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The leukotriene receptor antagonists (LTRAs) constitute the first completely new class of drugs for use in asthma for 25 years. Their development was based on the recognition that cysteinyl leukotrienes exhibit biological activities that mimic some of the clinical features of asthma and are detectable in increased amounts in asthmatic patients, particularly during exacerbations of asthma. Potent and specific LTRAs have been developed and marketed for use in the treatment of asthma in the UK. Their use by clinicians in the UK is usually as “add-on” therapy in chronic asthma at steps 3, 4, or 5 of the BTS asthma guidelines.
In this issue of Thorax Dockhornet al compare the effect of intravenous and oral administration of the LTRA montelukast on airway function.1 Their results confirm those of previous studies that have shown improved pulmonary function after administration of an LTRA in asthmatic patients, and they also found that intravenous montelukast had a rapid onset of action and a duration of action of about 24 hours in 51 patients with mild to moderate asthma.
Early studies with the LTRAs showed that administration of a single dose (orally or intravenously) was predictably associated with an improvement in lung function.2 ,3 This suggested that, in patients with asthma, leukotrienes were contributing to the increase in airway smooth muscle tone. This is in contrast to that of normal subjects in whom the LTRAs do not lead to any alteration in lung function. In the study by Hui et al the improvement in forced expiratory volume in one second (FEV1) was apparent even in those patients treated with inhaled corticosteroids.2 Studies of corticosteroid inhibition of stimulated leucocytes in vitro have shown variable effects on leukotriene production.4-6 In vivo, however, steroid treatment of asthmatics suggests that corticosteroids, both oral and inhaled, have little effect on the basal and stimulated generation of leukotrienes.7 ,8 Pretreatment of asthmatic patients with inhaled fluticasone was also unable to inhibit generation of leukotrienes in response to allergen challenge. This suggests that antagonism of the effects of the leukotrienes might provide additional benefit by suppressing that part of the asthmatic response not sensitive to inhaled and/or oral corticosteroids.
While treatment with inhaled and oral corticosteroids results in improvement in lung function, studies with montelukast and zafirlukast have shown that, even in the presence of moderate and high dose inhaled steroids, further improvements in lung function are possible.9 ,10 In one study with zafirlukast 80 mg twice daily, patients already on high dose inhaled steroids continued to show an improvement in lung function for more than six weeks.9This gradual improvement may be secondary to an anti-inflammatory activity additional to that of inhaled steroids since the LTRAs also reduce peripheral blood, sputum, and airway eosinophilia.11 ,12 In a four way comparison between placebo, montelukast alone, 400 μg beclomethasone alone, or montelukast plus beclomethasone, the greatest improvement was seen with combination treatment.10 A steroid tapering study has also shown that it is possible to maintain asthma control while reducing inhaled steroids by adding montelukast to the treatment regimen.13
An unexpected finding of some of the early studies of the LTRAs was the additive improvement in lung function seen with the β2agonists and the LTRAs. The study by Hui et al showed that, while ICI 204,219 (zafirlukast) caused bronchodilatation, the addition of inhaled salbutamol caused a further improvement in lung function.2 Gaddyet al reported similar findings with MK-571 given intravenously.3 Again there was bronchodilatation with a further improvement with inhaled salbutamol and then nebulised salbutamol. While both β2 agonists and LTRAs improve lung function, they appear to do it by separate yet complementary mechanisms; however, the exact mechanism is not yet clear. It is possible that β2 agonists and the LTRAs act at anatomically distinct sites, with some of the actions of the LTRAs being due to their effects on airway oedema. Clinical studies suggest that the two treatments are complementary and therefore can be used together to improve function.
Increased levels of leukotrienes are detectable in peripheral blood, bronchoalveolar lavage (BAL) fluid, sputum, and urine of patients with asthma, even when stable.14-16 In BAL fluid and urine there is, however, a considerable overlap between asthmatic patients and normal subjects. Leukotriene levels rise further following allergen challenge, and following aspirin challenge in aspirin sensitive asthmatic subjects.17 ,18 Several studies in adults and children have reported increased levels of leukotrienes in acute asthma that fall as the attack resolves.16 While existing studies have focused on the use of the LTRAs in chronic asthma, the findings in the paper by Dockhorn et al raise the possibility that leukotriene inhibition may also be beneficial in acute asthma. Dockhorn et al demonstrated a rapid onset of bronchodilatation, particularly with the intravenous formulation, but even the oral formulation achieved a peak effect within two hours. With these results it is tempting to speculate, as the authors do, that montelukast should be considered for the treatment of acute asthma. It is worth noting that the patients studied by Dockhorn and colleagues had mild to moderate asthma, in whom conventional treatment usually works. It may be that in these patients treatment with an additional drug will not provide a significant benefit over and above the usual treatment, but in those with more severe asthma, where aerosolised drug distribution to the airways in the presence of severe airways obstruction may be poor, the availability of an intravenous (or oral) drug with significant bronchodilator effect would be advantageous. It would be interesting to see if these results are also applicable to acutely unwell severe asthmatic subjects. There are anecdotal reports of the use of LTRAs in patients who are ventilated with acute severe asthma.
Finally, the effect of montelukast on airway function relates to the dosages used. The authors used 7 mg intravenously, based on previous pharmacokinetic and pharmacodynamic data which suggested that the maximum benefit obtained was with 10 mg orally. Preliminary dose response studies with montelukast showed that there was little further bronchodilation above 10 mg daily, even when doses as high as 50 mg were used.19 The results of Dockhorn and colleagues show, however, that superior bronchodilatation is achieved with intravenous montelukast in a dose of 7 mg compared with an oral dose of 10 mg which suggests that the oral dose of 10 mg may not, in fact, be the dose associated with a maximal clinical response. At present it is only licensed for use in the UK as a 10 mg tablet in adults and a 5 mg chewable tablet in children over the age of six years.
It is hoped that the study by Dockhorn and colleagues will pave the way for more studies of the use of the LTRAs in the treatment of acute asthma and, in particular, to examine whether they prevent hospital admissions, reduce the length of hospital stay, and prevent intubation and ventilation for acute severe asthma. Any such studies should evaluate doses of 10 mg and higher.
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