitize the ₂ receptor. These studies, however, have clear clinical implications for the coadministration of leukotriene antagonists with both inhaled corticosteroids and short- and long-acting ₂-agonists.

	STUDIES OF ASTHMATIC PATIENTS NOT TAKING INHALED CORTICOSTEROIDS

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A number of studies of patients with symptomatic asthma and not taking inhaled corticosteroids have now been reported in full or in preliminary form. The results have, to some extent, depended on the severity of asthma. In a study of patients with a baseline FEV₁ of between 50 and 80% of predicted and 12% reversibility to ₂-agonists, montelukast (10 mg, administered in the evening) caused a 9% improvement in FEV₁ over placebo (12). This improvement in FEV₁ came on rapidly, within the first day of starting the treatment, and was maintained without evidence of tolerance for the 12 wk of the trial. On cessation of medication, there was no evidence of any rebound worsening of disease. Accompanying the improvements in lung function, there were decreases in symptoms and ₂-agonist use of approximately 30% and improved quality of life, particularly in the symptom domain. There were also reductions in asthma exacerbations, defined as preset changes in pulmonary function, and a decrease in asthma attacks, defined as requirement for oral steroids. Similar results have been demonstrated with zafirlukast, with 20 mg twice daily causing an 11% improvement in FEV₁ over placebo (13). A large trial of zileuton involved the study of patients with more severe asthma and with a lower baseline FEV₁ (10); this study showed improvements in FEV₁ of 11% over placebo at a dose of 600 mg four times a day, again with evidence of a decrease in asthma exacerbations, particularly in patients with more severe asthma.

The effect on asthma exacerbations has been confirmed in a metaanalysis of studies with zafirlukast (14). In trials at least 13 wk in duration, asthma exacerbations were collected as an adverse event and defined either as a requirement for oral corticosteroids, attendance for emergency nebulization or admission to hospital, or (in one study) institution of inhaled steroids. All studies showed a decrease in exacerbation rate among patients taking zafirlukast, with the overall result being a 50% reduction. The mechanism by which leukotriene antagonists decrease asthma exacerbations is not known but may reflect an effect on airway inflammation.

	STUDIES OF PATIENTS TAKING INHALED CORTICOSTEROIDS

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Various national (15) and international (16) guidelines advocate the use of inhaled corticosteroids in all patients except those with mild asthma. While inhaled corticosteroids are undoubtedly effective there remain patients who, despite treatment, have incompletely controlled asthma and require additional therapy and a number of studies have investigated the effect of leukotriene antagonists in patients taking low- and high-dose steroids. The administration of montelukast (10 mg/d) to patients taking low-dose inhaled steroids (BDP, 400 µg/d) and who were inadequately controlled caused a 5% improvement in FEV₁ with associated decreases in symptom scores on ₂-agonist use (17). There are preliminary reports of studies comparing the addition of zafirlukast to doubling the dose of inhaled steroids (18). Although there was no placebo group, there were improvements with both treatment strategies, but improvements in pulmonary function were numerically greater with the addition of zafirlukast than doubling the dose of inhaled corticosteroids. In all these studies the pattern of response seen is a prompt increase in pulmonary function on starting the leukotriene antagonist, which is maintained for the course of the study.

One of the most interesting results is a preliminary report about the addition of zafirlukast (80 mg twice daily) to patients taking high-dose inhaled corticosteroids (19). Patients randomized into the study were taking either BDP or budesonide and the mean dose was more than 1,600 µg/d; despite this they had impaired lung function, with an FEV₁ between 50 and 75% of predicted and reversibility to ₂-agonists. The results of the study show a gradual improvement in pulmonary function in the actively treated group amounting to an approximately 19 L/min-increase in peak flow at the end of 6 wk. Associated with this there were improvements in symptoms and a reduction in asthma exacerbations (20). The gradual increase in peak expiratory flow rate has not been demonstrated in other studies and it is possible that in more severe asthma this represents an effect on airway inflammation, whereas in more mild asthma the major effect of these drugs is to relieve bronchial smooth muscle tone.

An alternative approach has been to determine if, in patients taking inhaled steroids, a leukotriene receptor antagonist can decrease the requirement for inhaled corticosteroids. These studies are methodologically demanding as they show large decreases in inhaled corticosteroid use in the placebo group. Furthermore, there is concern that although patients may be able to achieve a short-term (2-wk) reduction in inhaled corticosteroid dose without worsening of their asthma, they may have an increased risk of asthma exacerbations over a longer period. Two studies with zafirlukast failed to show a greater effect on reduction of inhaled steroid dose than placebo (21, 22). In a carefully performed study with montelukast, patients were able to decrease the dose of inhaled steroids from a mean of about 1,600 to 1,000 µg before randomization into the study (23). On beginning the active treatment, there was a further reduction in inhaled corticosteroid dose. At the end of the study the mean dose of inhaled steroids in the actively treated group was approximately 500 µg compared with about 700 µg in the placebo-treated group; this small difference in reduction in inhaled steroid dose was significant. The ability of leukotriene antagonists to allow a reduction in inhaled steroids may be of relevance in patients receiving high-dose inhaled steroids, and if the result could be reproduced in children this would be an important observation, if it could allow inhaled steroids to be reduced below the threshold at which effects on growth are seen.

The reason that leukotriene antagonists work even in the presence of inhaled steroids is that at the doses of inhaled steroids used clinically, they cannot prevent the production of leukotrienes (24).

	STUDIES OF SEVERE ASTHMA

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Except for a small group of patients with aspirin-sensitive asthma, treated with montelukast (25) and oral corticosteroids, there have been no formal studies of the effect of leukotriene receptor antagonists in oral steroid-dependent asthma. However, it is interesting to note that a large percentage of the prescriptions for zafirlukast in the United States have been for patients taking oral corticosteroids and a similar pattern has been observed in the United Kingdom and Scandinavia on the introduction of montelukast and zafirlukast.

	STUDIES OF CHILDREN

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One study of montelukast (5 mg/d) in children with moderate and severe asthma has been reported (26). This showed beneficial effects, with the active treatment causing a 5% greater improvement in FEV₁ compared with placebo. There were also decreases in symptoms and ₂-agonist use. Approximately 30% of the children were taking inhaled corticosteroids and benefit was seen both in the children taking inhaled steroids and those not taking inhaled steroids. It is interesting to note that the magnitude of the improvement in children is not as great as that seen in adults. A similar pattern of response is seen with salmeterol, which tends to be relatively less effective in children than in adults. The reason for this difference between children and adults is not clear but may have implications for relatively different mechanisms in adults and children.

	ACTIVE COMPARATOR STUDIES

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A limited number of active comparator studies have been reported. Two studies compared zafirlukast with disodium cromoglycate and showed no difference between the two treatments (27, 28). However, in retrospect, it is clear that these studies involved patients with extremely mild asthma, with more than 25% having normal lung function, and thus there was little opportunity for improvement in asthma control. Both zafirlukast and montelukast have been compared with low-dose inhaled steroids (BDP, 400 µg/d) (29, 30). The results of these studies were similar. The study with montelukast (29) showed that BDP caused approximately double the improvement in pulmonary function, with greater effects on symptoms and ₂ agonist use. The exacerbation rate in the studies was low but the difference between BDP and montelukast was marginal, with both showing a clear advantage over placebo. There was considerable heterogeneity of response to both treatments, with good responders and poor responders in both groups. Similar results were obtained with zafirlukast (20 and 80 mg twice daily) compared with BDP (400 µg/d) (30). Again BDP was more effective; there was a similar heterogeneity in the response. It is not clear whether the poor responders to one class of treatments may be good responders to another class, or whether these are a more difficult group of patients to treat with either agent. There are preliminary reports comparing the effect of administering the long-acting bronchodilator salmeterol or zafirlukast (20 mg twice daily) to patients who are symptomatic despite inhaled corticosteroids (31). These patients have shown greater improvements in pulmonary function with salmeterol than zafirlukast.

	SAFETY AND TOLERABILITY

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Many of the early leukotriene receptor antagonists were withdrawn from development because of poor efficacy or side effects or a combination of the two. The main side effects that emerged with the early leukotriene receptor antagonists such as L-649,923 (32) and LY-171,883 (33) involved the gastrointestinal tract and liver. These have been carefully evaluated in clinical trials of the newer agents. Montelukast is reported to have a tolerability profile that is indistinguishable from placebo and no greater increase in transaminases in the active treatment groups compared with placebo (34). For zafirlukast at 20, 40, and 80 mg twice daily, the incidence of side effects is similar in the active and placebo treatment groups. For 20 mg twice daily, there is no greater incidence of liver function abnormalities than with placebo. The more limited data at twice daily doses of 40 mg show no difference from placebo. There does seem to be a low incidence of abnormal transaminases on 80 mg twice daily (35). Clinical experience with zafirlukast has shown no greater incidence of liver function abnormalities compared with other drugs such as ranitidine and amoxycillin, which are not considered to be hepatotoxic, and no difference from the background of liver function abnormalities. Zileuton has an approximately 2% incidence of liver function abnormalities and monitoring of liver function is recommended when prescribing (36). Montelukast appears to have no important drug interactions. Zafirlukast interacts with warfarin to lengthen the prothrombin time, so closer monitoring of anticoagulation is needed when prescribing this drug (37). There are also reports of interactions with theophylline. The major issue to have emerged since leukotriene antagonists entered clinical practice concerns reports of pulmonary eosinophilia and Churg-Strauss syndrome. Churg-Strauss syndrome is an eosinophilic vasculitis that occurs almost exclusively in patients with asthma. Reports, which first occurred with zafirlukast, but have now occurred with montelukast, show occurrences of this syndrome. The occurrences have been mainly but not exclusively in patients with steroid-dependent asthma. The most likely explanation seems to be the unmasking of preexisting disease, although it cannot be excluded that the leukotriene antagonists are actually the cause of the syndrome in these patients. Caution needs to be exercised in patients with oral steroid-dependent asthma who are prescribed leukotriene receptor antagonists with the object of decreasing the dose of oral steroids.

	POSITION OF LEUKOTRIENE RECEPTOR ANTAGONISTS IN ASTHMA GUIDELINES

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It is clear that leukotriene receptor antagonists are active antiasthma drugs, but their position in asthma guidelines is not fully established. This is due to a combination of factors including their introduction since the revision of some guidelines, a lack of active comparator studies, and in an era of increasingly evidence-based medicine, the lack of full publication of some of the key trials until recently. The National Heart, Lung, and Blood Institute (NHLBI) guidelines position antileukotriene drugs as an alternative to low-dose inhaled steroids at step II of the guidelines but indicate that inhaled corticosteroids are the preferred option. Although leukotriene antagonists are not mentioned in many European guidelines, practitioners seem to be using them as additional therapy in patients already taking inhaled and/or oral corticosteroids, and this is indeed the only way in which they are licensed to be used in a number of countries. In Western Europe pediatric use of montelukast has been low. In Japan, with its tradition of using oral antiallergic drugs, there has been quite widespread use of pranlukast. Ultimately the position of this class of drugs in NHLBI and European guidelines will depend on further clinical trials, increased understanding of their possible antiinflammatory mechanism, and studies of their long-term effectiveness, particularly when taking into account the possibility that compliance with an oral medication may be better.

	Footnotes

Correspondence and requests for reprints should be addressed to N. C. Barnes, M.D., London Chest Hospital, Bonner Road, London E2 9JX, UK.

	References

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